Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo lymphocyte responses
Panush, R.S.; Delafuente, J.C.; Katz, P.; Johnson, J.
International Journal for Vitamin and Nutrition Research. Suppl 23: 35-47
1982
PMID: 6288604 Document Number: 5506
We have identified immunopotentiation of certain in vitro and in vivo cellular immune responses by vitamin C and considered possible mechanisms of these phenomena. Enhancement was related to time and duration of exposure to vitamin C. Enhancement was most pronounced for PEVM but was also noted _for other mitogens, antigens, and allogeneic PBL, suggesting possible subpopulation specificity as well as direct effects of vitamin C on responding cells. We next reported that vitamin C, at physiologic serum concentrations in vitro, significantly augmented concanavalin (con) a-stimulated PBL DNA synthesis in dose-response fashion under similar conditions. These observations described a heretofore unrecognized immunoenhancing effect of vitamin C in man and provided a useful in vitro model for examining pharmacologic augmentation of lymphocyte responses. We then examined cultured human IM9 (B-lvmphoblastoid) cells as responders rather than fresh PBL. Vitamin C consistently enhanced IM9 proliferation at experimental conditions of 10 µg/m1 vitamin C, 105 IM9 cells/m1, 24-72 h of culture, and 1.0 1.1Ci 3HTdR/culture. This enormously simplified our in vitro model system. To determine whether in vitro addition of vitamin C could normalize responses of PBL from patients with subnormal responses, we compared mitogen-stimulated normal with rheumatoid arthritis (RA) PBL with and without vitamin C. Responses of both groups improved comparably. We next investigated in vivo effects of vitamin C. Under certain conditions oral ingestion of vitamin C improved in vitro PBL responses to mitogens. Specifically, (i) responses to PWM were increased during ingestion of 1 or 3 g of vitamin C qd × 7 days and immediately after ingestion of 1 g of vitamin C qd; (ii) following ingestion of 3 g vitamin C qd responses rebounded to lower than control levels. However, (iii) ingestion (6.10 g vitamin C daily caused no effect on in vitro con a-stimulated responses. Along with in vitro lymphocyte studies, we also measured serum, leukocyte, and lymphocyte levels of vitamin C. To our knowledge, lymphocyte ascorbic acid levels have not previously been documented. As expected, (iv) plasma levels of vitamin C increased during ingestion of drug but cellular levels did not. (v) No correlations were noted between plasma levels and in vitro cellular responses. We also investigated the effects of vitamin C (10 g qd × 7 days) ingestion by normal individuals on cellular immunity as manifested by delayed-type hypersensitivity skin testing to antigens. (vi) Increased reactivity to antigens followed vitamin C ingestion. (vii) Also, cutaneous reactivity was significantly enhanced by administering antigens containing vitamin C (10 µg/m1). (viii) Patients with Chediak-Higashi syndrome, with deficient natural killer cell fiinction, normalized killing while taking 6-8 g qd vitamin C. We considered several possible mechanisms for the immunoenhancing effect of vitamin C. Vitamin C did not (i) induce the in vitro release of other soluble substances by PBL which in turn enhanced responses ofot her cells, or (ii) alter mitogen binding or receptors, for phytomitogen on PBL. (iii,) That the effects of vitamin C were not merely nutritional was suggested by the findings that congeners of vitamin C (D-, L-, dehydroascorbic acid and sodium ascorbate) all exhibited comparable effects on normal lymphocytes. (iv) Vitamin C immunoenhancement was not mediated by monocytes. (v) We considered that vitamin C may act as an enhancing agent by abrogating suppressor cell function or suppressor signals, thereby augmenting cultured cell responses. To the contrary, induction of suppressor cell function was enhanced in the presence of vitamin C. (vi) Lastly, data suggested that vitamin C increased PBL cyclic GMP levels. Thus, all of these observations suggest that ascorbic acid acts directly upon cells, possibly through pathways mediated by cyclic nucleotides.
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