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 -1ₜo₁20) combined with a tapered course of Tacrolimus (days -2ₜo₅6). 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.
Kubo et al. (Sun,) studied this question.