As the review above indicates, currently there is only scattered evidence for a positive effect on VA on antibody production in children, whereas, in animals, the evidence for a positive effect of VA in VA-deficient animals, and of RA, in both VA-deficient and VA-sufficient animals, is quite consistent. Several factors could possibly account for these differences and each should be considered including: species differences; the VA status of the host at the time of immunization; the timing of the dose; and the nature of the vaccine or antigen administered.
Although species differences are possible, it seems unlikely that humans and rodents differ in a fundamental way in their response to VA, or to vaccination, because these species are similar in their transport and metabolism of VA, they have mostly similar lymphocyte populations, and many of their genes are homologous.
The VA status of the host at the time of immunization could be a factor, as most animal studies of VA deficiency have been conducted after the animals have reached a state of nearly complete depletion of retinol, with low serum retinol (typically <0.2 mmol/L) and exhaustion of liver VA reserves. In the human studies, VA deficiency has been defined at a higher level of serum retinol (as high as <0.7 mmol/L), and mostly healthy, and often breast fed, children have been studied. It is therefore possible that an effect of VA supplementation on antibody production in children was not apparent in most of the studies because the VA status of the children enrolled was not low enough for differences between the VA-supplemented and placebo groups to have been discerned. This interpretation is supported by the results of an earlier animal study in VA-adequate neonatal rats in which VA supplementation neither increased nor decreased the anti-tetanus antibody response, although it was evident that the neonates responded to the immunization and produced a memory response (Gardner and Ross, 1995). It is interesting that the study of Bahl et al. (2002), in which 6-month-old children from a community with a high prevalence of low serum VA were immunized with OPV, showed a significant effect of VA for serum titers against OPV type 1. The VA status of these children may have been more tenuous than that of children in other studies where VA supplementation was given with immunization and the antibody response was measured.
The timing of the dose may also be a significant factor. In most of the human studies of VA and immunization, and in the WHO/EPI (World Health Organization, 1994) strategy for using immunization contacts to deliver VA and eliminate VA deficiency, VA has been, or is, administered at high dosage on a periodic basis. In animal studies, VA has been incorporated at a higher than usual level into the diet (Cui et al., 2000), or if provided as an oral supplement, usually given more than once. These differences may be significant because, although a single large dose of VA can quickly restore plasma retinol to a normal level and replenish liver reserves, it does not provide VA continuously for absorption from the intestines. In comparison, a diet enriched in VA, or oral VA supplements given in smaller divided doses, would not only restore plasma retinol to a normal level and replenish liver reserves but would also provide retinol substrate for formation of retinyl esters in the intestine, which are released bound to chylomicrons. VA is also, to some extent, oxidized to RA in the intestines. While most chylomicron-associated retinyl ester is taken up by the liver, a proportion of the newly absorbed chylomicron retinyl ester is taken up into extrahepatic tissues, especially tissues that express lipoprotein lipase and are active in the metabolism of chylomicron triglycerides. Additionally, some of the newly absorbed VA is oxidized in the intestine and absorbed as RA into the portal system (Ross, 2006). Newly absorbed VA and intestinally formed metabolites may have a metabolic fate different from that of retinol bound to retinol-binding protein. It was shown in studies of chylomicron metabolism that chylomicron-associated VA is taken up, in an apparently transient manner, by bone marrow (Hussain et al., 1989a,b). However, the implications of this uptake process for hematopoiesis and immune function have not been studied. It is also interesting that, among several large-scale community trials on the effect of VA on child mortality, the study showing the largest reduction in all-cause mortality, 54% (Rahmathullah et al., 1990), delivered VA as a weekly dose at a level near the recommended dietary allowance. This reduction in mortality was more than twice the average reduction of 23% for eight studies combined (Beaton et al., 1994), most of which delivered VA to children as periodic large-dose supplements. The delivery of VA as periodic supplements using vaccination contacts is convenient, but it may be that smaller, more frequent doses, or dietary improvement (Underwood and Smitasiri, 1999), provide benefits that are missed with larger infrequent doses.
Another difference between the human and animal studies that could be important is the form of the immunizing dose. The goal of experiments in animals is to demonstrate potential effects and mechanisms, and thus studies are often designed to optimize the researcher's ability to discriminate differences. In most of the animal studies of VA and immunity, the immunizing dose has been provided without additional adjuvants. In contrast, vaccines for humans have undergone optimization to safely produce strong antibody responses, and most contain proprietary or known adjuvants (Beverley, 2002; Del Giudice, 2003). It thus may be that the vaccines used in human studies already contain enough extra "help," due to the adjuvants they contain, to promote a strong antibody response. In animals, the addition of bacterial LPS, TNF-a (Arora and Ross, 1994), or PIC (DeCicco et al., 2001, 2000; Ma and Ross, 2005; Ma et al., 2005) significantly increased antibody production in both VA-deficient and VA-adequate animal models, and also reduced the difference in antibody response due to differences in VA status. In the study of antibody production in children immunized with OPV, it is interesting that percentage seroconversion was high for OPV types 2 and 3 (Bahl et al., 2002), even in children who did not receive VA, while VA increased the response to OPV type 1, for which the rate of seroconversion was the lowest. Similarly, the seroconversion response to measles immunization was relatively low, and in this study VA was effective in at least some subgroups of children (Benn et al., 1997), and may have promoted protection over a longer period of time (Benn et al., 2002). If some vaccines promote a strong response regardless of VA, this may explain why an effect of VA was not consistently evident in all studies. Therefore, it may be that the experimental animal models correctly predict the positive impact of VA on antibody production, but that this impact is only evident in children if the response to the vaccine is not already strong.
Treating animals with RA provides another way to explore the impact of VA on the immune system. The model is also relevant to the human condition because RA and other retinoids, due to their ability to induce cell differentiation, are used therapeutically in the treatment of leukemias, other cancers, and dermatological diseases (Altucci and Gronemeyer, 2001). In animals given RA, rather than VA itself, the physiological controls that otherwise regulate and limit the conversion of VA to RA are bypassed. The results of several animal studies have demonstrated the potential of RA, at a well-tolerated therapeutic level, to augment antibody production. Therefore, these results suggest that RA could be useful in the treatment of some forms of immunodeficiency. The tendency of VA and RA to promote Th2/type 2 responses may be beneficial in the response to certain types of pathogens and infectious diseases, but not to others. However, when RA is combined with other agents, such as PIC, that promote a Thl/type 1 response, a higher and well-balanced antibody response can be achieved. These results suggest that combination therapies in which RA is coadminis-tered with other immune stimuli could offer a range of possibilities for modulating the magnitude and the type of antibody response elicited by various vaccines.
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