Innate immunity and cardiac allograft rejection

Abstract

The development of immunosuppressive drugs to control adaptive immune responses has led to the success of heart transplantation as a therapy for end-stage heart failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained clinical significance as mounting evidence now indicates that innate immune responses have important roles in the acute and chronic rejection of cardiac allografts including cardiac allograft vasculopathy (CAV). Whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and in the development of CAV. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection. Finally, new data indicate that activation of complement is linked to acute rejection and CAV. In summary, the conventional wisdom that the innate immune system is of little importance in whole-organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, and complement will be necessary to prevent CAV completely and to eventually achieve long-term tolerance to cardiac allografts.

Inflammation in Myocardial Diseases

“…160 Involvement of both natural killer (NK) cells, a class of cytotoxic lymphocytes, and macrophages during early phases posttransplant, as part of the nonadaptive/ innate immune response, has been demonstrated in in vivo studies. 177,178 In a rat heart transplant model, infiltration of recipient NK cells and macrophages can be observed as early as 3 hours posttransplant in the myocardial interstitial regions and allograft vessel endothelium; at 3 days post-transplant, a maximum number of NK cells and macrophage were found in the endo-, epi-, and myocardial portions of the wall of the transplanted heart. 177,178 This is typically followed by the infiltration of T-and B-cell populations in the endo-and subendomyocardial walls.…”

“…177,178 In a rat heart transplant model, infiltration of recipient NK cells and macrophages can be observed as early as 3 hours posttransplant in the myocardial interstitial regions and allograft vessel endothelium; at 3 days post-transplant, a maximum number of NK cells and macrophage were found in the endo-, epi-, and myocardial portions of the wall of the transplanted heart. 177,178 This is typically followed by the infiltration of T-and B-cell populations in the endo-and subendomyocardial walls. 177,178 In CD28 Ϫ/Ϫ mice heart transplant models (deficient of costimulatory signal; thought to be dependent on CD8ϩ T cell and NK cells-mediated effects to cause rejection), blockade of a NK cell-activating receptor (NKG2D) using anti-NKG2D monoclonal Ab prevented the occurrence of acute cardiac rejection.…”

“…177,178 This is typically followed by the infiltration of T-and B-cell populations in the endo-and subendomyocardial walls. 177,178 In CD28 Ϫ/Ϫ mice heart transplant models (deficient of costimulatory signal; thought to be dependent on CD8ϩ T cell and NK cells-mediated effects to cause rejection), blockade of a NK cell-activating receptor (NKG2D) using anti-NKG2D monoclonal Ab prevented the occurrence of acute cardiac rejection. 179 Based on this observation, it has been suggested that NK cells may mediate CD8ϩ T-cell proliferation, possibly via cytokine secretion or dendritic cell (DC) maturation promotion, and thereby contribute to the myocardial inflammation process, leading to acute cellular rejection.…”

“…179 Based on this observation, it has been suggested that NK cells may mediate CD8ϩ T-cell proliferation, possibly via cytokine secretion or dendritic cell (DC) maturation promotion, and thereby contribute to the myocardial inflammation process, leading to acute cellular rejection. 178,179 …”

“…194 In Addition to Complement-and Allo-Antibody-Mediated Pathways, Granzyme and Perforin Effector Pathways are also Considered Major Contributors to Myocardial Inflammation in the Context of Cardiac Rejection 165 Cellular infiltrates observed in EMBs of cardiac recipients undergoing acute cardiac allograft rejection include lymphocytes (primarily T cells and some NK cells), as well as macrophages. 160,178 Granzyme and perforin are considered key effector molecules of cytotoxic T cells and NK cells. Specifically, granzyme and perforin are critical components of cytotoxic granules, which are exocytosed by T cells and NK cells into the immune-target cell synapse on recognition of foreign cells.…”