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Immunity Crisis

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

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Adaptive immunity in vertebrates

An important outcome of virus infection in a vertebrate host is the development of a virus-specific immune response triggered by the virus antigens. Regions of antigens known as epitopes bind to specific receptors on lymphocytes, activating cascades of events that result in the immune response. Lymphocytes are the key cells in specific immune responses. There are two classes of lymphocyte B lymphocytes (B cells), which develop in the Bursa of Fabricius in birds and in the bone marrow in mammals, and T lymphocytes (T cells), which develop in the thymus. Each lymphocyte is specific for a particular in the immune system have receptors for the Fc region of IgG (Figure 9.3), allowing these cells to attach to antibody-coated virions and cells. Cell types that have IgG Fc receptors include Helper T cells secrete specific cytokines and are characterized by the presence of CD4 molecules at the cell surface. Helper T cells play essential roles in the initiation of immune responses, for example...

Components Of The Adaptive Immune System

The lymphoid system can be conceptually divided into a central and a peripheral system. The central system generates the lymphocytes from stem cells in the bone marrow and provides for further differentiation of B cells in the bone marrow and T cells in the thymus. The peripheral lymphoid system, on the other hand, is where the lymphocytes and accessory cells initiate adaptive immune responses. Peripheral lym-phoid organs include tonsils, peripheral lymph nodes, spleen, and the mucosal lymphoid systems. In most lymph nodes, as well as in the spleen, lymphocytes are concentrated in the white pulp. T cells are found in the central region and B cells are found in the germinal centers, which are toward the periphery of the organ or node.1-3 Cell Types of the Adaptive Immune Response Many different cell types (see Fig. 11-3) participate in the various types of immune responses. Conventional B-cell development (B-2, not B-1) occurs totally within the bone marrow. As stem cells reproduce...

Maturation Of Immune Responses And Antimicrobial Immunity

Immune responses, initiated as outlined earlier, are subject to regulation that for antimicrobial immunity selects elements of the immune system adapted to contain specific pathogens and also regulates immune responses to minimize damage to surrounding cells and tissues due to uncontrolled inflammatory reactions.1-3 Although it was speculated for some time that there might be a subset of regulatory T cells (TR), it was not until these cells could be identified by cell surface markers that definitive studies could be performed. In both mice and humans, the major population of TR is CD25+, CD4+. CD25 is the a-chain of the high affinity IL-2 receptor. TR have rearranged T cell receptors and are antigen specific many of them react with host antigens. Once activated, the TR secretes IL-10 and TGF-0 and suppresses the immune response nonspecifically. The importance of TR has been shown in mice and humans. Mice that are depleted of CD25+, CD4+ lymphocytes rapidly develop autoimmune disease...

Books immune responses to virus infections

Chen Y.-B., Fannjang Y. and Hardwick J. M. (2004) Cell death in viral infections, Chapter 17 in When Cells Die II, editors Lockshin R. A. and Zakeri Z., Wiley Whitton J. L. and Oldstone M. B. A. (2001) The immune response to viruses, Chapter 11 in Knipe D. M. and How-ley P. M., editors-in-chief, Fields Virology, 4th edition, Lippincott, Williams and Wilkins

Intravesical Immunotherapy and Recurrence Progression Rates

Intravesical immunotherapy using BCG was first proposed by Morales et al. 49 in 1976. Conventional prophylactic regimes of 6 weekly instillations, similar to those used for chemotherapy, resulted in complete response rates of 60 to 100 at 1 year, 55 to 75 after 2 years, and mean recurrence-free intervals of 10 to 22.5 months 50 . Although the long-term response rates with BCG are less enduring, the reduction in recurrence appears to be better than the rates achieved using most chemotherapy agents. This superiority is supported by comparative studies of BCG and anthracycline agents, which suggest that BCG has a roughly twofold advantage over Adriamycin and epirubicin (with an overall BCG tumor recurrence rate reduction of approximately 30 ) 51 . In contrast, trials comparing MMC directly with BCG have been less consistent in outcome, and passionately debated. Of the published comparative MMC-BCG studies, three have suggested that MMC may have therapeutic equivalence to BCG for patients...

Protective Immune Responses

The vast majority of infectious diseases are caused by pathogens that infect mucosal surfaces or use them as portals of entry. Mucosal immune responses are the first line of defense against these pathogens that are inhaled, ingested, or sexually transmitted. However, some agents may be able to breach these defenses, and go on to cause systemic disease. Therefore, vaccines against these agents may need to induce both mucosal and circulating immune responses for optimal protection (1-3). The systemic and mucosal immune systems communicate, but are somewhat compartmentalized (1-3). In general, induction of immune responses via systemic immunization supports systemic responses. Under appropriate conditions, mucosal introduction of foreign substances (antigens) can induce both mucosal and systemic responses. Following oral delivery, for example, antigens or invading pathogens, which can survive the harsh acid and degradative environments encountered, may be taken up by the specialized...

General features of the immune system

(pollen, animal hair, chemicals, etc.) and to unwanted cells or cell products arising within the body from cancer or autoimmune diseases. The immune system comprises (1) cellular defence mechanisms mediated by several types of leucocytes and (2) humoral defence mechanisms mediated by soluble proteins, so-called because they are dissolved in the body fluids rather than being primarily associated with cells. Any immune response involves, firstly, recognition of the pathogen or other foreign material and, secondly, elimination of these invaders. When an immune response occurs in an exaggerated or inappropriate form, the term 'hypersensitivity' is applied. The fundamental concept underlying the function of the immune system is the ability to distinguish, at the molecular level, 'self' from 'non-self' (foreign) materials. All cells of the immune system originate from just one cell type in the bone marrow of adult mammals, the haemopoietic stem cell. These pluripotent cells give rise to two...

Hematopoiesis and Immune Function

Several observations have contributed to the idea that prolactin may be an important regulator of hematopoiesis and immune function in mammals. First, both the prolactin receptor and ligand have been identified in cells of the hematopoietic system (52-56). Second, pharmacological studies in animals and clinical correlations in humans have shown that prolactin alters parameters of hematopoiesis and immune function (57-61). Third, certain cells cultured from hematopoietic lineages respond to prolactin in vitro (62). Fourth, the prolactin receptor and downstream signaling molecules are homolo gous with proteins that mediate the actions of a variety of hematopoietic cytokines (13). Despite these types of evidence, it has remained difficult to reconcile the idea that prolactin is an essential immunoregulatory hormone with the fundamental requirements of its role in reproduction. prolactin is secreted at much higher levels in females than in males, and at highly variable levels at different...

Adaptive Immune System

The adaptive immune system contains two major arms. The cellular arm leads to the production of CTLs, also called killer T cells. The humoral arm leads to the production of antibodies that are secreted by B cells. T-helper cells are important players in generating these responses. Immune System Players

Treg Suppression of Antitumor Adaptive Immunity

Efficient immune response requires activation of CD4+ T cells. Adoptive immunotherapy combining tumor-specific CD4+ and CD8+ lymphocytes is more efficient than the sole CTL transfer (Antony, 2005). CD4+ T lymphocytes were the first target of Treg suppression identified in vitro (Thornton and Shevach, 1998) and are also consistently inhibited in vivo. Casares et al. (2003) have shown in a murine tumor model that Treg depletion restores IFN-7 production by CD4+ T cells and results in both CD8-dependent and CD8-independent protection from tumor growth. The reactivity of CD4+ T lymphocytes in the presence of tumor is detectable only after proper immunostimulation. Otherwise, these lymphocytes are kept in a strict state of anergy by tumor-derived immunosuppressive signals and fail to produce cytokines upon ex vivo restimulation (Cuenca et al., 2003). A consistent portion of such unresponsive CD4+ lymphocytes is phenotypically and functionally regulatory cells and includes not only...

Vitamins And Immune Function

A number of reviews available in the literature detail the cellular and molecular mechanisms by which vitamin A may influence immune function (Semba, 1998, 1999 Stephensen, 2001) to complement these, there is a comprehensive review of the effects of ''vitamin A supplementation on immune responses as well (Villamor and Fawzi, 2005). Briefly, vitamin A is believed to be important at all levels of the immune system (Ross and Stephensen, 1996 Semba, 1998) its various functions include maintaining the integrity of the epithelia, increasing the levels of acute phase reactants in response to infection, regulating monocyte differentiation and function, improving the cytotoxicity of natural killer cells, enhancing the antibody responses to tetanus toxoid (Semba et al., 1992) and measles vaccines (Coutsoudis et al., 1992), and increasing the total lymphocyte count, especially the CD4 subset. Similarly, various other vitamins regulate cellular and humoral immune function at a variety of levels....

Virus dynamics and the immune system

A wide class of Lotka-Volterra type of systems arises in the study of host-parasite dynamics. A typical example is virus immune system competition but epidemiology is closely related too. We now explain how differential systems can be extended to structured population systems in the case of virus dynamics. The next section treats epidemiology. The intent is mainly to give examples where the structuring variable has a physiological meaning (these are referred to as physiologically structured), besides the traditional space structure already mentioned for invasion fronts in Sections 1.1 and 1.3. 1.4.1 Virus dynamics, immune response Describing the immune response of a single individual is a domain full of differential equations. A simple idea is that virusses represent the prey and leukocytes are the predators, then a model like the prey-predator system of Section 1.2.2 is satisfactory. However many other effects have to be added. In the case of the competition between a tumor and the...

Role of GPIs in cell signaling and host immune response

As stated, Toxoplasma free-GPIs elucidate strong and early immunogenic responses during host infection. Data from other protozoa suggest that other functions of GPIs in host immune response are possible. In Plasmodium falciparum, the GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin-1 production by macrophages, and regulates metabolism in adipocytes (Schofield and Hackett, 1993). Deacylation with specific phospholipases abolishes cytokine induction. When administered to mice in vivo the malaria parasite GPI induces cytokine release, a transient pyrexia and hypo-glycemia, and profound and lethal cachexia, in the presence of sensitizing agents. The data suggest that the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process. It has been further demonstrated that Plasmodium GPI directly and specifically increases cell adhesion molecule expression in HUVECs, and parasite cytoadherence (Schofield et...

Neuroendocrine modulation of immune responses

It has long been known that stressful conditions can suppress immune functions, reducing the ability of an individual to recover from infection. This can be explained by the fact that the neuroendocrine and immune systems are interconnected, forming an integrated system with common mediators and receptors. Cells of the immune system have receptors for many hormones, hormone-releasing factors and neurotransmitters - evidence that these molecules regulate immune responses. Moreover, immune cells themselves produce hormones and endorphins. The interplay between the neuroendocrine and immune systems is bi-directional, as exemplified by the control of Cortisol release from the adrenal glands during stress. Cortisol has well-known anti-inflammatory properties and it also suppresses the immune system. The signal for the release of cortisol originates in the brain. Electrical signals generated in the brain, and also IL-1 and IL-6 synthesized in brain cells, stimulate the hypothalamus to...


Another avenue of research in HRPC is immunotherapy, which is dependent on a suitable target antigen being presented to the immune system by an antigen-presenting cell (APC), such as the dendritic cell. The dendritic cell was chosen specifically because it is the most potent in eliciting a T-cell immune response. This approach has been evaluated in a randomized, placebo-controlled, phase III trial in HRPC patients with the drug APC8015. This is a product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein of prosta-tic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. This treatment was well tolerated and antigen-specific immunity was evident, but only in the subset of patients with a low Gleason score was there a trend toward improvement in median time to progression. A confirmatory phase III trial in these patients is now underway 53 . Vaccine-based therapies are also being evaluated. In one randomized phase II study,...

Immune Response

Following V cholerae O1 infection, robust serum vibrio-cidal antibody responses and rises in immunoglobulin G (IgG) cholera antitoxin are observed.60,61 Approximately 90 of complement-dependent vibriocidal antibodies are directed toward the O antigen with the remaining 10 to 15 of antibodies being against protein antigens. In immunologically primed individuals, strong SIgA intestinal antibody responses are recorded following cholera infection. However, significant rises in SIgA anti-LPS and antitoxin are surprisingly sparse in nonprimed individuals. The detection of gut-derived, trafficking IgA antibody-secreting cells that make specific antibody to LPS and CT antigens is a good measure of priming of the intestinal immune system.62

Innate Immune System

The innate immune system is composed of a large number of elements that attempt to control infection by pathogens, but this system is independent of the identity of the particular pathogen. Complement is a component of the innate system as well as the adaptive system and has been described. Other components of the innate system include the cytokines, a complicated set of small proteins that are powerful regulators of the immune system. Many cytokines are critical for the function of the adaptive immune system, as described in part above. Cytokines are also important components of the innate system. The innate system also

Immune System

The answer is c. (Murray, 5 e, p 93.) Most of the antibody produced in a primary immune response is IgM. As time passes or at a second encounter with the same antigen, isotype (class) switching can occur. 6. The answer is c. (Murray, 5 e, p 110-111.) Innate immunity involves antigen-nonspecific immune defense. Neutrophils circulate in the blood and can migrate into tissue to ingest and kill bacteria. Although T and B cells can augment the innate immune response, they become inactivated in an antigen-specific manner. Eosinophils, also part of the innate immune response, are important in parasitic, rather than bacterial, infections. 11. The answer is b. (Roitt, 5 e, p 168.) The fetus and newborn infant can only produce measurable IgM antibody in response to infection. If IgG is detected, it is the result of an immune response by the mother and the antibody has crossed the placenta. 12. The answer is d. (Murray, 5 e, p 88, 121.) Usually an immunogen contains more than one molecule that...

Microbial Interactions With Human Hosts

Just as microorganisms have evolved over centuries or longer, mammalian hosts have evolved to contain and limit the deleterious consequences of infections with diverse microbes. The human immune system is composed of multiple elements, including those of innate immunity and those of adaptive immunity. Many of the elements of innate immunity are more primitive and found in invertebrate organisms, whereas the adaptive immune responses have evolved further in vertebrate hosts. Microorganisms that successfully infect human hosts must, at least in the short term, overcome elements of the host immune system, which then may react further to attempt to control these infections.

The Nature of Viruses

It is useful to think of the proteins encoded in viral genomes as belonging to three major classes. First, most viruses encode enzymes required for replication of the genome and the production of mRNA from it. RNA viruses must encode an RNA polymerase or replicase, since cells do not normally replicate RNA. Most DNA viruses have access to the cellular DNA replication machinery in the nucleus, but even so, many encode new DNA polymerases for the replication of their genomes. Even if they use cellular DNA polymerases, many DNA viruses encode at least an initiation protein for genome replication. An overview of the replication strategies used by different viruses is presented below, and details of the replication machinery used by each virus are given in the chapters that describe individual viruses. Second, viruses must encode proteins that are used in the assembly of progeny viruses. For simpler viruses, these may consist of only one or a few structural proteins that assemble with the...

Immune Interactions Immune Evasion

The human immune system has evolved in concert with microbes and is very sophisticated, especially with regard to host defenses against microbes, but the system is not perfect. Interactions of the immune system with microbes are an ongoing affair. Microbes have a high mutation rate compared to human beings. Microbes have evolved a diversity of mechanisms that can enable microorganisms to subvert immediate immunologically mediated elimination. Persistence within the host is necessary for the propagation of some parasites. There are multiple mechanisms by which microbes can persist in the body and evade the immune system. Tolerance is defined as specific reduction in the response of the immune system to a given antigen.101,102 In the case of transplacental infection, the fetus develops a certain degree of tolerance to antigens to which it is exposed. The immune system of fetuses is rather incompletely developed in utero, and microorganisms survive easily. Cytomegalovirus infects the...

Robert Edelman 1 Introduction

Adjuvants have been used to augment the immune response to antigens for more than 70 years. Ramon first demonstrated that it was possible to increase levels of diphtheria or tetanus antitoxin by the addition of bread crumbs, agar, tapioca, starch oil, lecithin, or saponin to the vaccines (1). In this chapter, an overview is provided of modern vaccine adjuvants as background for more detailed discussions of promising adjuvants in chapters to follow. After a more general discussion of adjuvants including their definition, mechanisms of action, safety, ideal characteristics, impediments to development, and preclinical and clinical regulatory issues, examples will be provided of experimental vaccine adjuvants that have entered clinical trial to enhance a variety of licensed and experimental vaccines in humans. For additional expositions on this complex subject and for a historical perspective, the reader is referred to recent textbooks on vaccine adjuvants (2-4) and a selection of useful...

Adhesion and Migration of White Blood Cells

Immune mechanisms also appear to play a role in the process. Albeit in small numbers in human plaques, T lymphocytes (implicated in the cell-mediated immune response) are present in both young and advanced fibrous lesions. A suggested role for T lymphocytes during ath-erogenesis is help in mobilizing macrophages, which is similar to their role in immune responses 14, 26 .

Mechanisms of Adjuvant Action

To date, most subunit vaccines are poor antigens, whether or not they are natural products, recombinant products, or synthetic peptides. Subunit antigens fail for a variety of reasons, such as incorrect processing by the immune system, rapid clearance, stimulation of inappropriate immune response, and lack of critical B-cell or T-cell epitopes. Potentially, some of these failures can be overcome by administering subunit antigens with adjuvants. It should be remembered, however, that the best adjuvant will never correct the choice of the wrong (nonprotective) epitope. Traditional live vaccines or whole-cell inactivated microbial vaccines are generally better immunogens than subunit vaccines. Live and inactivated whole organisms are structurally more complex than subunit vaccines, and so contain many redundant epitopes that offer more opportunity to bypass genetic restriction of the vaccinee. Such vaccines also provide a larger antigen mass than subunit vaccines, particularly if they...

Specific Immune Mechanisms

Some mechanisms of adjuvant action are discussed below, and which are summarized in Table 2. Vaccine adjuvants can (1) increase the potency of small, antigenically weak synthetic or recombinant peptides. (2) They can enhance the speed, vigor, and persistence of the immune response to stronger antigens. For example, aluminum adjuvants used with licensed pediatric vaccines (e.g., DTP) elicit early and higher antibody response after primary immunization than do unadjuvanted preparations. (3) Adjuvants can increase the immune response to vaccines in immunologically immature, immunosup-pressed, or senescent individuals. (4) Adjuvants can select for, or modulate humeral or cell-mediated immunity, and they can do this in several ways. First, antigen processing can be modulated, leading to vaccines that can elicit both helper T cells and cytotoxic lymphocytes (CTL) (reviewed in 7,43 ). Second, depending upon the adjuvant, the immune response can be modulated in favor of MHC class I or MHC...

Mouse Models in Biomedical Research

The remaining four chapters provide some entry points into the four fields of research addressed here, i.e., immunology (Chapter 15), atherosclerosis (Chapter 16), cancer (Chapter 17), and neurobiology (Chapter 18). Chapter 15 provides a protocol for bone marrow transplantation. At present, the use of bone marrow transplantation is not only restricted to immunologists, who are able to substitute part of the immune system of live mice. Other applications make use of the replacement of macrophages (atherosclerosis) or the introduction of somatic stem cells. Bone marrow transfer has also been used to develop the first gene therapy protocols using retroviral modified bone marrow. The most essential protocol for atherosclerosis studies is the measurement of the lesion area in the proximal aorta, which is provided here in detail. Chapters 17 and 18 review concepts regarding the use of transgenic models in cancer and neurobiology, illustrating many of the approaches that were outlined in the...

And Mutant Mouse Strains

Two fragments containing 1.4kb of 5'-flanking and 0.5 kb of 3'-flank-ing region of the Ea gene into (H-2bxs) mice that do not express their endogenous Ea gene. The transgene was expressed in thymic tissue and in adherent spleen cells, and was induced in peritoneal exudate cells by y-interferon. However, in contrast to normal mice, there was no expression of Ea in B-lymphocytes of the transgenics. Since transgenic mice made with constructs containing 3.2 and 2 kb of 5'-flank-ing sequences show the normal expression pattern of the Ea gene, it appears that deletion of 5'-flanking sequences between -1.4 and -2 kb inactivated or eliminated regulatory sequences required for expression of Ea specifically in B-cells. The presence of this B-cell control region at -2 to -1.4 kb was also confirmed by van Ewijk et al. (11), who analyzed the Ea gene expression in a more detailed fashion by the creation of a set of transgenic mouse lines after introduction of Ea genes carrying deletions in its...

Immune Suppressive Mechanisms and Cancer Understanding the Implications Paradoxes and Burning Questions

Since Paul Ehrlich's 1909 prediction that the immune system is capable of suppressing the growth of tumors, a large volume of evidence produced by the work of many investigators has demonstrated the existence of a natural immune protection against cancer. As a tumor develops, it acquires novel epitopes as a result of mutations in self-proteins, frame shifts, or protein splicing identified in some tumor cells. Many tumors acquire an anaplastic or de-differentiated histologic phenotype, losing tissue differentiation antigens and acquiring expression of embryonic or cancer-testis antigens. In addition, changes in glycosylation or levels of expression may also change the antigenic repertoire of tumor cells. Finally, virally transformed cells may harbor strongly immunogenic viral antigens. As a whole, these changes in antigenicity of tumor cells may permit the adaptive immune system to recognize a tumor as foreign, despite the fact that tumors arise from normal self-tissues, against which...

Persistent versus Chronic Infection

Chronic infection is a property of a group of cells or of an organism in which lytic infection is established in many cells, but many potentially susceptible cells escape the infection at any particular time, for whatever reason. The infection is not cleared and the continual appearance of susceptible cells in the population leads to the continued presence of replicating virus. One well-known example of a chronic infection in humans is HIV, in which the infection cannot be cleared by the immune system and virus continues to replicate. AIDS results when the immune system is finally overwhelmed by the virus. Hepatitis B and hepatitis C viruses are also well known for their ability to establish chronic liver infections that can persist for life.

Transformation of Cells

The normal outcome of the infection of a cell by a virus is the death of the cell and the release of progeny virus. The major exceptions are the persistent infection of cells by retroviruses and the latent infection of cells by viruses such as herpesviruses, in which the cell survives with its properties little altered except for the new ability to produce virus. However, another possible outcome is the transformation of the cell, which involves not only the survival of the cell but an alteration in its growth properties caused by deregulation of the cell cycle. Transformed cells may be able to induce the formation of a tumor if they are produced within an animal or are injected into an animal after formation ex vivo. Transformation of a cell needs to be distinguished from tumorigenicity, the ability of the transformed cell to cause a tumor. Transformed cells may fail to cause a tumor because they are rejected by the host's immune system or because the transformed cells lack some...

Induction of Immunological Tolerance

The immune system of an organism normally does not react to its own cells and tissues. Tolerance to self-antigens is a critical feature of the immune system. The repertoire for antigen bound to self-MHC proteins of peripheral T-lymphocytes in a given animal is controlled of great importance, since many of the major failures of tolerance to self (i.e., autoimmune disease) are owing to immune responses to these parenchymal self' antigens. It can be seen that the use of transgenic mice to study self-recognition by the immune system provides us with important information about the properties of tolerance toward self and the mechanisms by which it is achieved, which in turn reflects on the nature and development of the immune system. This approach of introducing into the germ line of an animal of a known gene coding for a normally foreign antigen by means of a specific promoter to direct its expression to specific tissues would allow the synthesis of this particular antigen as an authentic...

Antiphospholipid syndrome

Although the anticardiolipin antibody (which is responsible for a false positive syphilis test) and the lupus anticoagulant are both antiphospholipids, the immune response appears to be directed to modified proteins rather than to lipids, since a cofactor (most commonly, beta-2 glycoprotein I (p2-GPI), an activator of lipoprotein lipase) is required for anionic phospholipid binding prior to antibody formation. The lipid-binding peptide of (32-GPI is similar to those found in some bacteria and viruses, implying the potential for an infection to stimulate anticardiolipin antibody formation. The antibodies themselves are heterogenerous and usually polyclonal IgG or IgM. Although many different mechanisms have been postulated to explain their in vitro anticoagulant but in vivo thrombotic effects, it is likely that the antibodies themselves are directly responsible for the clinical effects and that the clotting test results are artifacts of non-flowing blood.

Comparative Vaccine Adjuvant Trials 111 Animal Studies

Such comparison trials, adjuvant choice may depend upon other factors. These include cost, commercial availability, reactogenicity, mode of action, and induction of the desired arm of the immune response. Nevertheless, results of comparative trials may fail to identify the best adjuvant or adjuvants. For example, two comparative trials of simian immunodeficiency virus (SIV) vaccines combined with different adjuvants were conducted in macaques (84,89). The results were disappointing in that the mechanism of immunity could not be clearly delineated, and the large number of primates (80 and 98 animals) was still insufficient to allow meaningful statistical comparison of protection between all adjuvant groups.

Gastrointestinal Infections

Gastrointestinal infections have a particularly important role in inducing a compromise in host nutritional status. Malabsorption in gastrointestinal illness may result from the epithelial destruction by the pathogen or by the immune response to the pathogen. Even common diarrheal illnesses can have a profound impact on nutrient absorption. In symptomatic rotavirus infection, the most common cause of acute severe diar-rheal illness worldwide, there is a 42 decrease in the absorption of nitrogen and fat, a 48 decrement in the absorption of carbohydrates, and a 55 decrease in the total energy absorp-tion.122 These indices for malabsorption are slightly more severe in both ETEC infections and shigellosis.25,122 In shigellosis,123 protein loss is sizable and important, and vitamin A is wasted.27 Giardiasis and ascariasis lead to the malabsorption of vitamin A.24 Large losses of zinc also occur in diarrhea.124

Cannabinoid Receptors

CB1 was the first cannabinoid receptor to be characterized it is found in the central nervous system, adipose tissue, the liver and many other tissues (2,3). CB2 receptors were subsequently identified and are localized mainly in the immune system and they share a 48 homology with CB1 (4-6). Both are 7-transmembrane-spanning G-j o receptors (negatively coupled to adenylyl cyclase and positively coupled to mitogen-activated protein kinase) (3,5). CB1 receptors are also positively coupled to inwardly rectifying potassium channels and negatively coupled to several subtypes of calcium channels (7,8).

Actuarial Survival Data on Corneal Transplantation

The probability of a complicated outcome is only part of the concept of risk. The consequences of an adverse outcome must also be considered. Outcome data should be applied to patients in their particular clinical context. For patients undergoing corneal transplantation the consequences of success or failure can be quite different from patient to patient. For patients with corneal disease in one eye and a normal contralateral eye very little is to be gained by the patient in a functional sense from a successful outcome. Visual ability is determined by how good the vision is in the better eye rather than the level of vision in the poorer eye. Grafts in anything but the favourable circumstances of keratoconus or stromal dystrophy are best avoided when vision is normal in the contralateral eye. Other patients have much to gain from achieving a functioning graft in high risk situations. Those with most to gain are those with poor vision due to corneal disease in an only...

Distribution of Cannabinoid Receptors

Although CB2 receptors are located mainly in tissues of the immune system (22), they have recently also been identified in neurons in several regions of the brain (23). It may therefore be the case that CB1 and CB2 within the brain have differing functions, and that selective CB1 or CB2 ligands could be used to differentiate manipulation of the neural circuits controlling energy homeostasis from those controlling mood, memory, or other behaviors influenced by ECs. Consistent with this, selective CB1 and CB2 ligands were found to differentially influence emesis in ferrets (23).

Sensitization to Corneal Alloantigens

There are other cells in close proximity to the graft that can present antigen to the immune system. The iris and trabecular meshwork contain Class II positive interstitial dendritic cells 4o .They are in a position to process antigen or antigen fragments released from the endotheli-um. Antigen injected into the anterior chamber fluid can be tracked to the spleen 41 , and antigen injected into the posterior chamber of the eye can be tracked to the local nodes, at least in the mouse 42 . Another group of antigen-presenting cells is located in the peripheral cornea and adjacent conjunctiva. Unlike the dendritic cells in the uvea these cells interact with antigen in an environment low in TGFb, and are more likely to direct the immune response along the Th1 response seen in the corneal allograft response 43 . At least some antigen released from the cornea appears in the cervical draining nodes in mice 44 .

Robert John Wilkinson Michael Levin Geoffrey Pasvol

Toward the middle of the 20th century, the concept that the genetic makeup of the host may influence the outcome of infection became apparent, and in this respect malaria served as a prototype. All but a few infectious diseases are characterized clinically by variation in both disease pattern and severity, even in epidemic circumstances, indicating that host response has an important influence on the outcome of disease. A classic study highlighted the importance of host genetic makeup in our susceptibility to infection.1 The cause-specific risk of dying in adopted children was compared, depending on whether their biologic (genetically related) or adoptive (environmentally related) parent died prematurely before the age of 50 years. The results were striking. The death of a biologic parent resulted in an increased relative risk of dying in the adoptee of 5.8 for infectious diseases, more than for cardiovascular disease (4.5) and much more than for cancers (1.2). The advent of molecular...

Topical Corticosteroids

Or dexamethasone is the mainstay of immuno-suppression for clinical corneal transplantation. There is argument about the appropriate dosage and the desirable period of administration. The unexpectedly good results in the Collaborative Corneal Transplantation Trial (CCTS) in both arms of the trial were attributed to the high dose of topical corticosteroids used, which was considered to be higher than what is generally used in clinical practice 37 .

Structure of the tissue cyst and bradyzoite

The structure of the mature tissue cyst observed from 3 to 24 months following infection (approximately the lifespan of the mouse) remained relatively unchanged (Figure 2.23D). The first important observation is that throughout this period the tissue cysts are retained within a viable host cell (Figures 2.23D, 2.23E). It had originally been thought that the mature cysts are extracellular however, on ultrastructural examination a thin rim of host-cell cytoplasm could be observed enclosing the tissue cysts (Ferguson and Hutchison, 1987b). This may explain the lack of an immune response to the tissue cysts they are masked by the host cell. With the limited host-cytoplasm available, it is difficult to identify the cell type however, in the majority of cases the host

Systemic Corticosteroids

Corticosteroids are potent modulators of the immune system but have low specificity and serious side effects. Their well-known and serious side effects, including osteopaenia, weight gain, hyperglycaemia, hypercholesterolaemia, hypertension, and skin fragility, can occur with modest doses administered over relatively short periods. Despite this they are widely used in solid organ transplantation, where their combination with other immunosuppressive agents enables the use of lower doses of the individual agents with a corresponding reduction in the side effects. However, even when used in combination, the side effects from systemic administration of They are used for graft rescue - to save corneal grafts that are undergoing allograft rejection - and for graft maintenance when the use of other agents is precluded by side effects, such as cyclosporin toxicity. The level of evidence for their efficacy is low. This is related to the long history of usage. Introduced into clinical practice...

Antiproliferative Agents

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). In vivo it is rapidly broken down into 6-MP, which readily crosses cell membranes and is converted into a number of purine analogues. These interfere with cell division and growth although the precise mechanisms are not known. The immunosuppressive effect is related to the prevention of proliferation of the cells involved in the immune response. Azathioprine was first reported as an effective treatment of high-risk corneal transplants in 1967 81 . Mycophenolate, a more recently introduced immunosuppressive drug, works in a similar manner, suppressing the proliferation of cells involved in the immune response. It is thought to do this more specifically in that it has less effect on non-lymphoid cells. Mycophenolate is a potent, selective noncompetitive and reversible inhibitor of monophosphate dehydrogenase which inhibits the de novo pathway of guano-sine nucleotide synthesis without incorporation into DNA. Because...

Envelope Glycoproteins

Attachment domains by which the virus binds to a susceptible cell. This activity is thought to be related to the ability of many viruses, nonenveloped as well as enveloped, to bind to and agglutinate red blood cells, a process called hemag-glutination. The protein possessing hemagglutinating activity is often called the hemagglutinin or HA. The viral glycoproteins also possess a fusion activity that promotes the fusion of the membrane of the virus with a membrane of the cell. The protein possessing this activity is sometimes called the fusion protein, or F. The glycoproteins, being external on the virus, are also primary targets of the humoral immune system, in which circulating antibodies are directed against viruses many of these are neutralizing antibodies that inactivate the virus.

Cyst rupture in immunocompetent hosts

One of the clinical problems in immunocompro-mised hosts is recrudescence of the infection resulting in stage conversion back to actively proliferating and tissue-destructive tachyzoites. To examine the situation in the immunocompetent host, the brains of immunocompetent chronically infected mice have been examined. It is found that, indeed, a very small percentage of tissue cysts are rupturing at any given time during chronic infections (Ferguson et al., 1989). The initial change appears to be the death of the host cell. With the exposure of the parasite antigen in the cyst wall, there is evidence of a rapid and massive cell-mediated immune response involving numerous inflammatory cells (monocytes and even neutrophils). These are observed around the still apparently intact cyst (Figure 2.25A). With the rupture of the cyst wall, there is a further influx of macrophages into the cyst (Figure 2.25C). The macrophages phagocytose the bradyzoites, where there is fusion with lysosomes...

Of Systemic Immunosuppression

The side effects of systemic immunosuppres-sion are common and can be serious and life threatening. The immune system is an integral part of our defence against the outside world and its suppression leads to vulnerability. It is difficult to identify the precise relationship between a particular agent and a specific side effect. The drugs are usually used for patients with serious systemic disorders and often in combination with other powerful agents. Some of the side effects encountered are non-specific in that they are a consequence of the immuno-suppression. Others are due specifically to a particular agent.

Helminthic Infections

Hepatosplenic schistosomiasis is believed to be largely due to the immune response to egg antigens, and there have been a number of studies on the role of HLA. Studies from Egypt and a single study from South America have consistently related HLA-B5 to hepatosplenomegaly in S. mansoni infection.77,78 Studies of Schistosoma japonicum infection tend to be small, yielding multiple HLA associations, although in the largest of these HLA-B44 was a risk factor for the development of hepatosplenic disease.79 In a more recent molecular analysis restricted to class II alleles, it was reported that hepatosplenic disease is associated with DQB1*0201.80

Meningococcal Disease

The host innate immune response to invading microorganisms is triggered following recognition of common structural motifs present on bacteria and viruses through a range of pattern recognition receptors.107-109 Endotoxin lipopolysaccharide (LPS) is able to trigger innate immune responses following recognition by a number of host proteins and surface receptors, including the family of TLRs and the CD14 molecule.109,110 The importance of TLRs in containing gram-negative organisms was first identified in mice with mutations in the LPS locus.111 LPS receptor-deficient mice (homologous to TLR-4 deficiency in humans) are unable to respond to bacterial endotoxin and show enhanced susceptibility to infection with Salmonella, Neisseria, Escherichia coli, and other gram-negative organisms.110-112 An excess of rare TLR-4 coding changes was found in patients with meningo-coccal disease compared to controls utilizing complete sequencing of the TLR-4 gene (p 2 X 10-6 odds ratio, 27).14 This study...

The Cancer Connection

One of the hallmarks of tumor cells is that they have accumulated mutations that not only relieve the cells from growth regulatory signals but also allow them to invade the circulatory system, avoid the immune response, and grow at distant sites usually in a different tissue environment. The current hypothesis for the genetic changes in tumor cells is that they have gone through a period of genomic instability and loss of checkpoint control 71 . It is not surprising then that human orthologues of the checkpoint genes identified in yeast Atm (Mec1 Tel1), Chk2 (Rad53), Brca1 (Rad9) are tumor suppressor genes and that mutations in these genes predispose individuals to cancer 12 .

CSpecific Factors That Influence Resistance

Host resistance to parasitic infection is very similar to the resistance shown against bacteria. The immune system works by the formation of antibodies against a limitless amount of substances recognized as foreign antigens by the B lymphocytes. These blood cells, due to constant mutation, are much different from each other in such a manner that the system contains myriads of coded lymphocytes. When a parasite meets with one of these B lymphocytes that have a specific antibody against its antigen, the lymphocyte reproduces at a high rate to produce plasma cells. When these second generation antibodies encounter the antigens coating the parasites, a neutralization process takes place that kills the invaders. Immunity against parasites can be inherited or acquired. The acquired immunity may be natural or artificial, while the artificial can be active or passive.

Classification of Diabetes Mellitus

A number of lines of evidence suggest a genetic predisposition to developing type 1 diabetes. The lifetime risk of type 1 diabetes is 0.4 in white populations and rises to 5 to 6 if a first-degree relative is affected. Concordance rates for monozygotic (identical) twins are approximately 50 , but only 6 for dizygotic (nonidentical) twins.17 Genome-wide screens for susceptibility genes for type 1 diabetes have identified more than ten chromosomal loci.18-21 The two loci that contribute most to the risk of type 1 diabetes are the HLA region (tissue compatibility genes) and the insulin gene locus. Detailed analysis of the HLA region on chromosome 6 has shown that HLA DR3 and DR4 haplotypes increase and HLA DR2 haplotype decreases the risk of type 1 diabetes. Because HLA cell surface molecules are involved in activating T-cell immune responses, it is hypothesized that the DR3 and DR4 forms somehow induce an aberrant immune response, perhaps secondary to a viral infection.

Reaction Profile of Freunds Adjuvants

In general, both FIA and FCA are indeed very efficient in raising high antibody titres. FCA with its mycobacterial components is able to skew a humoral immune response toward the Th1 profile with pronounced IgG2a stimulation with high titres in mice. The antibody profile, however, is not entirely limited to IgG2a other subclasses are seen as well. This ability to stimulate Th1 immunity is further sustained by a number of studies where FCA has been tested alone or in comparison with aluminium hydroxide, which is well documented (36,37) as a Th2 adjuvant. This model of investigating FCA vs aluminium hydroxide adjuvant is suited to illustrate the dichotomy of the immune response in terms of Th1 and Th2 immunity and its modulation. Uede and coworkers (38) isolated 13kDa IgE binding factors from the spleen cells of rats immunized with keyhole limpet hemocyanin (KLH) and Al(OH)3. This factor selectively potentiated the IgE response, whereas factors from KLH-FCA primed spleen cells supressed...

Histology of the Mucosa

Structure and function of the mucosal immune system. MALT consists of a diffuse lymphoid tissue (A) and of an organized follicular tissue (B), shown here at different enlargements. Mucosal tissues in general are composed of two sheets, the luminal epithelium (e) with its basement membrane (bm) and an underlying lamina propria (Ip), which both contain lymphocytes. The lamina propria is composed of loose connective tissue with small blood vessels (b), afferent lymph vessels (l) and numerous cells including lymphoid cells T-lymphocytes (black), B-lymphocytes (blue), plasma cells (p) . Accessory cells occur like fibroblasts f), macrophages (mf),mast cells (mc) or dendritic cells (dc). Intraepithelial lymphocytes are mainly CD8+ suppressor cy- Fig. 6.1 A, B. Structure and function of the mucosal immune system. MALT consists of a diffuse lymphoid tissue (A) and of an organized follicular tissue (B), shown here at different enlargements. Mucosal tissues in general are composed...

The Identification of Diagnostic Subtypes of Depressive Disorders

In our department we conducted studies involving 217 inpatients with DD occurring after a significant loss. These studies revealed several psychobi-ological changes in neuroendocrine and immune systems hypothalamic-pituitary axis (HPA) activation, increase of plasma concentration of beta-endorphin, reduction of thyroid secretion and significantly increased levels of thyrotropic hormone decreased levels of insulin an imbalance of cellular and humoral immunity. These changes were observed in patients with depressive disturbances of various degrees of severity 73.7 of the cases did not meet the criteria for a depressive adaptive reaction according to duration and severity. In 120 inpatients (females) having experienced the loss of a parent (21.7 ), a spouse (42.5 ) or a child (35.8 ), the criteria were fulfilled for DE in 33.3 of cases, for bereavement in 35.0 of cases, and for subsyndromal depression with unstable neurovegetative symptoms in 31.7 of cases. In 40 of patients dysthymia...

The Anatomy of the Human Breast Where Breast Cancers Begin

The lymphatic vessels drain fluid containing waste materials from the breast into a series of filters called lymph nodes (fig. 2.4). These are situated under the armpit (axillary lymph nodes), under the breastbone (internal mammary lymph nodes), and above the collarbone (supraclavicular lymph nodes). The nodes contain collections of immune system cells that detect and destroy invading foreign organisms and antigens (substances that elicit an immune response). When breast cancers spread, the cells tend to invade the lymphatics and travel to the axillary nodes Surgeons will often removed a number of nodes to check for the

Sensors for Pathogens

There are fluid phase molecules as well as cell receptors that can recognize pathogens and trigger an innate immune response. The sensors of innate immunity recognize the vital, conserved molecular patterns that evolved on bacteria and fungi. These molecular motifs, which are not shared by meta-zoans and higher animals, are called pathogen-associated molecular patterns (PAMPs).7 Some fluid phase sensors for PAMPs may also be effectors such as the defensins in the mucosal fluids, which bind and kill bacteria. Defensins are a family of cationic proteins in the 3500-kD molecular weight range, which are released by neutrophils and epithelial cells and are abundant in airway and gut secretions.8 Human cathelicidin, hCAP18, has a distribution similar to defensins. Within the primary granules of neutrophils, hCAP18 is inactive but once secreted, it is cleaved, yielding two antimicrobial peptides. The antimicrobial activity of both defensins and cathelicidins relies on their capacity to...

Vaccine Formulations and Delivery

The initial era of vaccine development was based on the use of killed or attenuated whole organisms as immunogens. Usually these produced reasonable immune responses because of their recruitment of innate immunity, but in some cases they are associated with adverse reactions. Examples of adverse reactions would include the encephalopathic responses to the older formulations of killed Bordetella pertussis vaccine and the allergy to contaminating egg protein of influenza vaccine, which is produced by growing the virus in chicken eggs. To avoid such issues, many newer vaccines use purified molecules as immunogens. Although there are benefits to recombinant subunit vaccines, one limitation is they are not very immunogenic when administered by themselves. Highly purified immunogens may not stimulate the innate immune system and fail to upregulate the costimulatory molecules on antigen-presenting cells, and thus fail to induce an immune response. The advantage of using whole organisms is...

Diffuse Lymphoid Tissue in EALT

The components of the secretory immune system (lamina propria plasma cells positive for IgA and its transporter molecule SC in the epithelium) have not been found consistently at the normal human ocular surface except for the lacrimal gland, which therefore appeared as the sole source of specific immune protection, whereas the same plasma cells in the conjunctiva were addressed as inflammatory cells. The universal presence of a secretory immune system that reaches continuously from the lacrimal gland via the conjunctiva into the lacrimal drainage system was only recently verified at the normal human ocular surface by studies that combined the histological and immunohis-tological investigation of complete tissue whole mounts from normal human body donors 22, 23,25,28 . Together with ultrastructural results on the differentiation of the employed cell types and molecular-biological evidence for the presence of the mRNA of IgA and SC 21 , this demonstrated the local production of...

Nonepithelial Cells and Hormone Receptors

Mucosa and skin, including that of the vagina, urethra, and vulva have immune surveillance mechanisms termed mucosa-associated lymphoid tissue (MALT) and skin associated lymphoid tissue (SALT) including the vulva. Consequently, occasional single intraepithelial lymphocytes are seen in the epithelium and stroma of all regions of the vulva and urethra. Jones found more in the labium minus than labium majus (11). However, not infrequently, asymptomatic women show a greater number of lamina propria lymphocytes, particularly in the vestibule, where they may be associated with minor vestibular glands and their ducts (Fig. 16). Consequently, the clinical significance of such an infiltrate in symptomatic women is doubtful.

TRPV1 expression outside the nervous system

As well as being expressed on the sensory innervation of the airways, TRPV1 is also expressed on airways epithelial cells, and activation of TRPV1 by particulate matter induces apoptosis, which may be an important mechanism for particulate matter damage to the airways 47 . Air pollutants are thought to cause a reduced immune function and lowered resistance to infection as well as hypersensitivity to allergens and may exacerbate asthma and chronic obstructive pulmonary disease (COPD). Environmental particulate matter can act like synthetic particles made from negatively charged polymers, which are thought to act by concentrating protons near proton-gated receptors. Particulate matter causes a slowly desensitizing activation of TRPV1, and the calcium influx leads to apoptosis in sensory neurons and lung epithelial cells 47 . The authors suggest that blocking TRPV1 receptors would be useful in alleviating particulate matter-induced inflammation and toxicity.

Immune Regulation at Mucosal Surfaces and the Th1Th2 Paradigm

To initiate immune responses, antigens must be recognized by naive T cells in order to activate them to effector cells. According to the present concept, two signals are necessary for the activation of T cells. Besides the correct recognition of a presented antigen (signal 1) by the interaction of the specific T-cell receptor, the peptide antigen and the antigen presenting MHC-class-II molecule on the APC, the presence of co-stimulatory signals (signal 2) such as CD80 86, CD40 or ICAM-1 on the APC is required. This is necessary to initiate the production of a sufficient amount of the cytokine interleukin-2 (IL-2) by the T cell that is required for the autocrine stim- Fig. 6.3. Basic functions of the mucosal immune system. One of the main functions of the mucosal immune system is the maintenance of a fine equilibrium between inflammatory immune protection against microbial infection and the generation of tolerance to the majority of non-pathogenic antigens that occur at mucosal...

Activation of TLymphocytes by Cytokines

TNF-a upregulates ICAM-1, which is known to be an important factor in lymphocyte adhesion and can provide co-stimulation during their activation, not only on endothelial and epithelial cells but also on eosinophils. The activated lymphocytes and other cell types in turn produce further cytokines. Thereby mast cell derived cytokines interrelate the innate immune response with a specific T-cell-mediated immune answer. Since it is shown that the conjunctiva contains a population of resident lymphocytes 28 that belong to the physiological mucosal immune system, an activation of lymphocytes is possible without the previous necessity of lym- In chronic allergic and vernal keratoconjunctivitis (AKC and VKC) various inflammatory leukocytes (primarily eosinophils) but also lymphocytes of the mucosal immune system are activated by mast cell cytokines. A T-cell-mediated inflammatory processes arises that is associated with an inflammatory cell infiltrate and corneal destruction

Immunological Characteristics of Keratoplasty

And transported to lymphoid tissue that is present in the form of the organized follicular con-junctival CALT, on the ocular surface itself and in the draining lymph nodes (afferent arm). Al-loantigens have to be processed so that a specific cellular immune response might be generated (central stage). Finally in the efferent arm cellular and humoral effector mechanisms are delivered to the graft and cause its destruction.

Chlamydia Antibody Tests

Chlamydia trachomatis is the species of chlamydia that causes trachoma, lymphogranuloma venereum, pelvic inflammatory disease, and inclusion conjunctivitis. In addition to these diseases, chlamydia is a frequent cause of sterility. Infections caused by Chlamydia trachomatis produce an immune response. Antibodies can be measured using complement fixation, IF A, and PCR techniques.

And Immune Modulatory Therapy

Kine release with activation, proliferation and differentiation of other lymphocytes. It is obvious that new methods to prevent allograft rejection must take place in this early phase of graft reaction before activation of the T cell. The respective molecules involved in the processing and presentation of antigens as well as in the activation of lymphocytes represent promising targets for immune modulation and immuno-suppression (Fig. 6.10). Much attention has therefore been paid in particular to the recognition behaviour of CD4+ cells (T-cell receptor) and the interaction with the target antigen and cytokines that are responsible for expansion of the immune response. Cells of the physiological mucosal immune system are involved in the afferent antigen recognition phase (mainly conjunctival and corneal dendritic cells) and also in the efferent effector phase (performed by T cells). Besides systemic immunosuppression as similarly performed in solid organ transplantation, topical...

Complement deficiency

The complement system is one of the four plasma enzyme cascades and together with the coagulation, fibrinolysis and kinin systems, it is involved in the bodily responses to injury. In particular, the complement system provides the major link between the process of inflammation and the immune system. It is thus involved not only in host resistance to infection, both immunological and nonspecific, but also in the mechanisms of tissue injury.

Human Leukocyte Antigens

The study of the genomic contribution to the immune system was initiated by the description of immune response genes. The genes involved in determining whether an animal was a high or low responder to specific antigens were mapped to a region that became known as the major his-tocompatibility complex (MHC) on chromosome 6 of the human. Although the MHC contains many genes involved in the immune system, the gene products primarily responsible for the immune response became known in the human as human leukocyte antigens as they were characterized by evaluating an individual's serologic reactivity to allogenic leukocytes. There are hundreds of allelic variations of HLA molecules and each individual generally has l2 alleles of the classical HLA genes (three Class I and three Class II alleles from each parent). Such heterogeneity allows an individual to present a wide range of pathogen-derived peptides to T cells in order to initiate the adaptive immune response, as well as peptides...

Diagnosis of Toxoplasma gondii infection in pregnant women

This problem has been partly solved by obtaining two samples from pregnant women to see whether there is any development of the immune response. It is generally agreed that there is development of the Toxoplasma-specific IgG antibody response within the first 8 weeks after infection, after which the IgG levels are maintained at a high level, with or without declining IgM antibodies (Jenum et al., 1997, 1998).

Immunomodulatory Properties

The effects of neem on the immune system are complex and have not been fully elucidated some evidence points to an immunostimulant effect, while other evidence suggests it can also act as an anti-inflammatory. The latter may be partly explained by inhibition of prostaglandin synthetase (Van der Nat et al., 1991 Okpanyi and Ezeukwu, 1981 Obaseki et al., 1985). However, Kroes et al. (1993) showed that in a classical Ayurvedic preparation for gout, nimba arishta, the anti-inflammatory activity is almost entirely attributable to ingredients other than neem. Here we review the evidence for the immunostimulant effects of neem, and to what extent this may explain its perceived efficacy in the treatment of malaria. There is a small amount of evidence that neem may boost both the humoral and the cell-mediated immune responses to malarial infection, but it comes mostly from mice, which may have different immune responses from man, and in which neem has not been shown effective against malaria....

How Does Breast Cancer Kill

Once a cancer has spread, it is difficult to control. Treatments such as surgery, chemotherapy, or radiation may reduce the mass of the tumor, but metastatic cells may remain in lymph nodes or elsewhere and eventually resume their rampage. Some cells develop resistance to chemotherapy or radiation. Those cells have a selective advantage and will continue to grow. Eventually, vital organs are destroyed and the patient dies of organ failure or hemorrhage. Cancer patients often develop fatal infections. White blood cells, which are critical for fighting infections, are made in the bone marrow. As mentioned above, chemotherapy destroys all fast-dividing cells including those in the marrow. The patients are left immunosuppressed and are susceptible to a variety of infections that people with intact immune systems normally overcome. The marrow may also be destroyed by direct invasion by the tumor cells. It is therefore extremely important for breast cancer or any fast-growing cancer to be...

Vaccine Candidate Selection and Expression

Roll motif and a C-terminal P-trefoil domain (see Chapter 2). This latter domain, comprising 150 amino acid residues, shows very little sequence homology among the different serotypes, suggesting that this domain may be principally responsible for determining serotype specificity. There is some evidence, however, that both halves of the Hc domain are required to elicit neutralizing antibodies and that accurate folding of the entire domain is essential. Vaccinating mice with only the N-terminal half, of the Hc domain, only the C-terminal half, or a mixture of the two failed to produce a notable protective immune response.55

The answer is e McPhee 2e p 109 Fauci 14e pp 337 and 640

The answer is d. (McPhee, 2 e, pp 117-119 Fauci, 14 e, pp 731 and 744.) Drugs induce thrombocytopenia by an immune response. The platelet is damaged by complement activation as a consequence of the formation of drug-antibody complexes. The incidence of thrombocytopenia is high in patients treated with heparin. The pathogenesis involves binding of heparin to platelet factor 4 (PF4), and the released heparin-PF4 combination acts as an antigen provoking the production of an IgG antibody. The properties of the cells may be abnormal. Precursor forms are often prominent in myeloid leukemias. A characteristic chromosomal translocation t(9 22) results in the Philadelphia chromosome although not exclusively restricted to chronic myelocytic leukemia, its presence in a chronic leukemia makes the diagnosis highly probable. The myelocytic leukemia commonly terminates following transition to an accelerated phase with transformation of the principal malignant cell to a blastlike form. The...

HLA and Disease Pathogenesis

The HLA system has been associated with disease for over 30 years, but the precise role of HLA molecules in disease pathogenesis is not well established 16 . While microbial pathogens may play a more direct role than currently appreciated even in diseases we now consider due to autoimmunity, it is likely that in many cases HLA associated uveitis is at least in part an autoimmune process resulting from loss of tolerance to self antigens. While a discussion of the proposed mechanisms of loss of tolerance is beyond the scope of this chapter, several observations are pertinent. Despite the known role of HLA molecules in antigen presentation and the establishment and maintenance of tolerance there is no direct evidence that antigen presentation by the HLA molecule is critical to disease pathogenesis. It may be that presentation of ocular peptides in the thymus plays a role in the susceptibility to uveitis. In one study that did suggest that the HLA molecule itself was critical, a mouse...

HLA Associations with Ocular Infections

While infections are clearly due to exogenous agents and therefore an environmental factor par excellence for ocular inflammatory disease, it is similarly clear that the host response is critical in determining disease outcome. An elegant animal model of herpes simplex virus (HSV) stromal keratitis that illustrates this, as well as the complexities of HLA in disease, has been reviewed elsewhere 16 . An HSV coat protein, UL-6, shares a seven amino acid sequence with IgG2a. Mice were protected from stromal keratitis if they had a certain IgG2a al-lele, IgG2a b. When mice were infected with HSV, it was thought that a corneal peptide that cross reacted with the specific IgG2a b allele and viral UL-6 was unmasked if mice had the IgG2a b allele they would have developed central tolerance and an immune response was not elicited.

Pathogenesis of Organ Dysfunction and Toxemia

The unique feature of typhoid fever is the relationship between S. Typhi and macrophages in the liver, spleen, intestinal lymphoid follicles, and mesenteric lymph nodes. Macrophages can produce an array of functionally active cytokines. These include tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and interferon-a and (IFN-a, IFN-0). Macrophages are also an important source of arachidonate metabolites and reactive oxygen intermediates. These macrophage products can cause cellular necrosis, recruitment of other inflammatory cells, stimulation of the immune system, vascular instability, initiation of the clotting mechanism, bone marrow depression, fever, and other abnormalities associated with typhoid fever. It is likely that S. Typhi endotoxin stimulates the macrophages to release these substances, which locally mediate the intestinal and hepatocellular necrosis found in the disease, and which, when released systemically, cause most of the other manifestations of the disease.69

Relative Risk of Clinical Prognostic Factors

Second endoscopic resection showing no residual tumor (at 3 months) Good response to intravesical chemotherapy immunotherapy No tumor recurrence during the first year of surveillance cystoscopy Large (greater than 1.5 cm) tumor Multifocal tumors Presence of carcinoma in situ (especially if distant to papillary tumor site) Second endoscopic resection showing residual tumor (at 3 months) Poor response to intravesical chemotherapy immunotherapy


System tissue and inactivated by phenol rather than drying was the accepted rabies vaccine for decades. In the 1960s, a safer inactivated virus vaccine derived from virus grown in cultured human cells was introduced. The rabies vaccine is unique in that it is normally given after exposure to the virus, in conjunction with anti-rabies antiserum. This is possible because there is a window of time following the bite of a rabid animal before rabies develops, during which a protective immune response can be induced. Veterinarians and wildlife workers who are potentially exposed to rabid animals, as well as biologists who work with rabies virus in the laboratory, are immunized prophylatically, but the protective immune response can be of short duration and immunity must be tested at regular intervals.

Host Response and Immunity

The innate immune system senses invasive Salmonella infections using Toll-like receptors that recognize conserved elements of bacterial structure, including recognition of LPS by Tlr4, bacterial lipoproteins by Toll-like receptor 2 (Tlr2), and flagellin by Tlr5.94 Activation of these receptors on phagocytes and epithelia leads to synthesis of cytokines that orchestrate the acute inflammatory response and instruct the subsequent antigen-specific immune response. Mice lacking a functional Tlr4 response are highly susceptible to Salmonella infection, confirming the importance of this initial response to infection.120 Studies in mice demonstrate that the initial control of S. typhimurium replication in host tissue requires recruitment and activation of macrophages.121 In both mice and humans, macrophage activation and efficient killing of Salmonella is associated with production of IFN-y, Il-12, and TNF-1.122-124 Mice with targeted disruptions in these genes are highly susceptible to...

Intravesical Therapy and Dose Scheduling

The traditional induction regimen of six weekly instillations of chemotherapy,initiated a week after resection, was based on original work using BCG immunotherapy. Delayed bladder instillation was intended as a prophylactic therapy for a secondary new occurrence, presuming that all previous tumors have been eradicated. It is now increasingly apparent that intravesical chemotherapy is best intended as an ablative therapy to mop up loose cells released at the time of extirpation and to prevent tumor reimplantation. Longitudinal studies have shown that tumor recurrences occur in two time-dependent peaks. The groups with early recurrence peaks are sensitive to chemotherapy, whereas those with delayed recurrences are generally resistant 35 . It is not surprising, therefore, that the influential study of the MRC demonstrated that immediate instillation of MMC within 24 hours of transurethral resection was as effective as conventional 6-week courses 61 . Indeed, more recent studies have...

Serum Markers for Prostate Cancer

Given that many men die with prostate cancer but not of it, it would be of clinical benefit to be able to distinguish which cancers are likely to be aggressive from those that will remain latent. Out of those that have already spread, to be able to determine which are likely to relapse rapidly following hormone treatment could be of clinical value. Whether some of the markers discovered for detection of cancer will also allow diagnosis to be made regarding aggressiveness or invasiveness of that cancer is not clear. It is more likely that another set of markers would be required to make those distinctions. Furthermore, it may not be a single marker that denotes any of these factors, but combined alterations, a signature, which could perhaps be detected by mass spectrometry. Yasui et al. 27 used SELDI to generate signature profiles for prostate cancer, BPH, and normal sera, which worked well in differentiating between normal and diseased prostate, but did not clearly distinguish between...

Pathogenesis And Immunity

The mucus-covered epithelium constitutes a major line of defense against most enteric microbes because they cannot cross this tight epithelial cell monolayer barrier. In addition, it is endowed with both intracellular and extracellular receptors to recognize microbial invasion and activate the innate immune system.15 Because Shigella requires mucosal invasion to cause disease, it has developed unique molecular strategies to breach the mucosal barrier. Convincing evidence now exists that shigellae initially traverse the mucosa, not through epithelial cells as originally believed, but rather through M cells, specialized for antigen processing.30 Organisms thus reach the underlying lymphoid follicles, apparently without disrupting the M cells, and encounter and are phago-cytosed by resident macrophages. Following lysis of the Thus, invasion of the epithelial mucosa actually involves three processes a primary translocation across the mucosa via M cells, a secondary invasion process in...

Viral Delivery Systems

Advantages of efficient transduction and easy manipulation in vitro. It is also relatively straightforward to produce high titers of purified virus. Moreover, adenoviruses infect both dividing and nondividing cells, and their DNA is not incorporated into the host genome, minimizing concerns about insertional mutage-nesis. The major disadvantages are the transient expression of its DNA insert and the immune responses generated in response to the vector. A major consequence of the antiadenovirus immune response is a marked reduction of transgene expression following multiple dosing, which appears to result mainly from stimulation of neutralizing antibody responses, although adenovirus-specific cytotoxic T lymphocytes (CTLs) have been detected. In addition to specific antiadenovirus transgene-directed immune responses, nonspecific inflammation can also significantly reduce transgene expression. It has been possible to increase the duration of adenovirus gene expression through the use of...

Tissue Repair in Models of Diabetes Mellitus

There are also changes in the basement membrane of the capillaries that lead to perfusion problems. Another key factor is the neuropathy of diabetes mellitus. The lack of sensation can lead to deeper wounds by allowing persistent damage owing to a loss of protective actions. In addition, neuropathy leads to muscle wasting that leads to the loss of the normal arch of the foot. The loss of the normal arch positioning causes increased pressure over the head of the metatarsals. The loss of autonomic nerves leads to decreased sweating, and dry, cracking skin that causes the skin to have an increased risk of breakdown. Finally, diabetes mellitus leads to impaired immune function so that a small wound has a higher propensity for infection. One can see that the many factors that predispose diabetics to healing problems are difficult to completely reproduce in an animal model. Investigators should choose the model that most closely resembles the problem that they wish to study.

Enhancing Immunological Responses

Prostate cancer has several factors that make it a good candidate for adoptive immunotherapy. Although prostate cancer is a visceral tumor, the primary tumor site is relatively easy to access and image. Effector immune cells can be readily and accurately injected directly into the tumor assisted by transrectal ultrasonography. In addition, prostate cancer expresses a number of unique tumor and tissue markers including prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and members of the ErbB gene family. These markers not only can serve for screening and monitoring of prostate cancer, but also those markers expressed on the cell surface may provide useful targets for active and passive immunotherapy. Finally, although many of these prostate cancer-associated antigens are also expressed on normal prostate tissue, the prostate is not a vital organ and thus any damage to neighboring cells can be accepted as a consequence of treatment. One method of generating an...

The Supporting Cast Liver Gallbladder and Pancreas

The major pathology of the intestinal tract in a person with Crohn disease or ulcerative colitis is chronic inflammation. Inflammation is a natural response when the body's immune system attacks a foreign entity (antigen). Inflammation is characterized by four conditions heat, redness, pain and swelling. The antigen can be viral, bacterial, parasitic, or chemical it can be a foreign physical object such as a wood splinter or foreign tissue such as a transplanted organ. But with Crohn disease or ulcerative colitis, there is no obvious immediate antigen at hand. The immune response seems inappropriate the body creates inflammation with no reason to do so. Researchers today are focusing on a number of key questions about the inflammatory process. They are trying to determine not only how, but, more important, why the inappropriate inflammatory response occurs in those with Crohn disease and ulcerative colitis. Some of the key questions are What triggers the immune system response What is...

Recurrent Aphthous Ulcers

Recurrent aphthous ulcer (RAU) (figure 1-10) is a chronic inflammatory disease with repeated episodes of ulcerations. Recent investigations seem to indicate that the aphthous lesion is associated with an altered local immune response. This disease is characterized by small, whitish ulcers with red borders. The disease normally occurs as a single lesion or, infrequently, as multiple lesions on the wet mucous membranes of the lip, tongue, cheek, or floor of the mouth. Lesions appear as depressions on the mucous membrane and are covered by a grayish-white or light-yellow membrane. There is no vesicle formation before the ulcer appears, distinguishing this disease from viral diseases of the oral mucosa. Associated with the development of a recurrent aphthous ulcer is generally trauma, endocrine change, psychic factors, or allergy. The lesions are painful however, the condition is self-limiting with the lesions usually healing in 10 to 14 days without leaving scars. Recurrent aphthous...

How does stress affect the body

So, when you experience stress, your body prepares itself physiologically to counter any threat to its survival - the 'fight or flight' response. Stress may lead to physical problems when you cannot respond in a way that eliminates it, the stress continues unabated and so do the symptoms. An inability to do anything to relieve the stress may cause even more stress, creating a vicious circle and this can take its toll on your body. In fact, many researchers believe that prolonged stress puts such a strain on your body that your immune system may ultimately break down, making your body more vulnerable to a number of diseases.

Cytokines and Chemokines

Cytokines are small, secreted proteins of up to 20 kDa that affect the behavior of immune cells as well as other cells. They include the interleukins lymphokines and several related signaling molecules, such as tumor necrosis factor-a (TNF-a), TNF-P, and interferons. Chemokines are a subset of cytokines that stimulate chemotaxis and extravasation of immune cells via binding to G-protein-coupled receptors on the surface of target cells. It has long been thought that the proinflammatory cytokines, including interleukin-1a (IL-1a) and IL-10, IL-6, and TNFa, play an important role in wound repair. They likely influence a series of crucial biological effects at the wound site, including stimulation of keratinocyte and fibroblast proliferation, synthesis and breakdown of ECM proteins, fibroblast chemotaxis, and regulation of the immune response.

Reinhard Glck 1 Introduction

In the past, vaccine development was mainly empirical, and based on attempts to mimic natural infection. Vaccinology has entered a new era, which might be linked to rational drug design vs brute force screening. The development of new or improved vaccines will rely on a sophisticated understanding of the molecular biology, mechanisms of pathogenesis, and interactions with the immune system particular to a given pathogen. As information continues to accumulate, it is becoming increasingly obvious that the immune response to natural infection by microbial pathogens does not define the limits of the possible immune responses to those antigens. It may also not represent the optimal protective response. Pathogens can influence the spectrum of the immune response, often subverting the capacity of the immune system to aggressively interfere with the infectious process (1). In addition, certain aspects of the natural immune response contribute to or are largely responsible for pathogenesis...

The Virosomal Vaccine Approach

It has been hypothesized that anchorage of a peptide in a liposomal bilayer might mimic the normal presentation of antigen on an infectious agent (i.e., multivalent and projecting outward from an anchor on the surface of the cell) and thereby potentiate the immune response to the peptide. To test this hypothesis, peptides were covalently linked to a phospholipid, providing a hydropho-bic anchorage into the phospholipid bilayer. Current concepts regarding the mechanisms through which peptide epitopes are presented to CD8+, major histocompatibility complex (MHC) Class I -restricted cytotoxic T lymphocytes (CTL) indicate that a crucial aspect of this process is the capacity to introduce antigen into the cytoplasm (but not endosomes) of antigen-presenting cells (18). This explains, at least in part, the success of live-attenuated and live-vector vaccines for stimulating cell-mediated immune responses.

Mechanisms Underlying B7H1Mediated Suppression

Employing cell culture systems which are reconstituted with B7-H1-expressing cell lines, B7-H1 and PD-1 blocking antibodies and tumor-specific T cells, experimental data unequivocally support the idea that tumor-associated B7-H1 negatively affects T-cell functions in multiple aspects, including inhibition of T-cell proliferation, T-cell production of IL-2 and IFN7, promotion of IL-10 production and suppression of cytolytic activity of tumor-specific CD8 T cell (CTL) (Dong et al., 2002). In several mouse tumor models in vivo, tumor-associated B7-H1 induces CTL apoptosis or confers resistance to lysis by CTL. In addition, B7-H1+ tumors are shown to be resistant to T-cell adoptive-transfer immunotherapy or therapeutic antibody anti-CD137. Furthermore, B7-H1 was shown to be necessary for the maintenance of T-cell exhaustion in a chronic infection mouse model of lymphocytic choriomeningitis virus (LCMV). Recent in vivo anergy tolerance models also reveal a critical role of B7-H1-PD-1...

Experimental Models to Study Viral Retinitis

Pertinent permissive cell cultures, such as retinal glial cells or retinal pigment epithelial cells, have been used to study HCMV replication (Fig. 10.2). Virus replicates slowly and progressively 11,16 . In the era of highly active anti-retroviral therapy, intraocular inflammation, like cystoid macular edema, vitritis or papillitis, has been reported in patients presenting with completely cicatricial retinitis. It was therefore of interest to analyse different pathways involving antiviral immune responses that might potentially play a role in these situations. The model of retinal pigment epithelial cells was used to analyse virus-host interactions. The occurrence of HCMV retinitis in the late phase of immunosuppression may be related to perturbation of cytokine production and secretion, associated with the progressive loss of the CD3+CD4+ cell subset. The effects of different cytokines such as IFN-g, IFN-p, IL-1P, TGF-p and TNF-a, which are present in the eye under different...

The Immunology Contribution

AIDS research has furthered our understanding of how the immune system works and also of how it doesn't work properly in diseases such as Crohn disease and ulcerative colitis. Inflammatory bowel disease is the result of abnormal control of the immune response to environmental triggers. These triggers may include the bacteria that occur naturally in a person's own gastrointestinal tract. The immune system is responsible for manufacturing cells that recognize and destroy antigens that invade the body These cells include lymphocytes, monocytes, granulocytes, mast cells, and macrophages. Lymphocytes are the most prevalent player in the immune response. They produce T cells, so called because they are produced in the thymus gland. One of these types of T cells, THi cells, along with macrophages, attack the offending antigen, promoting inflammation by producing three proinflammation chemicals, interleukin-i (IL-i), IL-2, and tumor necrosis factor-alpha (TNF-alpha). TH2 cells, on the other...

Role of Bacille Calmette Gurin in the Treatment of Carcinoma in Situ

To date, BCG remains the treatment of choice for CIS disease. Although cytotoxic chemotherapy agents have shown initial response rates as good as 48 using anthracyclines and 53 for MMC, most series have demonstrated that this response is time limited, with fewer than 20 remaining disease free at 5 years 72 . This apparent chemoresistance may well reflect the high grade of CIS disease, whereas higher grade may imply greater antigenicity and therefore susceptibility to BCG immunotherapy. Bacille Calmette-Guerin therapy gives complete response rates of 60 to 70 with a median duration beyond 3 years and projected 5-year responses of 45 . Nevertheless, 30 to 40 of patients with CIS disease do not respond to a single induction course of BCG 72 . The response rates and the durability of response may be improved with maintenance therapy. Advocates of long-term maintenance refer to the SWOG 8507 study (see above) 69 ,although this was not specific for CIS. Further credence to maintenance BCG...

Rationale For Interest In Va Supplementation And Antibody Production

Animal experiments have demonstrated that an adequate level of VA is necessary to mount an efficient antibody response to many antigens however, previous studies have also revealed that VA-deficient animals are capable of producing a strong antibody response to some antigens (Ross, 1996a,b). Thus, the requirement for VA may be better considered as conditional, as it apparently differs with and depends on the type of immune stimulus employed. Antigens that require T-cell help T-cell-dependent (TD) antigens such as tetanus toxoid and cellular antigens in the initiation phase of the antibody response, or antigens that, while considered T-cell independent are nonetheless regulated by T-cells (TI-2 antigens such as polysaccharides), were poorly immunogenic in VA-deficient animals, while TI-1 antigens lipopolysaccharides (LPS) were strongly immunogenic in VA-deficient animals as well as controls (Arora and Ross, 1994 Ross, 1996a,b). Indeed, in response to some types of antigenic challenge,...

Wound Repair in Aging

To provide a framework for a review of aging and wound healing, this chapter begins with a summary of how age affects the morphology and function of the skin (2-4). As the outermost layer, the epidermis is the first line of defense after tissue injury. The total thickness and the four layers of stratified squamous epithelial cells (keratinocytes) are maintained in aged skin, but the cells become more variable in size, shape, and orientation. In addition, the turnover time, the number of days for keratinocytes in the basal layers of the epidermis to migrate and be shed from the skin surface, increases by 50 in the aged. Other cells in the epidermis such as melanocytes (which provide pigment) and Langerhans cells (which are responsible for the immune response in the epidermis) are also reduced in number. Whereas barrier function against water is maintained in aged skin, there is a significant decrease in the ability of the epidermis to regenerate in response to noxious substances such...

Experimental Models

With other immune stimuli are of interest. For example, our laboratory has investigated the effects of VA or RA combined with LPS, now known as a ligand for TLR4, and of VA combined with tumor necrosis factor (TNF)-a, a ligand for several receptors of the TNF-a family that are critical for immune regulation. Each of these combinations increased the antibody response to tetanus toxoid in VA-deficient rats, and also elevated the level of anti-tetanus antibodies above the normal level in VA-adequate rats (Ross, 2000). We have also combined VA and RA with polyriboinosinic acid polyribocytidylic acid (PIC), a double-stranded RNA that is a mimetic of double-stranded RNA viruses and a ligand of TLR3 (Janeway and Medzhitov, 2002 Takeda and Akira, 2005). PIC has been studied by others and ourselves for its ability to elicit type I IFNs and activate NK cells, but it is now known that PIC-stimulated dendritic cells and peripheral blood mononuclear cells produce an array of cytokines, including...

Vogt KoyanagiHarada Syndrome VKH

VKH is a multisystemic disorder involving eyes, ears, skin and meninges. It appears to be concentrated in certain racial and ethnic groups. The pathophysiology of VKH remains unclear. A specific antigen-driven immune response may occur in this disorder. However, the concept that VKH is a viral-induced disease has been attractive. EBV seems to be associated with VKH but molecular data are still needed before further conclusions are drawn 6 . Interestingly, atypical forms of VKH may occur in hepatitis C virus-infected patients treated with alpha interferon.

Ra Treatment And Antibody Production In A Vadeficient Model

Alone, and RA combined with PIC, can increase antigen-specific antibody production, VA-deficient rats were immunized with tetanus toxoid and treated orally with all-trans RA, PIC, or the combination at the time of primary immunization (DeCicco et al., 2000). After the primary response has subsided, all rats were reimmunized with tetanus toxoid however, no additional RA or PIC was administered. VA-deficient rats produced low primary anti-tetanus IgG response ( 20 of the VA-adequate control group) and a very low secondary anti-tetanus IgG response (< 10 of the VA-adequate control group). The primary response was increased by RA alone and by PIC alone. The primary response was increased much more strongly, in a synergistic manner, by RA + PIC (P < 0.0001). Interestingly, the secondary response was equally augmented by RA + PIC, even though these treatments were given only at the time of first immunization (priming). PIC alone, however, did not promote the secondary anti-tetanus...

Resistance to CTL Lysis The Molecular Shield Hypothesis

In addition to the induction of apoptosis upon contacting T cells, B7-H1 on tumor cells is also found to confer resistance to lysis by CTL. In a mouse P815 tumor model, transfer of a tumor-specific TCR transgenic CTL clone P1A eradicates established wild-type P815 tumors. However, B7-H1-transfected P815 tumors are much more resistant to CTL lysis, which is not associated with T-cell apoptosis. Interestingly, when mock-transfected and B7-H1-transfected P815 were mixed in equal number and co-cultured with P1A CTL, 90 of mock-transfected P815 tumor cells were killed in contrast, only 35 of B7-H1+ P815 were lysed. After engaged by B7-H1-positive P815, no obvious increase of apoptosis of P1A CTL was observed. Similarly, we also found that B7-H1+ P815 cells were also more resistant to 2C transgenic T-cell lysis in vitro (data not shown). Taken together, these findings provide a new interpretation, in addition to apoptosis, for our previous observation that B7-H1+ P815 tumor is resistant to...