Desensitization: Overcoming the Immunologic Barriers to Transplantation

Abstract

HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection.

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

“…[8][9][10] HLA Abs, which arise from pregnancy, blood transfusion, or prior transplantation, present a significant and often impenetrable barrier to kidney transplantation, leading to increased morbidity and mortality. 17,18 B cell depletion with rituximab was shown to reduce preformed HLA Abs in only 10% of treated patients and failed to target BMPCs. [13][14][15][16] Transplantation across HLA barriers, through preconditioning with intravenous immune globulin (IVIg), alone or combined with plasmapheresis, or the CD20 monoclonal Ab rituximab provides short-term reductions in HLA Ab levels.…”

“…[13][14][15][16] Transplantation across HLA barriers, through preconditioning with intravenous immune globulin (IVIg), alone or combined with plasmapheresis, or the CD20 monoclonal Ab rituximab provides short-term reductions in HLA Ab levels. 17,18 B cell depletion with rituximab was shown to reduce preformed HLA Abs in only 10% of treated patients and failed to target BMPCs. Thus allosensitization represents an urgent and unmet medical need in organ transplantation because current desensitization methods fail to provide durable effects on HLA Ab responses.…”

Belatacept in renal transplant recipient with mild immunologic risk factor: A pilot prospective study (BELACOR)

“…2 The growing number of sensitized patients before transplant has become a major challenge. 5 Those protocols involved antibody clearance using apheresis (immunoadsorption or plasmapheresis), 5 B cell-modulating therapies (high dose of intravenous immunoglobulin or rituximab) 5 or plasma cell depletion (bortezomib), 5 complement inhibition (eculizumab) 5 and, more recently, IgG-inactivating agents. 3 Numerous strategies to improve access to kidney transplant of sensitized recipients with preformed anti-HLA DSAs have been developed, including specific graft allocation policies 4 and immunosuppressive protocols that attempt to remove antibodies.…”

“…3 Numerous strategies to improve access to kidney transplant of sensitized recipients with preformed anti-HLA DSAs have been developed, including specific graft allocation policies 4 and immunosuppressive protocols that attempt to remove antibodies. 5,6 In kidney allograft recipients with preformed DSAs, induction therapy with antithymocyte globulin is strongly recommended. 6 The principal limitation of those strategies is the high prevalence of acute and chronic ABMR (up to 30%) early after transplant associated with poor allograft survival.…”

“…3 Numerous strategies to improve access to kidney transplant of sensitized recipients with preformed anti-HLA DSAs have been developed, including specific graft allocation policies 4 and immunosuppressive protocols that attempt to remove antibodies. 5 Those protocols involved antibody clearance using apheresis (immunoadsorption or plasmapheresis), 5 B cell-modulating therapies (high dose of intravenous immunoglobulin or rituximab) 5 or plasma cell depletion (bortezomib), 5 complement inhibition (eculizumab) 5 and, more recently, IgG-inactivating agents. 6 The principal limitation of those strategies is the high prevalence of acute and chronic ABMR (up to 30%) early after transplant associated with poor allograft survival.…”