In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances a T-dependent humoral immune response

Abstract

Metallothionein (MT) is a small stress response protein that can be induced by exposure to heavy metal cations, oxidative stressors, and acute phase cytokines that mediate inflammation. In previous experiments, we have shown that exogenous MT can affect cell proliferation, macrophage and cytotoxic T lymphocyte function, and humoral immunity to T-dependent antigens. In the studies described here, we have explored the effect of a monoclonal anti-MT antibody (clone UC1MT) on the role that endogenous MT plays in the humoral immune response. In vivo injection of UC1MT significantly increased the humoral response to simultaneous challenge with ovalbumin (OVA). In contrast, mice immunized with OVA in the presence of an isotype-matched antibody control (MOPC 21) showed no change in the anti-OVA humoral response. The predominant anti-OVA response that was enhanced by UC1MT treatment was the IgG(1) response; the IgG(2a) anti-OVA response was not altered by UC1MT treatment. UC1MT treatment increased the numbers of IgG anti-OVA secreting cells as measured by ELISPOT assay, suggesting that blocking the effects of MT synthesized during the immune response augments the differentiation of antigen-specific plasma cells. The percentages of T and B cells in the spleens of animals from each treatment group were not significantly different, suggesting that this regimen of UC1MT treatment does not significantly affect hematopoiesis, but rather alters antigen-induced differentiation of lymphocytes. These observations are compatible with previous results from our laboratory that suggest that endogenous MT synthesized during the normal immune response or as a consequence of toxicant exposure suppresses in vivo immune function. In light of the fact that significant amounts of MT can be synthesized during toxicant exposure, manipulation of MT levels with an anti-MT antibody may ultimately represent an important therapeutic approach to the treatment of immune dysfunctions that result from toxicant exposure.