Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection

Over the past three decades, improved immunosuppression has significantly reduced T cell–mediated acute rejection rates, but long‐term graft survival rates have seen only marginal improvement. The cause of late graft loss has been under intense investigation, and chronic antibody‐mediated rejection (AMR) has been identified as one of the leading causes, thus providing a strong rationale for basic science investigation into donor‐specific B cells and antibodies in transplantation and ways to mitigate their pathogenicity. In 2018, the American Society of Transplantation launched a community‐wide online discussion of Outstanding Questions in Transplantation, and the topic of B cell biology and donor‐specific antibody prevention emerged as a major area of interest to the community, leading to a highly engaged dialogue, with comments from basic and translational scientists as well as physicians (http://community.myast.org/communities/community-home/digestviewer). We have summarized this discussion from a bedside to bench perspective and have organized this review into outstanding questions within the paradigm that AMRis a leading cause of graft loss in the clinic, and points of view that challenge aspects of this paradigm. We also highlight opportunities for basic and translational scientists to contribute to the resolution of these questions, mapping important future directions for the transplant research field. The authors summarize the continuum of discussion regarding B cell biology, donor‐specific antibody formation, and antibody‐mediated rejection, focusing on the degree to which these processes contribute to graft loss, and discuss points of view that challenge aspects of this paradigm. See the introduction to this minireview on page 2149.