Humoral immunity in chronic allograft rejection: puzzle pieces come together

Modern immunosuppressive armamentarium inadequately controls the humoral arm of recipient immune response, which in turn plays a central role in the pathogenesis of chronic rejection, a major cause of late allograft failure. A consensus sequence has progressively emerged from the integration of both experimental and clinical data, in which the binding of circulating donor-specific antibodies to mismatched HLA molecules expressed by graft microvasculature leads to chronic inflammation and progressive tissue destruction. Recent data suggest however that beyond their role in antibody production, B cells are also endowed with critical, yet overlooked, antibody-independent functions. Their abilities to present antigens and drive lymphoid neogenesis within rejected organ place them at the center of immune regulation with the power to enhance or inhibit antigraft immunity. The key challenges for the next few years will be to learn how these conceptual progresses can be translated into innovative B cell-targeting therapies to improve long-term allograft outcome.