Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Abstract

Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.

Keywords: autoimmunity; beta cell replacement; immunomodulation; immunosuppression; islet transplant; type 1 diabetes.

Figure 1

Induction and maintenance immunosuppression in islet transplantation by era. Immunosuppression regimen of 1,108 individuals with T1D who received Islet Transplant Alone (n = 992) or Islet after kidney (n = 186) between 1999 and 2022 and were followed by the CITR. Data source: Collaborative Islet Transplant Registry Coordinating Centre: Eleventh allograft report 2022. TCD, T cell depleting agents; Inh, inhibitor; CNI, calcineurin Inhibitor; IMPDH, Inosine-5′-monophosphate dehydrogenase; IL1RA, IL1 receptor antagonist. Reproduced from “Caldara R, Tomajer V, Piemonti L. Enhancing Beta Cell Replacement Therapies: Exploring Calcineurin Inhibitor-Sparing Immunosuppressive Regimens. Transpl Int. 2023 Jun 8;36:11565” with permission from the authors.