*Purpose: Although the recent progress in xenograft survival in pig-to-nonhuman primate heart and kidney transplantation, little is known about retransplantation in pig antigen-sensitized recipient. This study was conducted to assess and regulate the levels of de novo synthesized anti-pig antibodies in GT-KO pig-to-cynomolgus monkey artery retransplantation with specific immunosuppressant regimens.

*Methods: We had performed GT-KO pig-to-cynomolgus monkey artery xenotransplantation/retransplantation (n=4) with triple immunosuppressant, anti-CD154 monoclonal Abs (mAbs), and with (n=2) or without (n=2) rabbit anti-thymocyte globulin (rATG) treatment. We have recently investigated the effect of addition of rituximab (n=1) or rituximab plus tocilizumab (n=2) treatment. We examined the levels of the induced anti-pig antibodies and serum-mediated cytotoxicity using donor pig peripheral blood mononuclear cells (PBMCs) in response with serum samples which were serially harvested from each recipient.

*Results: In first artery transplantation, there were no critical antibody-mediated responses and the intact artery grafts were observed. In artery retransplantation with same immunosuppressant protocol as first transplantation, however, the anti-pig IgM and IgG levels were significantly increased within 7 days after transplantation in all recipients despite the treatment of anti-CD154 mAbs and/or rATG treatment and serum-mediated cytotoxicity against donor PBMCs were quite severe. In addition, blood clotting was observed in artery grafts of all recipients. The additional rituximab treatment inhibited the acute induction of anti-pig IgM and IgG in all recipients. However, we lost our cases at postoperative day 7, 11, and 12, respectively, without any signs of graft rejection and each grafted artery was intact.

*Conclusions: This study showed that severe anti-pig antibody responses were provoked in GT-KO pig-to-cynomolgus monkey artery retransplantation regardless of anti-CD154 mAbs and/or rATG treatment. The rituximab treatment seem to inhibit the acute induction of anti-pig antibody production in the artery retransplantation. Long-term observation for investigating the effect of rituximab treatment and the mechanism of anti-pig antibody production in the artery retransplantation need to be studied further.

This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2014M3A9D3034034).

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