Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

Abstract

Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell‐directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody‐mediated rejection (AMR) treatment by targeting CD20 found on B‐lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific

“…10 As evidence supporting antagonism of the CD28 pathway to combat alloantibodies mounts, 19 it is foreseeable that more potent forms of CD28 blockade will be desired in cases of highly sensitized patients or potential costimulation blockade-based desensitization protocols. 6 Here, we demonstrate that selective CD28 blockade is better than CTLA-4-Ig at inhibiting the humoral alloresponse in a clinically relevant full allogeneic mismatch model and that this superior inhibition is mechanistically CTLA-4-dependent and Tfh cell specific.…”

“…These donor‐specific antibodies (DSA) have been increasingly recognized to cause immunologic injury of kidney allografts and present a barrier to improving long‐term outcomes. Despite the deleterious role of DSA, large knowledge deficits exist regarding the mechanisms underlying their development and maintenance, and therapeutic strategies to control DSA‐mediated allograft dysfunction are lacking 5‐7 …”

“…Results from a clinical trial designed to evaluate the ability of belatacept to prevent DSA formation in kidney transplant recipients with failed allografts indicate that belatacept alone is not sufficient to completely prevent DSA in this setting 18 . As more liberal use of belatacept in higher immunologic risk recipients is beginning to occur because of increased recognition of the benefits of CD28 blockade on humoral alloimmunity, 6,19 more potent methods of CD28 blockade will be highly desirable. Moreover, we have shown that selective CD28 blockade is superior to CTLA‐4‐Ig at preventing alloantibodies in a minor antigen mismatch murine transplant model 20 .…”

“…Despite the deleterious role of DSA, large knowledge deficits exist regarding the mechanisms underlying their development and maintenance, and therapeutic strategies to control DSA-mediated allograft dysfunction are lacking. [5][6][7] Targeting of the CD28 costimulation pathway with belatacept, a second-generation CTLA-4-Ig, has achieved translation and improved long-term outcomes following kidney transplantation. 8 However, de novo use of belatacept has been limited by acute rejection rates and uncertainty in immunologically high-risk patients.…”

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection

“…Here, we discuss novel and emerging therapeutics that likely will offer significant benefits over existing therapies in prevention and treatment of AMR. [1][2][3] A review of the immune activation pathways responsible for AMR are shown in Figure 1A and Table 1.…”