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 augment in vivo CTL responses. Specifically, administration of NG-monomethyl-l -arginine (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 the augmented CTL response resulted from inhibition of the NO synthase pathway is supported by the finding that macrophage NO production from NGMMA-treated mice was reduced. Also, in vitro inhibition of NO production by peritoneal exudate cells from P815 tumor-challenged mice augmented the secondary CTL response observed. Cell proliferation was augmented by NGMMA in these cultures, suggesting that macrophage NO may suppress CTL by inhibiting clonal expansion. NO-mediated inhibition was observed in vivo in this experimental system, even though the CTL response is not suppressed, in that tumor rejection occurs. Therefore, the present results are consistent with the conclusion 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. Most important, the results indicate that NO-mediated suppressor macrophage activity can be an important CTL immunoregulatory element in vivo.
Medot-Pirenne
M
M
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Heilman
M J
MJ
Saxena
M
M
McDermott
P E
PE
Mills
C D
CD
D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D012515:Mast-Cell Sarcoma / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014611:Vaccination; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase