Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation.

摘要

Natural killer (NK) cells are key members ofudthe innate immune system. In a self-environment,udthey sense and kill target cells lackingudmajor histocompatibility complex class Iudmolecules and release various cytokines onudactivation. The discovery of human leukocyteudantigen (HLA) class I specific inhibitoryudreceptors (including the allotype-specificudkiller immunoglobulin-like receptors), andudof various activating receptors and theirudligands, provided the basis for understandingudthe molecular mechanism of NK-celludactivation and function, mainly resultingudfrom the balance between activating andudinhibitory signals. In an allogeneic setting,udsuchasTcell–depleted haploidenticalhematopoieticudstem cell transplantation, NK cellsudmay express inhibitory killer immunoglobulin-udlike receptors that are not engaged byudany of the HLA class I alleles present onudallogeneic cells.Such“alloreactive”NKcellsudgreatly contribute both to eradication ofudleukemia blasts escaping the preparativeudregimen and to clearance of residual hostuddendritic cells and T lymphocytes (thusudpreventing graft-versus-host disease andudgraft rejection, respectively). Improvedudprevention of graft-versus-host diseaseudmight be achieved by redirecting to lymphudnodes adoptively transferred, alloreactiveudNK cells by inducing CCR7-uptake inudvitro. Recent studies suggested that, afterudimmune-suppressive therapy, alloreactiveudNK cells from an HLA-haploidenticaluddonor may prevent leukemia recurrenceudalso in patients who have not receivedudallogeneic hematopoietic stem cell transplantation.