Peri-transplant Interleukin-6 Receptor Blockade delays Acute Cellular Rejection and Significantly Prolongs Kidney Allograft Survival in Tacrolimus/CTLA4Ig-treated Nonhuman Primates

Acute cellular rejection remains a major barrier to long-term allograft survival.Interleukin-6 (IL-6) promotes co-stimulation blockade (Co-SB)-resistant T cell mediated rejection (TCMR) in rodent transplantation models.We evaluated the IL-6 receptor(R) blockade using Tocilizumab, a monoclonal antibody that is FDA-approved for autoimmune diseases, on kidney allograft survival in nonhuman primates treated with calcineurin inhibition and Co-SB.MHCmismatched recipient rhesus monkeys received CTLA4Ig (Abatacept; days -1_to_120) combined with a tapered course of Tacrolimus (days -2_to_56).Tocilizumab (5mg/kg or 10mg/kg) was administered on days -1, 6, 13 and 20.Tocilizumab administration significantly prolonged graft survival compared with control recipients (median 67 versus 35 days; p < 0.05).Additionally, Tocilizumab administration reduced circulating effector and memory T cell, and enhanced regulatory T cell percentages in secondary lymphoid tissues, associated with reduced pSTAT3 expression in CD4 + and CD8 + T cells.However, IL-6R blockade was associated with transient elevation of serum IL-6, and significantly higher serum soluble IL-6R levels after transplant (p<0.0001).Histopathological features of acute TCMR in kidney allografts were reduced in Tocilizumab-treated recipients.Overall, these observations indicate that peri-Tx therapeutic targeting of IL-6 can delay cellular rejection and prolongs kidney allograft survival in Tacrolimus/CTLA4Ig-treated recipient monkeys.J o u r n a l P r e -p r o o f * Widespread venous thrombosis, likely related to TCMR; ** graft failure related to TCMR; several tubules showed intra-luminal neutrophils.Pyelonephritis should be excluded but not felt to be the cause of graft failure.