Abstract
CD103 mediates T-cell infiltration and organ allograft rejection, and depletion of CD103-expressing cells is a promising therapeutic strategy for allograft intolerance. Recently, we verified that M290-MC-MMAF, an anti-CD103 antibody-drug conjugate, potently eliminates CD103-positive cells in vivo, with high specificity and minimal toxicity. However, the contribution of M290-MC-MMAF to blocking the CD103/E-cadherin pathway involved in transplant rejection remains unclear. Herein, we examined the impact of systemic administration of M290-MC-MMAF on allografts in an islet transplantation model. M290-MC-MMAF treatment maintained the long-term survival of islet allografts (>60 days) compared to mock injection or unconjugated M290 antibody treatment (<18 days). The change was associated with a decrease in CD103+CD8+ effector T cells and an increase in CD4+CD25+ regulatory T cells. CD103+CD8+ effector T-cell transfer or CD4+CD25+ regulatory T-cell depletion resulted in a rapid loss of allografts in long-surviving islet hosts. Moreover, M290-MC-MMAF treatment reduced IL-4, IL-6, and TNF-α expression levels and increased IL-10 expression in the grafts, which presented an immunosuppressive cytokine profile. In conclusion, targeting CD103 with M290-MC-MMAF induced immunosuppression and prolonged the survival of pancreatic islet allografts in mice, indicating the potential clinical value of M290-MC-MMAF in therapeutic interventions for allograft rejection.
Highlights
Introduction Type1 diabetes is caused by the destruction of insulinproducing β cells by the autoimmune system
Through the interaction of CD103 and E-cadherin, CD103-expressing CD8 effector cells infiltrate and accumulate in the epithelial compartment of rejected renal allografts in mice[3]. This subset of CD8 effector cells has been detected at the site of clinical renal allograft rejection[4]
These data are consistent with those of our previous study showing that M290-MC-MMAF targets CD103, which is mainly expressed in the CD8 compartment
Summary
Introduction Type1 diabetes is caused by the destruction of insulinproducing β cells by the autoimmune system. Through the interaction of CD103 and E-cadherin, CD103-expressing CD8 effector cells infiltrate and accumulate in the epithelial compartment of rejected renal allografts in mice[3]. This subset of CD8 effector cells has been detected at the site of clinical renal allograft rejection[4]. CD103-deficient CD8+ cells are not retained and do not degrade the host intestinal epithelium in a mouse model of graft-versus-host disease[8]. These findings demonstrate a causal role of CD103+CD8+
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