Effects of timing and dose of vitamin A on tissue retinol concentrations and antibody production in the previously vitamin A-depleted rats.

The effect of retinol repletion in previously vitamin A-depleted Lewis rats on antibody production to pneumococcal polysaccharide (SSS-III) was studied. When vitamin A-depleted rats were given either 0.35 mumol (0.1 mg) or 5.2 mumol (1.5 mg) retinol, plasma retinol became normal within 8 h. Liver and lymphoid-organ retinol concentrations were normalized by 1 d after repletion with 5.2 mumol but not 0.35 mumol retinol. Antibody production to SSS-III was compared after administering 5.2 mumol retinol either as a divided dose (half given 4 d before and half given on the day of immunization) or as a single dose concurrent with immunization. Vitamin A-depleted rats produced very little SSS-III-specific antibody. The divided dose of retinol consistently restored anti-SSS-III production whereas the single concurrent dose was less effective despite equal effects on tissue retinol concentrations. Interestingly, normalization of plasma retinol was not always a good predictor of the immune response to pneumococcal polysaccharide.

Vitamin A depletion and repletion: effects on antibody response to the capsular polysaccharide of Streptococcus pneumoniae, type III (SSS-III).

To determine the ability of young rats to produce antibody against pneumococcal polysaccharide (SSS-III), weaning rats were fed a semipurified diet containing no retinol (A-) or 4 micrograms retinol/g diet (A+). Splenic antibody response specific to SSS-III was 17% (p less than or equal to 0.05) of control for A- Sprague-Dawley rats; similarly, the response of retinol-depleted Lewis rats was 22% (p less than or equal to 0.05) of pair-fed controls. No kinetic differences were observed in the antibody response between A- and control Lewis rats. Retinol depletion more markedly reduced the antibody response of male rats than female rats despite equally low tissue retinol concentrations. For both strains, retinol repletion near the time of immunization normalized antibody production. When male Lewis rats were fed the A- diet longer, the antibody response of A- rats was only 3% of pair-fed controls; repletion again normalized antibody production. Thus, retinol supplementation near the time of immunization can restore the immune response in previously compromised A- rats.

Effects of food or nutrient restriction on milk vitamin A transfer and neonatal vitamin A stores in the rat.

We have investigated the effects of maternal diets low in fat or protein, or restricted in total food intake on vitamin A transfer from the dam to her pups. When animals were fed on diets moderately restricted in fat or protein, minimal differences in milk, serum, and liver vitamin A concentrations were observed compared with animals fed on a control diet. In a second study, dams were fed on diets more severely restricted in protein, or fat, or both, or were fed on a control diet equal to 50% of the intake of control rats but containing an equal amount of vitamin A. The quantity of milk obtained from these more severely restricted dams' nipples or the pups' stomachs was greatly reduced; however, there were no differences in milk vitamin A concentration. Body-weight, liver weight, and total liver vitamin A stores of undernourished pups were just half those measured for control pups, although serum vitamin A and serum retinol-binding protein were nearly normal in concentration. We conclude that (a) moderate restrictions in fat or protein in the maternal diet are insufficient to affect transfer of vitamin A to the suckling pup; (b) further dietary restrictions could cause decreased milk production with little change in milk vitamin A concentration and, hence, (c) the neonates' hepatic retinol accumulation during the suckling period is markedly reduced when maternal diets are severely deficient in fat or protein or of normal composition but restricted in amount.

Vitamin A status and the immune response to pneumococcal polysaccharide: effects of age and early stages of retinol deficiency in rats.

Production of antibodies to pneumococcal polysaccharide from Streptococcus pneumoniae, type III was determined in young rats at different ages and stages of vitamin A deficiency. At 30, 35 and 45 d of age, serum retinol concentrations of vitamin A-depleted rats were 46, 35 and 9%, respectively, of the serum retinol concentrations of pair-fed controls. Specific antibody production was low at 30 d of age for both vitamin A-depleted rats and control rats. Between 30 and 45 d of age, antibody production increased considerably in normal rats; however, the response of vitamin A-depleted rats was only 22% (P less than or equal to 0.001) that of controls at 35 d of age and 8% that of controls (P less than or equal to 0.001) for 45-d-old rats. Lymphocyte populations were examined by flow cytometry. The numbers of immunoglobulin M- and immunoglobulin D-positive cells changed with age, but not as a result of dietary treatment. The numbers of total T cells or helper and suppressor T cell subsets did not differ with age or with vitamin A status. These studies showed that the normal antibody response to pneumococcal polysaccharide develops rapidly after 30 d of age in the rat, that this antibody response is impaired even during the early stages of vitamin A deficiency, and that impaired antibody production does not seem to be accompanied by quantitative differences in splenic lymphocyte populations.

The antibody response of vitamin A-deficient rats to pneumococcal polysaccharide is enhanced through coimmunization with lipopolysaccharide.

Although the antibody response of vitamin A-deficient rats immunized with pneumococcal polysaccharide (SSS-III) was barely detectable, coimmunization with SSS-III plus 2 or 20 micrograms of Pseudomonas aeruginosa lipopolysaccharide (LPS) resulted in an anti-SSS-III response that was equal to or greater than that of vitamin A-sufficient rats immunized only with SSS-III. Doses of 2 and 20 micrograms of LPS, but not 0.1 and 0.5 micrograms, produced significant adjuvanticity, and LPS functioned as an adjuvant when given concomitantly with SSS-III (day 0) or up to 3 days later. Thus, vitamin A deficiency per se does not preclude the anti-SSS-III response, and LPS or factors released in response to LPS, even after initiation of the response to SSS-III, may substantially enhance antibody production to this thymus-independent, type 2 antigen.

Acute renal failure after intravenous immunoglobulin therapy.

We describe 3 patients given intravenous immunoglobulin (IVIG) who developed acute renal failure temporally related to IVIG therapy. The rise in BUN and creatinine appeared to be transient and reversible 8-14 days after discontinuation of the drug. Renal dysfunction was mild in 2 patients but was severe in one who presented with azotemia, worsening congestive heart failure, severe hyponatremia, hyperkalemia, and metabolic acidosis necessitating hemodialysis. Renal dysfunction was not associated with a specific immunoglobulin preparation or dose.

Immunological memory to tetanus toxoid is established and maintained in the vitamin A-depleted rat.

We have previously shown that vitamin A deficiency severely impairs the young rat's ability to produce specific antibodies after primary immunization with tetanus toxoid (TT). In the present studies, we asked whether immunologic memory to TT is established even in the vitamin A-depleted animal, and if so, whether such memory can be elicited after subsequent repletion with retinol. Vitamin A-depleted rats produced very low concentrations of TT-specific IgM and IgG antibodies in both the primary and secondary responses; however, the ratios of secondary to primary IgM anti-TT and of IgG anti-TT were normal. When rats were repleted with retinol 1 day after immunization, IgM and IgG anti-TT concentrations in both the primary and secondary responses were at least as great as those of control rats. For rats repleted with retinol 2 days before the booster immunization, secondary IgM and IgG anti-TT concentrations were equal in magnitude to those of vitamin A-sufficient controls. For all groups, the kinetics of the antibody response were similar. We conclude that immunological memory is intact in the vitamin A-depleted animal, as shown by 1) the normal ratio of its secondary to primary antibody responses, 2) the restoration of a quantitatively normal secondary antibody response in previously vitamin A-depleted animals repleted with retinol just before boosting with TT, and 3) a normal class switch from IgM to IgG. Retinol deficiency is also characterized by an abnormal elevation of total plasma IgG, despite the inability of the vitamin A-depleted animal to produce normal quantities of specific antibodies after challenge with antigen.

Antibody production in vitamin A-depleted rats is impaired after immunization with bacterial polysaccharide or protein antigens.

Vitamin A nutritional status has been implicated as important in maintaining the integrity of immune functions. We have determined the effect of vitamin A (retinol) depletion on the ability of young animals to produce antibodies after challenge with various bacterial antigens. Male Lewis rats raised on vitamin A-free or adequate diets were immunized either near 40 days of age, before signs of vitamin A deficiency were apparent, or near 47 days of age when symptoms of deficiency were beginning to be manifest. For rats immunized with polysaccharide antigens from Streptococcus pneumoniae or Neisseria meningitidis, antibody production did not exceed 0-19% of the response of control rats. Vitamin A depletion also severely compromised the response to two T cell-dependent antigens, tetanus toxoid and sheep red blood cells. In striking contrast, retinol-depleted rats immunized with lipopolysaccharides from Pseudomonas aeruginosa and Serratia marcesens produced an antibody response indistinguishable from retinol-sufficient animals. These lipopolysaccharides could elicit antibodies in rat pups, whereas the capsular polysaccharide antigens could not. This is consistent with the characteristics of type 1 and type 2 antigens, respectively. These studies indicate that retinol status is an important determinant of the humoral immune response to certain types of antigen and suggest that antibody production to capsular polysaccharides and T cell-dependent antigens is particularly dependent on adequate retinol status.

Vitamin A deficiency decreases natural killer cell activity and interferon production in rats.

We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interferon (IFN) production. Rats were weaned at 16 or 21 d of age onto semisynthetic diets containing either 0 or 4 micrograms retinol/g diet. At the time of study, retinol-depleted rats had serum vitamin A concentrations less than 7% of those of pair-fed controls. In two studies, rats exhibited no external signs of retinol deficiency, but with further depletion some symptoms were observed. Splenic NK cell activity against chromium-51-labeled YAC-1 cells was significantly decreased in vitamin A-depleted rats (22-80% of values for control rats, depending on the degree of retinol deficiency), regardless of the ratio of effector to target cells used. When vitamin A-depleted rats were repleted orally with retinol, NK cell activity was consistently normalized. To understand the possible mechanisms involved in decreasing NK cell activity, we investigated IFN production by concanavalin A-stimulated spleen cells from vitamin A-depleted, from repleted and from control animals. IFN titers were significantly decreased (22-33% of values for control rats) in supernatants of spleen cell cultures of the vitamin A-depleted rats. Repletion with vitamin A resulted in IFN activities ranging from 80 to 130% of controls. Adding alpha/beta IFN in vitro to the spleen cells of vitamin A-depleted animals increased their NK cell activity. The number of spleen cells reacting with a monoclonal antibody specific for rat NK cells was slightly lower in retinol-depleted rats, but not enough to account for the differences in NK cell and IFN activities. These data suggest that vitamin A deficiency affect the nonspecific arm of the immune system, possibly by altering the functional capacity of cells to produce lymphokines needed for the generation of an appropriate cytolytic response.