BACKGROUND: Inflammatory responses have been linked to the development of acute and chronic rejection after lung transplantation in various models. Previous studies have demonstrated that blockade of IL-6 pathway or the administration of anti-thymocyte globulin (ATG) can promote regulatory T cells (Treg). AIM: we sought to test 1) whether ATG with inhibition of IL-6 can promote in vivo Treg expansion, and 2) whether this strategy can prolong allograft survival, using an orthotopic non-human primate lung transplantation model. METHODS: 1) Cynomolgus monkeys received the anti-IL6 receptor mAb, tocilizumab (aIL6R) and/or equine ATG without lung transplant and peripheral lymphocytes were examined. 2) Lung transplants were performed with triple immunosuppression (tacrolimus, mycophenolate mofetil, and steroid), alone (n=4), with ATG (n=5), and with aIL6R + ATG (n=6). Histology of biopsies and circulating donor-specific antibody (DSA) were examined. RESULTS: 1) Peripheral Tregs increased transiently only when ATG and aIL6R were both administered, while IFN-γ-producing type 1 pro-inflammatory cells decreased. Increased Tregs expressed several activation markers . 2) In the absence of ATG / aIL6R, all grafts rejected with DSA detected in all animals. With ATG and aIL6R, all animals survived >100 days (p < 0.01), without developing DSA . ATG alone did not significantly improve allograft survival . CONCLUSION: In vivo Treg expansion was achieved by co-administration of ATG and aIL6R. The combined use of these agents led to improved lung allograft survival, possibly due to this mechanism, a technique that could be applicable to human transplantation.

CITATION INFORMATION: Aoyama A, Tonsho M, Smith R.-N, Colvin R, Dehnadi A, Madsen J, Cosimi A, Benichou G, Kawai T, Allan J. Non-Human Primate Lung Allograft Survival Is Prolonged by IL-6 Inhibition and ATG Treatment Possibly Through Expansion of Peripheral Regulatory T Cells. Am J Transplant. 2016;16 (suppl 3).

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