Neonatal-age treatment with vitamin A delays postweaning vitamin A deficiency and increases the antibody response to T-cell dependent antigens in young adult rats fed a vitamin A-deficient diet

Abstract

Vitamin A supplementation for infants and young children is recommended by WHO/UNICEF for countries with a high prevalence of vitamin A deficiency, and vitamin A is often administered at immunization contacts. Using a rat model, we tested whether supplementation with vitamin A or other retinoids at the time of neonatal immunization has prospective benefit in terms of preventing postweaning vitamin A deficiency and promoting antibody responses to T-cell dependent (TD) antigens administered at the neonatal stage and at the young adult stage. Rats were treated orally on postnatal d 6-8 with oil (placebo control), vitamin A, retinoic acid, or a combination of both (VARA) (n > or = 12/group), and immunized with tetanus toxoid (TT) on d 7. The primary anti-TT response was measured on d 21, after which weanling rats were fed the vitamin A-deficient diet until approximately 10 wk. At 8 wk, rats were immunized again with TT to determine the recall response, and with a novel TD antigen, keyhole limpet hemocyanin (KLH), to assess the adult primary response. None of the supplements affected the plasma titer of anti-TT immunoglobulin G (IgG) on d 21 (P = 0.25). However, neonatal-age supplementation with vitamin A or VARA at the young adult stage resulted in: >5 times higher anti-TT IgG recall response (P < 0.01); 5- and 9-times higher anti-KLH primary IgM and IgG responses, respectively (P < 0.05), and plasma retinol in the normal range (approximately 1.0 micromol/L vs. approximately 0.35 micromol/L in retinoic acid-treated and control groups, P < 0.0001). We conclude that early-life supplementation with vitamin A or VARA can prospectively benefit the primary and recall antibody responses to TD antigens administered at the young adult stage, which may involve the maintenance of normal plasma retinol levels.

FIGURE 1

Schematic of study design. VA, vitamin A, Ab, antibody; Ag, antigen; 1°, primary; 2° secondary. Closed arrows indicate days of neonatal supplementation (d 6–8), closed triangles indicate times of immunization, and open upward arrows indicate times of blood collection. The dashed line indicates the duration of the experimental diet, either vitamin A-deficient or vitamin A-adequate.

FIGURE 2

Neonatal supplementation with vitamin A or VARA increases the secondary antibody response to TT in rats fed vitamin A-deficient diet after weaning. Values are means ± SEM, n = 12/group (A, B, and C). Groups with superscripts with different letters differ, P < 0.01 (B and C). Primary anti-TT IgG titer assayed 14 d after primary immunization with TT on d 7 (A). Secondary (recall) anti-TT IgG titer (B). Ratio of secondary to primary anti-TT IgG titer (C). Correlation between the primary and secondary anti-TT IgG titer, tested for all rats, n = 61, (D).

FIGURE 3

Vitamin A supplementation at the neonatal age increases the young-adult–age primary response to a novel T-cell dependent antigen, KLH, in rats fed vitamin A-deficient diet. The KLH antibody response [anti-KLH IgM (A) and anti-KLH IgG, not shown] was measured 10 d after primary immunization at 8 wk of age (A). Values are means ± SEM, n = 6/group. Groups with superscripts with different letters differ, P < 0.05. Correlation of the primary anti-KLH IgG response with the secondary anti-TT IgG, both at young adult age (B).

FIGURE 4

Supplementation at the neonatal age maintains plasma retinol concentration of young adult rats fed vitamin A-deficient diet, which is correlated with the adult-stage antibody response. Plasma retinol was measured in young adult rats ≈9 wk of age (A). Values are means ± SEM, n = 12/group. Groups with superscripts with different letters differ, P ≤ 0.0001. Correlation of primary anti-KLH IgM titer at young adult age with plasma retinol (B).