Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28−/− mice

Abstract

Successful transplantation of allogeneic organs is an important objective in modern medicine. However, sophisticated immune defense mechanisms, primarily evolved to combat infections, often work against medical transplantation. To investigate the roles of natural and adaptive immune responses in transplant rejection, we functionally inactivated key effector systems of the innate (NK cells) and the adaptive immune system (CD28-mediated costimulation of T cells) in mice. Neither of these interventions alone led to acceptance of allogeneic vascularized cardiac grafts. In contrast, inhibition of NK-receptor-bearing cells combined with CD28-costimulation blockade established long-term graft acceptance. These results indicate a concerted interplay between innate and adaptive immune surveillance for graft rejection. Thus we suggest that inactivation of NK-receptor-bearing cells could be a new strategy for successful survival of solid-organ transplants.

Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection

“…However, despite the reduction in NK cell recruitment, allograft survival was not prolonged in the CX 3 CR1 -/-mice unless they were treated with low-dose CsA. This finding suggests that the NK cells act in concert with CsA-sensitive T cells to effect graft rejection and agrees nicely with the work of Maier et al (43), who found that CD28 -/-mice rejected cardiac allografts vigorously and that depletion of NK cells by injection of the Ab NK1.1 dramatically prolonged graft survival. These authors also reported that treatment of the CD28 -/-mice with CsA failed to prolong allograft survival and concluded that CsA did not abrogate NK cell function (43).…”

Immunosuppression for lung transplantation

“…Consequently, the transplant setting might represent a constant and powerful stimulus for NK-cell activation. NK-cell activation and elaboration of cytokines have been implicated in the pathogenesis of chronic allograft damage in a variety of solid organs (110). Inhibition of the mammalian target of rapamycin (mTOR) may mitigate the development of these conditions (111).…”

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

“…Cytokines in cell-free supernatants were quantified by ELISA using Ab pairs for TNF, IL-2, IL-1␤, IL-1R antagonist (IL-1ra), 3 and IFN-␥ (Endogen, Munich, Germany) as well as human rTNF (Bender, Vienna, Austria), IL-1␤, IL-1ra, IL-2, and IFN-␥ (Endogen) standards as previously described (24).…”

“…Indeed, a broad range of potential sources of infection as well as the adverse effects of antimicrobial drugs used for prophylaxis and therapy represent important challenges to overcome (2). A concerted interplay between innate and adaptive immune surveillance for graft rejection has been indicated (3). A robust innate immune response, characterized by macrophage infiltration and up-regulation of multiple cytokines, chemokines, and chemokine receptors, has been demonstrated within the first day after transplantation in an alymphoid murine model.…”