Abstract and Introduction
Despite new immunotherapies aimed at B and T cells, plasma cells and their lifelong antibody secretion constitute a major immune barrier to long-term graft survival. In this mini-review, we survey the recent advances that have been made in the biology and immunometabolism of long-lived plasma cells, and outline aspects of plasma cell function that can be exploited for clinical benefit in recipients of solid organ transplants. A handful of ongoing studies are already targeting plasma cells to achieve desensitization and reduce the alloantibody burden in individuals posttransplant. In reviewing the recent strides made in our understanding of the molecular basis of plasma cell survival, we will place our discussions in the context of existing preclinical and clinical studies.
B lymphocytes, prime components of the adaptive immune system, terminally differentiate into a unique cell lineage that constitutively secretes antibodies. These antibody-secreting cells, known as plasma cells, are fundamental to the maintenance of humoral immunity as they allow the body to counter infectious foreign invaders, forming the bedrock of clinical immunization. In addition to neutralizing pathogens, antibodies perform a diverse set of effector functions including the regulation of hypersensitivity reactions, activation of the complement cascade, as well as regulation of mucosal bacterial populations.[3,4] Despite their crucial role in immune surveillance, plasma cell activity can be a bane in the setting of solid organ transplantation. In individuals with end-stage organ failure, transplantation is often the only lifesaving treatment option; plasma cells and alloantibodies, however, present the most vexing barrier to a successful organ transplant.[5,6]
It was first recognized over 80 years ago that allotransplantation results in the production of donor-specific antibodies (DSAs) and that a genetic locus (the major histocompatibility complex) is important in determining whether a transplant would be accepted by the host. We now know that the products of this genetic locus encode for the human leukocyte antigen (HLA) proteins, and that the immune response to an allograft is determined by the disparities between the donor and recipient HLA class I and II loci. In mediating transplant rejection through both the cellular and humoral arms of the immune system, plasma cells play a salient role. The principal mechanism by which plasma cells underlie chronic graft failure is through secretion of large quantities of antibodies (Abs). Current immunosuppressive drugs have largely centered on T cell–mediated immunity, and despite being successful in controlling acute cellular rejection, have failed to curtail humoral immune responses. Consequently, Ab-mediated rejection (AMR) remains a leading cause of allograft failure, with an incidence of ≈5% in unsensitized patients and up to 25% in highly sensitized recipients, such as those with ABO incompatibility or multiple prior blood transfusions.[8–10] AMR accounts for between one quarter and half of the acute graft dysfunction cases, and plays a role in majority of the chronic rejection episodes.[10,11] Less commonly, mature plasma cells can directly infiltrate the allograft and facilitate an albeit rare form of graft failure, known as plasma cell–rich acute rejection. Currently, when long-term graft survival remains a challenge in transplantation, it is especially imperative to assess strategies that can help restrain humoral defenses.
Plasma cells single-mindedly produce enormous quantities of Abs for as long as they live. Mismatched- or non-HLA molecules on cells of the donor tissue can recruit antibodies as well as other effector immune cells through complement-dependent and -independent pathways, leading to graft thromboses. Moreover, both pre-existing and de novo IgG DSAs are strongly correlated with allograft injury for all solid organ transplants, including that of the kidney, heart, lung, and liver.[13–16] Although plasmapheresis and intravenous immunoglobulins (IVIG) are commonly used approaches in several posttransplant protocols against AMR, their efficacy remains transient. Consequently, it is tempting to surmise that in conjunction with currently available immunosuppressive drugs, novel immunotherapy strategies specifically aimed at plasma cells might help improve long-term allograft tolerance. In this mini-review, we will first provide an overview of plasma cell formation, followed by a discussion of the extrinsic and intrinsic factors that contribute to their survival and maintenance of metabolic demands. Subsequently, we review results from recent clinical and preclinical studies that further support modulation of plasma cell function in the setting of transplantation.
American Journal of Transplantation. 2020;20(8):1984-1991. © 2020 Blackwell Publishing