In non-human primate lung transplantation, allograft acceptance has been achieved using a delayed mixed-chimerism approach consisting of 4 months of triple-drug immunosuppression followed by donor bone marrow transplantation (DBMT) along with equine-ATG, anti-IL6R mAb, anti-CD154 mAb and anti-CD8 mAb. With this protocol, 3 out of 4 monkeys accepted their grafts long-term (>299, >813, >464 days). However, anti-CD154mAb and anti-CD8 mAb are not clinically available. In kidney transplantation, persistent allograft acceptance in Cynomolgus macaques was achieved using an alternative immunosuppression protocol relying on the clinically available reagents, rabbit-ATG and belatacept. Here, we have tested the same protocol in Cynomolgus macaques transplanted with fully allogeneic lung grafts.

Methods: Five Cynomolgus macaques underwent left orthotopic lung transplantation. Immunosuppression administered included equine-ATG (3 x 50mg/kg on days -2, -1 and 0) and anti-IL6R mAb (10mg/kg days 0, 7, 4 and 28) in addition to triple-drug immunosuppression for 4 months. Prior to DBMT (cryopreserved cells), a nonmyeloablative conditioning regimen including total body irradiation (3 Gy) as well as thymic irradiation (7 Gy) was conducted. Rabbit-ATG (10 mg/kg), belatacept (20 mg/kg), and anti-IL6R mAb (10 mg/kg) were given in addition to a 28-day course of cyclosporine. All immunosuppressant drugs were stopped on day 29 after DBMT.

Results: One monkey (M8216) rejected its lung prior to DBMT on day 78 after transplant due to antibody-mediated rejection after developing donor-specific antibodies. Four monkeys underwent DBMT and developed donor chimerism. Two monkeys (M6516 and M5816) developed fatal PTLD and were euthanized on day 41 and day 72 post DBMT, respectively. The remaining two monkeys (M7416 and M4116) showed severe cellular rejection on day 70 and day 42 post DBMT.

Conclusion: Although the thymoglobulin and belatacept-based protocol showed success in a kidney transplantation model, it failed to induce tolerance in a Cynomolgus lung allotransplant model, highlighting the organ-specific differences in the ability to achieve immunological tolerance. Taken together, these data suggest the need for approaches that result in greater regulatory T cell induction, while minimizing overall immunosuppression.

CITATION INFORMATION: Sommer W., O. J., Robinson K., Dehnadi A., Hanekamp M., Rosales I., Pruner K., Smith R., Colvin R., Kawai T., Benichou G., Madsen J., Allan J. Organ-Specific Differences in a Thymoglobulin and Belatacept-Based Protocol for Tolerance Induction in Non-Human Primates Am J Transplant. 2017;17 (suppl 3).

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