A GROUNDBREAKING preclinical study has demonstrated that a chemotherapy-free, non-myeloablative conditioning regimen can induce durable mixed haematopoietic chimerism, restore immune tolerance, and completely reverse autoimmune type 1 diabetes in mouse models. The findings could pave the way for safer transplantation-based approaches for correcting autoimmunity in humans without the toxicity associated with traditional bone marrow conditioning.
Mixed Haematopoietic Chimerism as a Pathway to Immune Tolerance
Mixed haematopoietic chimerism has long been recognised as a strategy capable of promoting tolerance to donor-matched organs and correcting autoimmune processes. However, its clinical use has remained limited by the toxic conditioning regimens required to enable engraftment. To address this, researchers developed a chemotherapy-free, non-myeloablative approach using a combination of anti-c-Kit monoclonal antibody, T-cell depleting antibodies, JAK1/2 inhibition and low-dose total body irradiation.
In prediabetic NOD mice, this regimen enabled successful engraftment of MHC-mismatched B6 haematopoietic cells, establishing stable mixed chimerism. Strikingly, diabetes development was prevented in 100% of treated animals, demonstrating complete protection against autoimmune destruction of pancreatic islets.
Correction of Established Diabetes and Allograft Tolerance
In mice with overt diabetes, the same conditioning protocol was combined with B6 haematopoietic cell transplantation and islet transplantation. All chimeric mice achieved durable correction of hyperglycaemia without the need for ongoing immunosuppression. No cases of graft-versus-host disease were observed, and immune competence was maintained, as shown by normal blood count recovery and rejection of third-party allogeneic islets.
Mechanistic analyses revealed both central thymic deletion of autoreactive T cells and peripheral regulatory mechanisms, confirming restoration of immune tolerance. Adoptive transfer experiments further demonstrated that autoimmune activity had been corrected rather than temporarily suppressed.
Toward a Type 1 Diabetes Cure
These results suggest that non-toxic, mixed haematopoietic chimerism could eventually offer a transformative therapeutic pathway for autoimmune type 1 diabetes, enabling durable immune reset, islet allograft tolerance and reversal of established disease. While translation to humans will require careful evaluation, the study provides compelling evidence that effective immune reprogramming may be achievable without the risks of traditional conditioning.
Reference
Bhagchandani P et al. Curing autoimmune diabetes in mice with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning. J Clin Invest. 2025; DOI:10.1172/JCI190034.
