Funkcionalne i imunofenotipske karakteristike NK ćelija regionalnih limfnih čvorova obolelih od melanoma i njihova in vitro aktivacija IL-2 i IL-15

Abstract

Melanom, maligni tumor melanocita, iako ima brojna imunogenicna svojstva, predstavlja tumor kože sa najvišom incidencom smrtnosti. Za anititumorsku imunost u melanomu posebno su znacajne celije prirodne ubice (NK celije), efektorske celije sistema uroene imunosti koje mogu neposredno da prepoznaju maligno transformisane celije i da ih liziraju citolitickim enzimima (perforin i granzimi) kao i da produkcijom citokina i hemokina regulišu adaptivnu i uroenu amtitumorsku imunost. NK celije su prisutne u mnogim tkivima i organima. Kod melanoma su uglavnom proucavane NK celije u perifernj krvi i u tumorskom tkivu, dok NK celije regionalnih limfnih cvorova (LC) obolelih nisu do sada ispitivane. NK celije su CD3-CD56+ i obuhvataju dve funkcionalno razlicite subpopulacije, imunoregulatornu, CD3-CD56sjajno+ i citotoksicnu, CD3-CD56potmulo+. Funkcija NK celija je regulisna balansom signala koji poticu od aktivacionih i inhibitornih NKcelijskih receptora. Aktivacioni receptori prepoznaju stresogene ligande na tumorskim celijama, dok inhibitorni ubilacki receptori slicni imunoglobulinima (engl. Immunoglobulin-like Killer Receptors, KIR) vezivanjem za MHC molekule klase I inhibiraju NK celijsku funkciju i pored toga omogucavaju toleranciju NK celija na celije sopstvenog organizma. NK celije su prisutne u T celijskoj zoni LC, gde se odvija njihovo sazrevanje i diferencijacija. U fiziološkim uslovima u LC perifernom cirkulacijom dospeva uglavnom nezrela (CD3-CD56sjajno+) NK celijska subpopulacija koja cini veci deo NK celijske populacije u mirujucim limfnim cvorovima. Pod uticajem endogenih citokina u LC ova subpopulacija sazreva u citotoksicnu CD3-CD56potmulo+ perforin+CD16+KIR+ subpopulaciju koja zatim napušta LC. U patološkim stanjima dolazi do povecane zastupljenosti CD16+KIR+ NK celija u reaktivnim LC što može biti posledica povecane produkcije citokina uroene imunosti od strane dendriticnih celija, kao i Th1 citokina od strane stimulisanih T celija antigenima u LC, kao i selektivne migracije CD16+KIR+ NK celija u LC...

Introduction: Melanoma, malignant neoplasm of melanocytes, despite of its immunogenicity is skin cancer with the highest mortality rate. In antitumor immunity im melanoma, natural killer (NK) cells as innate immune system effector cells play an important role as they are able to recognize malignantly transformed cells, lyse them by cytolitic enzymes (perforin and gramzymes) and also regulate adaptive and innate antitumor immunity by production of cytokines and chemokines. NK cells are present in many tissues and organs. In melanoma NK cells have been studied mostly in peripheral blood and in tumor tissue, while NK cells in regional lymph nodes (LN)s have not been investigated. NK cells are CD3-CD56+ and comprise two functionally distinct subsets, immunoregulatory, CD3-CD56bright+ and cytotoxic, CD3-CD56dim+. NK cell function is regulated by the balance of signals mediated by activating and inhibitory NK cell receptors. Activating receptors recognize stress induced ligands on tumor cells, while the inhibitory immunoglobulin-like killer receptors (KIR) by binding to MHC class I molecules inhibit NK cell function and enable self tolerance. NK cells are located mostly in T cell zone of LNs, where NK cell differentiation and maturation may occur. In physiological conditions, by peripheral circulation mostly immature CD3-CD56bright+ NK cell subset migrates to LNs and represents the majority of NK cell population in resting LNs. Endogenous cytokines in LN mediate maturation of this subset into cytotoxic CD3-CD56dim+ perforin+CD16+KIR+ subset that subsequently leaves LN. In pathological conditions, increase in CD16+KIR+ NK cell population in reactive LNs may be the consequence of increased production of innate immunity cytokines by dendritic cells, as well as Th1 cytokine production by antigen stimulated T cells in LNs, or selective migration of CD16+KIR+ NK cells into LNs...