Characterisation of the immunomodulatory action of a unique anti-cxcr3 monoclonal antibody exploiting a conserved human and murine epitope for transplantation

of foreign tissues into genetically dissimilar recipients, called an allograft, results in an inflammatory immune response against the allograft, necessitating suppression of the rejection response. However, current immunosuppressive drugs broadly supress the immune system and have number of associated side-effects. More selective, alternative therapies such as inhibition of T cell migration to sites of allograft are for this reason of great interest. CXCR3 is a chemokine receptor highly expressed on activated Th1 and CD8+ T cells, with elevated expression in patients undergoing allograft rejection and animal models of allograft rejection and autoimmune disease. Due to the clinical application of islet transplantation for use in patients with diabetes we investigated the efficacy of a novel anti-CXCR3 mAb in models of islet transplant, autoimmune diabetes and islet transplant into autoimmune diabetic recipient mice. We hypothesised that transient blockade of CXCR3 signalling would delay islet allograft rejection and alter diabetes incidence. As anticipated inhibition of CXCR3 signalling impaired chemotaxis of CXCR3 expressing cells and prolonged islet allograft survival in models of islet transplant. This was associated with reduced CD8+CD44 expression and reduced CD8+ effector and memory T cells. An increased frequency of Treg was also seen in islet allograft recipients. Further, Islet allograft survival was prolonged in autoimmune diabetic allograft recipients, a finding yet to be shown within the literature. The role of CXCR3 in diabetes is ambiguous; with some prior studies indicating accelerated diabetes onset, while others show a delay. Of note treatment with our anti-CXCR3 antibody showed no change in diabetes incidence or pathology. In particular recruitment of Tregs from the pancreas to the pancreatic lymph node was unaffected, in contrast to previous literature showing impaired Treg migration and resultant accelerated diabetes onset. Therefore transient antibody targeting of CXCR3 signalling with our antibody shows promise for use in allograft, in particular in islet allograft with safety in models of diabetes