Targeted CD103+ CD8 T cell depletion prolongs the survival of diabetic mice

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Targeted CD103+ CD8 T cell depletion prolongs the survival of diabetic mice

Type 1 diabetes is caused by the destruction of insulin producing β cells by the immune system. Islet cell transplantation therapy represents a viable therapeutic approach for treating type 1 diabetes. This approach requires the use of immunosuppressive drugs to avoid islet rejection. Unfortunately, these drugs significantly increase the risk of specific malignancies and opportunistic infections.

CD103-expressing CD8 T cells have been detected at the site of renal allograft rejection. CD103 is an integrin which allows T cells to migrate. Interestingly, the majority of pancreatic islet allografts survive indefinitely in CD103-deficient mice.

To evaluate the potential of targeting CD103+ CD8 T cells in the intervention of islet allograft rejection, Dr. Lei Zhang’s group from Harbin Medical University in China, synthesized an antibody-drug conjugate able to deplete CD103+ CD8 T cells. The conjugate consisted of Bio X Cell’s anti-mouse CD103 M290 clone conjugated to monomethyl auristatin F (MMAF). MMAF is a cytotoxic metabolite that inhibits microtubule polymerization and induces target cell death.

To test the therapeutic potential of M290-MC-MMAF, the researchers used a mouse model of diabetes. BALB/c islet allografts were transplanted under the left renal capsule of diabetic C57BL/6 recipients. Islet allograft rejection occurred within 18 days in the control groups. In contrast, M290-MC-MMAF treated mice exhibited prolonged islet allograft survival. M290-MC-MMAF treatment eliminated the CD103+ CD8 T-cell population in the graft at the time when allograft rejection occurred in the other two recipient groups. Importantly, immunohistochemical analysis revealed more insulin producing islets in M290-MC-MMAF-treated mice compared with controls.

To evaluate the immunosuppressive effects of M290-MC-MMAF treatment in the pancreatic islet allografts, the expression of inflammatory cytokines at the graft site was determined 15 days after islet transplantation. M290-MC-MMAF treatment was found to reduce the levels of the pro-inflammatory cytokines IL-4, IL-6, and TNF-α and increase the expression of the anti-inflammatory cytokine IL-10 at the graft site. Additionally, CD25+ CD4 regulatory T cells were found in higher frequencies in M290-MC-MMAF treated mice. Depletion of Tregs using Bio X Cell’s anti-mouse CD25 clone PC-61.5.3 in M290-MC-MMAF treated mice resulted in swift islet allograft rejection and decreased survival, indicating that Tregs are indispensable in maintaining the long-term functionality of islet allografts.

This study demonstrates the therapeutic potential of targeting CD103+ CD8 T cells in the intervention of islet allograft rejection.

See the complete article in Cell Death & Disease: https://www.nature.com/articles/s41419-019-1980-8

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