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

Abstract

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 AMR is 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.

Regulatory B cells require antigen recognition for effective allograft tolerance induction

“…Classically, B cells are thought to have 2 primary functions: antigen presentation and antibody production. In the transplant setting, these features primarily contribute to allograft rejection . However, recent work has identified a subset of B cells that have significant suppressive functions, promoting allograft tolerance .…”

Effect of Optimized Immunosuppression (Including Rituximab) on Anti-Donor Alloresponses in Patients With Chronically Rejecting Renal Allografts

“…However, other factors associated with the presence of DSA might influence the progression of pathology, rate of functional deterioration and timing of eventual graft failure. There is significant debate within the field about the contribution of cell-mediated immune processes in CAMR (12). We've previously defined that B lymphocytes play a role in CAMR as antigen presenting cells (APC) for interferon-gamma (IFNγ) production by indirect pathway antidonor T cells, revealed in Enzyme-Linked Immunosorbent Spot (ELISPOT) assays (13).…”

Rejection of xenogeneic porcine islets in humanized mice is characterized by graft-infiltrating Th17 cells and activated B cells

“…B cells have been shown to contribute to transplant rejection through several important mechanisms including generation of humoral responses, antigen presentation, priming of effector cells, and primary cytokine production . As such, rituximab has been used traditionally in immunosuppressive induction therapy to counteract these mechanisms by depleting peripheral B cells, and to a lesser extent, B cells in secondary lymphoid organs .…”