[Background] Pre-formed antibody is a substantial immunological barrier in organ transplantion. Antibodies to xenoantigens can lead to rapid antibody-mediated rejection (AMR) in xenotransplantation. We previously showed that donor-specific alloantibodes were significantly reduced by treatment with carfilzomib (proteasome inhibitor) and tocilizumab (anti-IL6R mAb) in an allosensitized non-human primate model. Here, we evaluated the levels of xeno-reactive antibody upon allo-sensitization and desensitization.

[Methods] Two skin grafts were exchanged between maximally MHC mismatched Rhesus macaque pairs for allo-sensitization and subjects then treated with carfilzomib (8 mg/kg, IV) and tocilizumab (20 mg/m², IV) once weekly for a month for desensitization (n=6). Alloantibody was measured by T- and B-cell flow crossmatches (FXM) against rhesus donor cells or non-donor cells. Xeno-reactive antibody was measured by T- and B-cell flow FXM with pig splenocytes.

[Results] Rhesus macaques underwent skin grafts without immunosuppression. Donor-specific antibody (DSA) was significantly elevated compared to non-grafted control monkeys and pre-sensitization time points. Combined carfilzomib and tocilizumab treatment after stabilization of DSA levels significantly reduced levels of alloantibody. As expected, some MAMU antigens elicited more alloantibody than others. For instance, MAMU*B012b mismatch elicited more robust antibody production than MAMU*A004. Finally, we evaluated crossreactivity against xeno-antigens with pig splenocytes before and after allosensitization. We observed preexisting or natural antibodies against the pig cells before the allosensitization. However, elevated anti-MAMU antibodies did not increase the level of xeno-reactive antibodies against pig cells after allosensitization, and xeno-reactive antibody was not reduced by desensitization.

[Conclusion] Rhesus mokneys showed natural xeno-reactive (anti-pig) antibodies without sensitization. However, allosensitization does not elevate xeno-reactive antibodies. Treatment with combined carfilzomib and tocilizumab did not lower xenoantibodies despite lowering alloantibodies.

CITATION INFORMATION: Yoon J., Ezekian B., Manook M., Kwun J., Knechtle S. Rhesus Monkey Have natural Antibody toward Swine That is Not Influenced by Allosensitization nor by Carfilzomib/tocilizumab Am J Transplant. 2017;17 (suppl 3).

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