Immune stimulatory properties of metalloporphyrins.

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Abstract
A possible approach to the immunotherapy of tumors is to stimulate either specific or nonspecific immune responses in vivo. We recently found that provision of a mitogenic signal to PBMC, by incubation with the oxidizing mitogens, enhanced the effect of IL-2 in generating cytolytic activity. We therefore searched for a mitogen that might safely be administered to patients. The present study is an investigation of the mitogenic properties of iron and tin (Sn)-protoporphyrin and their capacity to induce cytotoxicity in human PBMC. These agents have been administered to humans with little toxicity. Both iron- (hemin) and Sn-protoporphyrin induce mitogenicity in peripheral T cells. This effect is markedly enhanced by low concentrations of IL-2. Hemin and Sn-protoporphyrin, in combination with IL-2, increase IL-2R on PBMC. Hemin alone, and to a greater extent in combination with IL-2, induces cytotoxicity for NK-sensitive and NK-resistant cell lines. Sn-protoporphyrin, a more potent mitogen than hemin, fails to induce cytotoxicity, and has a marked inhibitory effect on cytotoxicity induced by IL-2. Hemin and Sn-protoporphyrin stimulate TNF-alpha and IFN-gamma production by PBMC. IL-2 is synergistic with the metalloporphyrins in eliciting this effect. Metalloporphyrin-induced mitogenesis has a stringent requirement for macrophages. Scavengers of oxygen-free radicals and inhibitors of peroxidase inhibit mitogenicity induced by hemin but not that induced by Sn-protoporphyrin. Hence, an oxidative event may mediate the mitogenic effect of hemin. Our results indicate that hemin is an immunostimulatory agent in vitro and the data warrant further evaluation of its in vivo immunostimulatory and antitumor effect.