HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

Abstract

The presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient’s blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient’s morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation.

Case report: Daratumumab for treatment of refractory late or chronic active antibody-mediated rejection in renal allograft recipients with high levels of de novo donor-specific antibodies

“…CD4 + T cell activation may assist splenic B cells or memory B cells to reactivate, differentiate, and produce antibodies (similar to the process of acute AMR), making DSA removal more difficult with anti-plasma cell therapy plus PP/IVIG. Daratumumab can also act on regulatory cells and reduce them, which may theoretically promote the occurrence of acute cellular rejection ( 19 , 20 ). The risk of acute cellular rejection with long-term daratumumab treatment warrants further attention in future studies.…”

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

“…There is now recent experimental and clinical evidence suggesting that interference with the surface molecule CD38 could be an effective strategy in ABMR prevention and treatment [ 12 , 38 ]. Efficacy of such treatment was suggested by a recent case report: one case of successful ABMR treatment after ABO blood group-incompatible kidney transplantation [ 39 ], two patients with severe heart allograft rejection [ 25 , 40 ], and a case of chronic active HLA DSA-triggered ABMR in a renal transplant recipient [ 24 ].…”

Targeting CD38 in Neoplasms and Non-Cancer Diseases

“…Corresponding targeting of CD38 with daratumumab for plasma cell and NK cell depletion may be also useful in the treatment of chronic active antibody-mediated kidney allograft rejection (including ABO-incompatible), as well as AMR after heart transplantation [ 189 , 190 , 191 , 192 , 193 ].…”