Kidney Transplantation Research: New Findings in Antibody-Mediated Rejection

December 23, 2020

Paul Fadakar, MD, is an assistant professor of pediatrics in the Department of Pediatrics at the University of Pittsburgh School of Medicine, and an attending nephrologist in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh. Dr. Fadakar joined the Division in 2018 after completing his nephrology fellowship training at UPMC Children’s. During his fellowship, Dr. Fadakar’s research focused on translational investigations of transplant immunology at the Thomas E. Starzl Transplantation Institute.

Dr. Fadakar’s work involved ongoing projects in the laboratory of Diana M. Metes, MD, investigating the role of T follicular helper cells in antibody-mediated rejection (ABMR) in renal transplant recipients.

One of those research projects in which Dr. Fadakar was a collaborator was published in October in the Journal of the American Society of Nephrology (JASN) under the title of “Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation.”1

Research Summary

A leading cause of kidney transplant allograft failure is antibody-mediated rejection, a chronic attack upon the allograft tissues caused by antibodies directed against donor-
specific HLA molecules, blood group antigen isoagglutinins, or endothelial cell antigens.2

While much has been uncovered about how ABMR functions, many of the basic cellular and molecular pathways that lead to donor-specific antibody responses in the host are not well understood. Uncovering these processes and pathways may lead to more effective antirejection protocols and therapeutic targets.

The study in which Dr. Fadakar was a participant examined aspects of T follicular helper cells (TFH) and B cells, and their interactions and signaling in kidney transplant patients experiencing antibody-mediated rejection.

“Our study isolated a cohort of 20 individuals from a larger population of kidney transplant patients who were both positive for ABMR and the presence of donor-specific antibodies. We looked at these individuals’ levels of TFH and B cells compared to other kidney transplant patients. We uncovered a number of important observations in how the T cells and B cells interact and signal, and what the products of those interactions are,” says Dr. Fadakar.

According to the clinical implications summary from the paper, “… the authors identified highly coordinated responses of circulating TFH cells and activated B cells at phenotypic, functional, and transcriptional levels in patients with antibody-mediated rejection. The levels of circulating TFH cell and B cell activation were predictive of DSA pathogenicity, histologic severity, and allograft loss. This study provides novel mechanistic insights into the cellular and molecular processes underlying antibody-mediated rejection and a rationale for monitoring and therapeutic targeting of circulating TFH cell–B cell interaction during antibody-mediated rejection.”

“For decades, the University of Pittsburgh and UPMC Children’s have been pioneering leaders in transplantation medicine — for children and adults — built upon the seminal work of Dr. Thomas Starzl and many other colleagues. Our new research is an extension of that legacy, another building block on the path toward the day when the complication of rejection in organ transplantation is a distant memory,” says Dr. Fadakar.

References

1. Louis K, Macedo C, Bailly E, et al. Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation. JASN. October 2020; 31(10): 2457-2474.

2. Singh N, Pirsch J, Samaniego M. Antibody-Mediated Rejection: Treatment Alternatives and Outcomes. Transplant Rev. 2009; 23(1): 34-46.