Adenozin által okozott T limfocita diszfunkció szepszisben = The role of adenosine in septic T lymphocyte dysfunction

A projekt soran in vitro Th1/Th2 polarizacios rendszer, Th1 es Th2 iranyba differencialtnak tekinthető hibridoma sejtek, illetve in vivo immunizalassal nyert Th1 es Th2 sejtek felhasznalasaval, valamint A2A receptor specifikus agonista CGS21680, A2A specifikus antagonista ZM241385 es A2A KO allatok alkalmazasaval kimutattuk, hogy az A2A receptorok aktivaciojanak erős gatlo hatasa van mind a Th1, mind a Th2 sejtekre a limfocita aktivacio korai es kesői szakasza soran. Eredmenyeink alapjan a hatas hattereben a sejtek proliferaciojara kifejtett gatlas es a citokin termelesre mRNS szinten kifejtett kozvetlen gatlo hatas all. Emellett az adenozin fontos szerepet jatszik a T limfocitak szamara antigent bemutato makrofagok műkodesenek, kulonosen azok citokin termelesenek szabalyozasaban. A szabalyozas ebben az esetben is mar transzkripcios szinten ervenyesul. Vegezetul kimutattuk, hogy az adenozin T limfocitakra gyakorolt hatasa kiemelt jelentőseggel birhat bizonyos autoimmun hatterű betegsegekben, peldaul az 1-es tipusu diabeteszben, ahol a limfocitak citokin termelesenek gatlasan keresztul kivedheti a beta-sejtek pusztulasat. Az adenozinnak ezert a hatasaert elsősorban az A2B receptorok lehetnek felelősek, de az A1 es A3 receptorok is hozzajarulhatnak. A tovabbi előrehaladas az adenozin immunoszuppressziv hatasainak megerteseben segithet a gyulladasos, autoimmun es neoplasztikus betegsegeket celzo terapias megkozelitesek kifejleszteseben. | During this project, we demonstrated that A2A receptor activation has strong inhibitory actions on both Th1 and Th2 cells during early and late stages of lymphocyte activation using in vitro Th1/Th2 polarizing system, hybridomas differentiated towards Th1 and Th2 direction, and Th1 and Th2 cells gained from in vivo immunized mice as well as A2A receptor specific agonist CGS21680, A2A specific antagonist ZM241385 and A2A KO mice. Based on our results the inhibition of cell proliferation and the direct inhibitory effect on cytokine production at mRNA level are in the background of these effects of adenosine. Besides, adenosine has an important role in the regulation of function, especially cytokine production, of macrophages presenting antigens to T lymphocytes. In this case, the regulation also prevails at transcriptional level. Finally, we demonstrated that the effect of adenosine on lymphocytes may have special importance in certain autoimmune diseases such as diabetes type 1, where adenosine may prevent beta cell death through the inhibition of cytokine production of lymphocytes. Principally A2B receptors may be responsible for this effect of adenosine, but A1 and A3 receptors may contribute to this. Further advances in understanding the immunosuppressive effects of adenosine may help develop therapeutic approaches to target inflammatory, autoimmune, and neoplastic disorders.