The role of B cells and alloantibody in chronic cardiac allograft rejection

Increasingly effective methods of preventing and treating rejection in cardiac transplant recipients have increased patient survival, but graft loss due to chronic rejection remains a barrier to long-term graft survival. Immunosuppressive regimens that currently focus on targeting T cells have decreased the amount of graft loss due to acute cellular rejection, however, rejection due to antibody mediated processes remains. Although the presence of B cells and plasma cells has been characterized in kidney transplants, their presence had not previously been described in human cardiac transplants. We have characterized the prevalence and patterns of distribution of B cells and plasma cells in human cardiac transplants with chronic rejection. In our study, we evaluated 16 cardiac allografts removed at retransplant because of chronic rejection. We found that B cells and plasma cells were a consistent finding in and around coronary arteries with chronic rejection. Many of the infiltrates formed nodules, some of which had distinct compartmentalization similar to tertiary lymphoid nodules. The frequency of B cells and plasma cells within and surrounding vessels with allograft vasculopathy was significantly higher than in coronaries with native atherosclerosis or surgical procedures.We extended our findings in humans to develop a mouse model where the role and interactions of B cells, T cells, and alloantibodies could be tested. We have developed a SCID mouse model where minimal numbers of T cells can be transferred with larger populations of B cells or monoclonal alloantibodies. The transfer of CD4 T cells resulted in the maximal T cell and macrophage infiltration into the graft and the greatest degree of vascular pathology. Surprisingly, the transfer of B cells or alloantibody with naive CD4 T cells dampened the infiltration and vascular damage to the graft. Our work suggests that B cells and alloantibody interact with T cells to modulate immune responses to cardiac allografts.