Cytokines in EAU

Cells polarized towards a Th1 phenotype secrete interleukin-2 (IL-2) and interferon-g (IFNg), which are thought to be primarily responsible for cell-mediated inflammatory reactions, de-layed-type hypersensitivity (DTH), and tissue injury in autoimmune diseases (Fig. 8.2). In contrast, Th2 cells produce IL-4, IL-5, IL-6, IL-9 and IL-10 and are efficient promoters of antibody responses. The imbalance between these two types of response is considered to be involved in the pathogenesis of autoimmune disease. Both susceptible as well as resistant animal strains initially mount a balanced Th0 type response to the uveitopathogenic antigen [16]. However, EAU susceptibility is characterized by polarization of the early Th0 response toward Th1 in susceptible strains and Th2 in resistant strains. Since cy-tokine production may play a critical role in the mechanism of human uveitis and biologic agents that interfere with cytokine action are becoming available as potential therapeutic agents, it is important to understand the role of various Th1 and Th2 cytokines in pathogenesis of EAU.

IFNg. IFNg is a homodimeric protein produced by NK cells, CD4+Th1 cells, and CD8+ T cells. It is the signature cytokine of the Th1 subset. IFNg promotes the differentiation of naive CD4+ T cells to the Th1 subset and inhibits the proliferation of Th2 cells [17]. IFNg can also stimulate expression of MHC class I, MHC class II, and costimulatory molecules on antigen presenting cells. Elevation of IFNg was observed in eyes affected by EAU which may be directly responsible for the observed ocular overexpression of MHC class II molecules during experimental uveitis. Additionally, levels of IFNg expression following antigenic challenge are higher in EAU-susceptible as compared to EAU-resistant species.

Further evidence for the importance of this molecule in uveitis is provided by studies using transgenic rats with constitutive overexpression

Fig. 8.2. Simplified diagram of major immunopathogenic mechanisms and cytokines in immune-mediated disease

of IFNg in the eye [18]. In these transgenic rats IFNg increases both the severity and acceleration of the onset of experimental autoimmune uveitis. However, studies using cytokine deficient mouse strains provide conflicting evidence for the role of IFNg in EAU pathogenesis. However, studies using IFNg knockout mice(IFNg-/-) provide evidence for additional pathogenic pathways in uveitis development. This mouse strain does not promote the development of a Th1 response, yet it may develop EAU following an appropriate antigenic stimulus. Strong MHC class II expression is apparent in the eyes of IFNg-/- mice with EAU, indicating alternative pathways for MHC upregulation. IFNg-/- mice exhibited an antigen-specific effector response with upregulation of IL-5, IL-6 and TNF-a in the uveitic eyes. There was no significant increase in IL-4 and no upregulation of inducible nitric oxide synthase (iNOS) in these studies. Therefore, tissue damage in the IFNg-/- mice appears to be mediated by a different mechanism than in the wild-type [19]. These seemingly conflicting results in the over-expressing rat strain and the knockout mouse strain may indicate distinct roles for IFNg in immunomodulatory pathways in mice and rats during uveitis or may simply reflect redundancy of the proinflammatory pathway.

IL-2. IL-2 is a growth factor for antigen-stimulated T lymphocytes and is responsible for T-cell clonal expansion after antigen recognition. IL-2 is produced by activated CD4+ T lymphocytes and, in lesser amounts, by CD8+ T cells. IL-2 production is transient, with peak secretion occurring about 8-12 h after activation. The IL-2 receptors (IL-2R) consist of three non-covalently associated proteins: a, b and g. The a and b chains are involved in cytokine binding, and b and g chains are involved in signal transduction. Expression of functional IL-2R is enhanced by antigen stimulation. In EAU, upregulation of the IL-2R is observed and believed to be an important step in the patho-genesis of disease. Therapeutic use of antibodies against the IL-2R in EAU results in the decrease of acute ongoing inflammation in the eye. In addition, use of low dose IL-2 with small quantities of antigen may enhance the induction of oral tolerance in the EAU model [20].

IL-4. IL-4 is the major stimulus for the production of Ig E antibodies, development of Th2 cells from naive CD4+ T cells, and functions as an autocrine growth factor for differentiated Th2 cells. In EAU, an inverse relationship between IL-4 and IFNg is observed and it is hypothesized that IL-4 may exert a dose-dependent differential effect on the induction of immune responses and on autoimmunity. Experimentally, administration of IL-4 shifts an autoimmune response towards a non-pathogenic Th2 pathway [2i]. In addition, evidence for a role of IL-4 in suppressing autoimmunity is supported by increased IL-4 mRNA in orally tolerized mice.

IL-6. In animal models of EIU, conflicting evidence supports the role of IL-6 as a proin-flammatory mediator in ocular inflammatory disease [22, 23]. Upregulation of IL-6 in the anterior chamber is reported during EIU and levels of IL-6 positively correspond to cellular infiltration; however, IL-6 was not sufficient to induce uveitis and neither did the absence of IL-6 prevent uveitis induction. Studies of anterior chamber-associated immune deviation (ACAID) demonstrate reduced ACAID after exposure to IL-6 and increased aqueous humor immunosuppression following IL-6 depletion

IL-10. IL-i0 inhibits activated macrophages and dendritic cells and is involved in the control of cell-mediated immunity. IL-i0 can inhibit the production of IL-i2,and expression of both cos-timulatory and MHC class II molecules on macrophages and dendritic cells. Studies indicate that endogenous expression IL-i0 limits development of EAU and,reciprocally,IL-i0-de-ficient mice are susceptible to EAU [2i, 25, 26]. Both IL-4 and IL-i0 are required for induction of protective oral tolerance, providing additional evidence for the protective role of IL-i0 in EAU.

IL-12. IL-i2 is a key inducer of cell-mediated immunity. The principal sources of IL-i2 are activated mononuclear phagocytes and dendritic cells. Although IL-i2 was originally identified as an activator of NK cell cytolytic function, one of its critical actions is to stimulate IFNg production by T cells and NK cells and to polarize differentiation of CD4+ helper T lymphocytes into IFNg-producing Thi cells. An elevated level of IL-i2 is observed in the ocular tissues of EAU animal species, supporting a role for IL-i2 in EAU pathogenesis. Studies to evaluate the role for endogenous IL-i2 were performed using

IL-i2 p40-deficient mice [27]. These mice were resistant to EAU; however, they were able to develop a Th2 polarized antigen-specific response to the inciting uveitogenic antigen. In contrast, EAU developed in these animals after receipt of syngeneic, antigen-specific cells that had been incubated with antigen in the presence of IL-i2. These findings support the critical role for IL-i2 in the induction phase of EAU and that resistance to EAU may involve the inability to develop a pathogenic Thi response in response to antigenic stimuli.

IL-13. IL-i3 is a pleiotropic cytokine produced by Th2 CD4+ T cells. IL-i3 inhibits the synthesis of proinflammatory cytokines IL-i, IL-6, IL-8 and TNF-a, and induces B-cell proliferation, IgE production, and expression of certain adhesion molecules on endothelial cells. IL-i3 does not exhibit an autocrine affect and therefore has no direct action on the T cells. However, by inhibiting the production of IL-i2 and IFNg, IL-i3 may indirectly prevent the active development of the Thi lymphocyte pathway. Use of IL-i3 in uveitis therapy was studied in a monkey model of EAU. At the onset of EAU in monkey, IL-i3 was injected subcutaneously once a day for 28 days [28]. Dramatic improvement of the inflammatory signs of uveitis was observed in the IL-i3 treated group as compared to the controls. This study suggests a potential therapeutic role for IL-i3.

Thi and Th2 cytokines have been implicated in pathogenesis, recovery, and resistance of EAU. Many experimental evidences point to an important role of a Thi type response in the pathogenesis of autoimmune uveitis. However, the Th2 type response may contribute to the spontaneous termination of EAU and resistance to autoimmune response. New approaches for the immunotherapy of inflammatory autoimmune disease are based on the observations in these experimental systems in which polarization of the pathogenic Thi response towards an immunosuppressive, Th2 response is beneficial in disease prevention or reduction.

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