Vitamin A supplementation and retinoic acid treatment in the regulation of antibody responses in vivo

Abstract

Vitamin A (VA, retinol) is essential for normal immune system maturation, but the effect of VA(1) on antibody production, the hallmark of successful vaccination, is still not well understood. In countries where VA deficiency is a public health problem, many children worldwide are now receiving VA along with immunizations against poliovirus, measles, diphtheria, pertussis, and tetanus. The primary goal has been to provide enough VA to protect against the development of VA deficiency for a period of 4-6 months. However, it is also possible that VA might promote the vaccine antibody response. Several community studies, generally of small size, have been conducted in children supplemented with VA at the time of immunization, as promoted by the World Health Organization/UNICEF. However, only a few studies have reported differences in antibody titers or seroconversion rates due to VA. However, VA status was not directly assessed, and in some communities children were often breast fed, another strategy for preventing VA deficiency. Some of the vaccines used induced a high rate of seroconversion, even without VA. In children likely to have been VA deficient, oral polio vaccine seroconversion rate was increased by VA. In animal models, where VA status was controlled and VA deficiency confirmed, the antibody response to T-cell-dependent (TD) and polysaccharide antigens was significantly reduced, congruent with other defects in innate and adaptive immunity. Moreover, the active metabolite of VA, retinoic acid (RA) can potentiate antibody production to TD antigens in normal adult and neonatal animals. We speculate that numerous animal studies have correctly identified VA deficiency as a risk factor for low antibody production. A lack of effect of VA in human studies could be due to a low rate of VA deficiency in the populations studied or low sample numbers. The ability to detect differences in antibody response may also depend on the vaccine-adjuvant combination used. Future studies of VA supplementation and immunization should include assessment of VA status and a sufficiently large sample size. It would also be worthwhile to test the effect of neonatal VA supplementation on the response to immunization given after 6 months to 1 year of age, as VA supplementation, by preventing the onset of VA deficiency, may improve the response to immunizations given later on.

Figure 1

Primary and secondary (memory) anti-tetanus antibody responses of adult (A, B) and neonatal (C,D) mice treated at the time of initial dose (priming) with retinoic acid (RA, given orally), polyriboinosinic acid: polyribocytidylic acid (PIC, i.p.), or both RA+PIC. For determination of the memory response, animals were re-immunized with tetanus toxoid without additional treatment with RA or PIC. Data from Ma et al., 2005 and Ma and Ross, 2005.

Figure 2

Innate immune cells in rats and mice are regulated by dietary VA and acute treatment with RA. In a study of long-term VA status (A, B), rats were fed either a VA-marginal, VA-adequate, or VA-supplemented diet from weaning until the age indicated (Young, 2-3 months old; Middle-Aged, 8-10 months old; Old, 18-22 months old). A. Natural Killer (NK) cells in peripheral blood were decreased in rats fed VA-marginal diet and increased in rats fed VA-supplemented diet, while age was also a factor for NK cell number. Data from Dawson et al., 1999. B. Natural Killer T-cells (NKT cells) in peripheral blood were regulated by diet in a reciprocal manner compared to NK cells; age was also a factor for NKT cells. Data from Dawson and Ross, 1999. The % of NKT cells was inversely correlated with the ratio of CD4:CD8 T cells in peripheral blood (not shown, Dawson and Ross, 1999). C. Neonatal mice were treated in a short-term (3 days after priming with tetanus toxoid) study with RA (days -1. 0, 1 and 2 before cells were analyzed on day 3), PIC (day 0 only) or both RA+PIC. Total NK1.1+ cells, CD3+NK1.1+ (NKT), and CD3-NK1.1+ (NK cells) were analyzed by flow cytometry after double staining with fluorescently-labeled anti-NK1.1 and anti-CD3 antibodies. Data from Ma and Ross, 2005.