Augmentation of an antitumor CTL response in vivo by inhibition of suppressor macrophage nitric oxide

Evidence is provided that inhibition of macrophage NO production can augmen t in vivo CTL responses. Specifically, administration of NG-monomethyl-L-ar ginine (NGMMA) via osmotic pumps increases the tumor-specific CTL response against the P815 mastocytoma in the peritoneal cavity of preimmunized mice, Both the magnitude and duration of the CTL response were increased. That t he augmented CTL response resulted from inhibition of the NO synthase pathw ay is supported by the finding that macrophage NO production from NGMMA-tre ated mice was reduced, Also, in vitro inhibition of NO production by perito neal exudate cells from P815 tumor-challenged mice augmented the secondary CTL response observed. Cell proliferation was augmented by NGMMA in these c ultures, suggesting that macrophage NO may suppress CTL by inhibiting clona l expansion. NO-mediated inhibition was observed in vivo in this experiment al system, even though the CTL response is not suppressed, in that tumor re jection occurs. Therefore, the present results are consistent with the conc lusion that macrophage NO-mediated inhibition of the CTL response is a side effect of activating macrophages rather than resulting from the action of a distinct subset of what have long been termed suppressor macrophages. Mos t important, the results indicate that NO-mediated suppressor macrophage ac tivity can be an important CTL immunoregulatory element in vivo.