Successful Use of Anti-IL-6R Therapy to Achieve Cardiac Allograft Tolerance in Non-Human Primates

Abstract

<h3>Purpose</h3> In contrast to kidney allografts, attempts to achieve tolerance of isolated cardiac allografts in non-human primates (NHPs) using a mixed chimerism strategy have been unsuccessful. IL-6 is a pro-inflammatory cytokine known to play an important role in allograft rejection. We investigated whether adding anti-IL-6R therapy to our mixed chimerism protocol would enable the induction of tolerance in NHP recipients of MHC mismatched heart allografts. <h3>Methods</h3> Ten cynomolgous NHPs underwent heart and bone marrow transplantation (BMTx) with non-myeloablative conditioning including total body and thymic irradiation, ATGAM, anti-CD154 mAb, and cyclosporine until post-operative day (POD) 28, with or without anti-IL-6R therapy (tocilizumab, 10 mg/kg IV on POD 0, 7, 14, 21, 28, 56, 84). Group A (n=2) received allogeneic BMTx without anti-IL-6R therapy, Group B (n=6) received allogeneic BMTx with anti-IL-6R therapy, and Group C (n=2) received autologous BMTx with anti-IL-6R therapy. <h3>Results</h3> In Group A, both recipients experienced allograft failure due to rejection on POD 104 and 132 [Table]. In Group B, 3 recipients achieved long-term cardiac allograft survival of >400 days off immunosuppression; one recipient is ongoing at POD 360. Two rejected on POD 169 and 383. For Groups A and B, peak lymphocyte chimerism was 10.1% and 18.1%, respectively and duration of lymphocyte chimerism was 57 and 178 days, respectively. In Group C, one recipient rejected on POD 131 and one is ongoing at POD 120. There was no significant difference in magnitude of peripheral T_reg expansion between groups (p=0.77). Compared to Group A, Groups B and C had lower CRP levels (mean 12.3 vs 54.3 μg/mL) and higher free serum IL-6 (mean 23.0 vs <7.7 pg/mL) while receiving anti-IL-6R therapy. <h3>Conclusion</h3> Tolerance of cardiac allografts has been achieved for the first time in NHPs using a combination of IL-6 signaling blockade and mixed chimerism. This approach represents significant progress towards clinical cardiac allograft tolerance.