Background: In the pig-to-baboon artery patch model with no immunosuppressive therapy, a graft from a GTKO pig elicits a significant anti-nonGal IgG response, indicating sensitization to the graft. An anti-CD40mAb-based regimen prevents sensitization. As anti-CD40mAbs are not currently FDA-approved, we explored the efficacy of FDA-approved agents on the adaptive immune response in this model.

Methods: Artery patch xenotransplantation in baboons was carried out using GTKO/CD46 pigs with (n=2) or without (n=1) the transgene for CIITA-knock-down. Immunosuppressive therapy consisted of induction with ATG and anti-CD20mAb, and maintenance with either (i) tacrolimus+CTLA4-Ig (n=1), (ii) tacrolimus+sirolimus (n=1), or (iii) tacrolimus+CTLA4-Ig for 1 month followed by tacrolimus+sirolimus for 5 months (n=1). All 3 baboons received daily corticosteroids, the IL-6R blocker (tocilizumab), and the TNF-α blocker (etanercept). To determine whether sensitization to pig xenoantigens developed, recipient blood was monitored for anti-nonGal antibody levels by flow cytometry (using GTKO/CD46 pRBCs, PBMCs, and pAECs), and mixed lymphocyte reaction (MLR). CD22⁺B cell profiles (naïve [IgD+/CD27-], non-switched [IgD+/CD27+], and switched [IgD-/CD27+] memory B cell subsets) were measured by flow cytometry.At 6 months, the baboons were euthanized and the grafts examined histologically.

Results: At 6 months, histologic examination showed no features of rejection. No elicited anti-pig antibodies developed in any baboon. MLR showed no proliferative T cell response when a CTLA4-Ig-based regimen had been administered (n=2; regimens (i) and (iii)), but a proliferative response was seen in the absence of CTLA4-Ig. The frequency of naïve memory B cells increased significantly (from 33% to 89%, p=0.0015) and there was a significant decrease in switched memory B cells (from 17% to 0.5%, p=0.015).

Conclusions: The data suggest that immunosuppressive therapy with only FDA-approved agents, especially a CTLA4-Ig-based regimen, may be adequate to prevent an adaptive immune response to a genetically-engineered pig graft, and inhibit the development of donor-specific memory B cells. The regimens are currently being tested in the pig-to-baboon kidney transplant model.

CITATION INFORMATION: Yamamoto T., Hara H., Wang L., Li Q., Li J., Zhou H., Eckhoff D., Tector A., Ayares D., Cooper D., Iwase H. Prevention of an Adaptive Immune Response by FDA-Approved Immunosuppressive Agents in Baboons with Pig Artery Patch Xenografts Am J Transplant. 2017;17 (suppl 3).

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