Nitric oxide as a regulatory and effector molecule in the immune system.

Nitric oxide (NO) as a small ubiquitous molecule influencing a great variety of biological processes in the organism. Within the immune system, increased levels of NO were observed in various immunopathological situations, inflammatory reactions and during the response to transplantation and tumour antigens. It appears that NO can influence various facets of immune response. We studied involvement and the role of NO in immune response to skin allograft in mice. The production of NO at the site of graft rejection correlated well with the kinetic of rejection reaction and with the fate of the allograft. Graft infiltrating macrophages were identified as a principal cell population producing NO and the production of NO by macrophages was dependent on the presence of activated CD4(+) T cells. Survival of skin allografts was significantly prolonged by the treatment of graft recipients with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of inducible NO synthase (iNOS). These results suggest a role for NO as the effector cytotoxic molecule involved in the graft rejection. Experiments in vitro demonstrated that NO, in addition to its effector function, acts as a modulator of cytokine production. Spleen cells stimulated with alloantigens in the presence of AMT or S-ethylisothiourea (EIT), an another selective iNOS inhibitor, produced considerably more interleukin (IL)-4 and IL-10 than the cells stimulated in the absence of iNOS inhibitors. The production of Th1 cytokines IL-2 and interferon (IFN)-gamma was not enhanced by the inhibition of NO synthesis. The results altogether show that NO can act in transplantation reactions as an immunomodulator on cytokine production level and as an effector molecule involved in the graft destruction.