Anti-metastatic activity induced by the in vivo activation of purified protein derivative (PPD)-recognizing Th1 type CD4+ T cells.

The Th1 type Cd4+ T cell clone (MH2), which is capable of recognizing purified protein derivative from Mycobacterium tuberculosis (PPD), was examined for its anti-metastatic activity against melanoma. In using an in vitro proliferative assay, MH2 was able to recognize PPD-derived antigen in a major histocompatibility complex class II-restricted manner. MH2 showed neither any natural killer (NK) activity nor cytolytic activity against syngeneic B16 melanoma. This clone produced interferon-gamma, tumor necrosis factor and interleukin-2, but not interleukin-4, when co-cultured with PPD and irradiated syngeneic C57BL/6 spleen cells, suggesting that this clone could thus be assigned to the Th1 subset. An intraperitoneal (i.p.) co-injection of 2 x 10(6) MH2 and 50 micrograms PPD increased the NK activity of the peritoneal exudate cells (PEC) and the percentage of NK1.1+ cells in the PEC. These activated NK cells showed a low but significantly cytolytic activity against B16 melanoma. The augmented NK activity induced by the co-injection of MH2 and PPD was maintained by the weekly additional i.p. injections of PPD alone. Using a murine metastatic model, and i.p. co-injection of MH2 and PPD-induced anti-metastatic activity against B16 melanoma. This anti-metastatic activity was then abrogated by the in vivo administration of anti-asialo GM1 serum. In addition, the NK activity in both peripheral blood and metastatic lungs was significantly augmented in the mice which were co-injected with MH2 and PPD. Taken together, these findings indicate that the in vivo activation of Th1 type CD4+ T cells augmented the NK activity in vivo and thus could potentially be an efficient immunotherapeutic weapon against metastasis of melanoma. These results also imply that adoptive immunotherapy could induce anti-metastatic activity through cytokine production but not through any direct cytolytic activity.