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.

• MeSH
• cytokiny biosyntéza   MeSH
• inhibitory enzymů farmakologie   MeSH
• kinetika MeSH
• kultivované buňky MeSH
• makrofágy imunologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• oxid dusnatý fyziologie   MeSH
• přežívání štěpu účinky léků   imunologie   MeSH
• rejekce štěpu imunologie   MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• T-lymfocyty - podskupiny účinky léků   imunologie   MeSH
• thiaziny farmakologie   MeSH
• transplantace kůže imunologie   MeSH
• transplantační tolerance MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine MeSH Prohlížeč
• cytokiny MeSH
• inhibitory enzymů MeSH
• Nos2 protein, mouse MeSH Prohlížeč
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého MeSH
• thiaziny MeSH

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin (IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase (iNOS), arginase, heme oxygenase-1 (HO-1) or indoleamine-2,3-dioxygenase (IDO), the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as iNOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules (NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

• Klíčová slova
• Arginase, Graft rejection, Immunoregulation, Macrophages, Nitric oxide, Th1/Th2 balance, Tolerance,
• Publikační typ
• časopisecké články MeSH