Harnessing the B Cell Response in Kidney Transplantation – Current State and Future Directions

Abstract

Despite dramatic improvement in kidney transplantation outcomes over the last decades due to advent of modern immunosuppressive agents, long-term outcomes remain poor. Antibody-mediated rejection (ABMR), a B cell driven process, accounts for the majority of chronic graft failures. There are currently no FDA-approved regimens for ABMR; however, several clinical trials are currently on-going. In this review, we present current mechanisms of B cell response in kidney transplantation, the clinical impact of sensitization and ABMR, the B cell response under current immunosuppressive regimens, and ongoing clinical trials for ABMR and desensitization treatment.

The impact of IdeS (imlifidase) on allo‐specific, xeno‐reactive, and protective antibodies in a sensitized rhesus macaque model

“…23,41 NHP models have been particularly well-utilized in developing agents that target long-term survival, which currently lag behind the IS regimens targeting acute rejection. 42,43 AMR, a leading cause of long-term rejection, occurs more often in sensitized patients undergoing incompatible transplant. 4 While there is no FDA-approved treatment for AMR or desensitization, plasmapheresis is used to physically remove antibody and allow for transplantation in sensitized patients.…”

“…Previous NHP models have played an important role in evaluating and developing modern immunosuppressive approaches for organ transplantation given physiological and immunological similarities to humans 23,41 . NHP models have been particularly well‐utilized in developing agents that target long‐term survival, which currently lag behind the IS regimens targeting acute rejection 42,43 . AMR, a leading cause of long‐term rejection, occurs more often in sensitized patients undergoing incompatible transplant 4 .…”

CXCR5+CD8+ T Cell–Mediated Suppression of Humoral Alloimmunity and AMR in Mice Is Optimized With mTOR and Impaired With Calcineurin Inhibition

“…AMRs in human KTx recipients are often resistant to treatment with standard immunosuppressive agents, 40 and strategies to reduce the quantity of DSAs (eg, IVIg, plasmapheresis) are based on low-quality evidence 9 and dramatically lose efficacy once AMR is established. 40 Additionally, immunotherapeutic strategies targeting costimulatory blockade (CD28/CD80/CD86), B cells (CD20), plasma cells (CD38), or cytokines (IL-6) that are reported to initially decrease DSAs are also associated with unintended consequences such as rebound increased quantity of DSAs and/or development of acute T cell-mediated rejection. 10 Thus, there is a vested interest in developing novel therapeutic approaches to treat AMR.…”

Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury

“…The disorder of single-cell transcriptional heterogeneity is an inevitable outcome of persistent allosensitive responses after transplantation. − Alloantigens are rapidly drained into the secondary lymphoid tissue once the graft is implanted to the recipient, activating an adaptive immune response . Afterward, donor-specific antibodies (DSAs) are produced and bound to the antigens exposed on the surface of vascular endothelial cells, activating the complement system or directly leading to endothelial cell apoptosis and detachment through cytotoxicity . Endothelial cell injury not only causes the proliferation and activation of alloreactive immune cells but also promotes the infiltration of inflammatory cells, including neutrophils, monocytes, and lymphocytes, thus leading to multitype and multidimensional single-cell transcriptional disorders. , However, less is known about the repairing strategies to prevent or reverse single-cell transcriptional drift after DSA-mediated alloreactive damage.…”