Introduction and Objective: Immune-mediated rejection remains a major barrier to durable pancreatic islet transplantation for type 1 diabetes. Mesenchymal stromal/stem cells (MSCs) possess immunomodulatory properties, and engineering MSCs to overexpress alpha-1 antitrypsin (AAT) may enhance their therapeutic potential. This study evaluated whether co-transplantation of human islets with AAT-overexpressing MSCs (AAT-MSCs) improves graft survival and modulates human immune responses in a humanized mouse model.Methods: Humanized-NSG mice were generated by irradiation and transplantation of human CD34+ hematopoietic stem/progenitor cells to reconstitute human T and B cells. Diabetic mice received intrahepatic transplantation of human islets alone or with AAT-MSCs and were monitored for six weeks. Graft function and immune responses were assessed through blood glucose monitoring, serum immunoglobulin measurements, immune cell phenotyping, graft histology, and in vitro assays evaluating B cell differentiation and cytokine production.Results: Co-transplantation with AAT-MSCs significantly improved glycemic control, prolonged islet graft survival, and reduced rejection compared with islets alone. These effects were associated with reduced serum IgM levels, which inversely correlated with graft rejection, and expansion of regulatory B cells. This was accompanied by suppression of Th1, Th17, and cytotoxic T cell responses. Histological analysis showed improved insulin preservation and enrichment of IL-10+ cells in co-transplant grafts. In vitro, AAT-MSCs promoted regulatory B cell differentiation, shifted cytokine production toward IL-10 rather than IL-6, and protected human islets from activated B cell-mediated cytotoxicity.Conclusion: AAT-MSCs co-transplantation promotes immune tolerance and sustains human islet graft function, highlighting its potential to improve clinical islet transplantation and reduce reliance on systemic immunosuppression.
W. Gou: None. J. Kim: None. T.N. Yeung: None. W. Cui: None. C. Strange: Other – CEO and owner working on stem cell therapies for diabetes; Current; Exollent Therapeutics. H. Wang: None.
National Institutes of Health (R01 DK105183, DK120394, DK118529, and DK125464) and the Department of Veterans Affairs (VA-ORD BLR&D Merit I01BX004536)
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