Effector Cells Derived from Host CD8 Memory T Cells Mediate Rapid Resistance against Minor Histocompatibility Antigen-Mismatched Allogeneic Marrow Grafts without Participation of Perforin, Fas Ligand, and the Simultaneous Inhibition of 3 Tumor Necrosis Factor Family Effector Pathways

摘要: Abstract Reduced-intensity conditioning regimens for transplant recipients have heightened awareness of immunologic resistance to allogeneic bone marrow transplants (BMT). Although T cell-mediated cytotoxicity has been assumed play a role in the against donor hematopoietic stem and progenitor cell grafts, several studies reported relatively unimpaired by who lack perforin, Fas ligand (FasL), other cytotoxic mediators. This study compared early kinetics B6 (H2b) cytotoxically normal versus deficient after transplantation with major histocompatibility complex-matched, minor antigen (MiHA)-mismatched grafts. Wild-type or double-deficient perforin−/−/gld+/+ (B6-cdd) mice were sensitized complex-matched BALB.B C3H.SW MiHA transplanted high dose (1 × 107) cell-depleted marrow. CD8 memory cells shown be present before BMT, anti-CD8 monoclonal antibody infusion abolished resistance, thus demonstrating that are host effector population. Donor-committed proliferative potential numbers markedly diminished 48 hours both wild-type B6-cdd anti-donor MiHA-sensitized recipients. These observations indicate pathway used was potent rapidly induced—consistent T-cell response. To examine Tumor necrosis factor-like weak inducer apoptosis (TWEAK)- TL1A-mediated this strong newly generated antibodies specific these ligands administered antigens. Recipients syngeneic B6-gfp exhibited significant colony-forming unit BMT. In contrast, low absent levels detected recipients, including those lacked perforin FasL received anti-TWEAK, anti-tumor factor-related apoptosis-inducing ligand, anti-TL1A antibodies. findings extend previous existence effected mediated independent 2 pathways cytotoxicity. Together findings, results support notion derived from populations can mediate MiHA-disparate engraftment using mechanism is contribution FasL, known death receptor pathways.