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Prevention of an Adaptive Immune Response by FDA-Approved Immunosuppressive Agents in Baboons with Pig Artery Patch Xenografts

T. Yamamoto,1 H. Hara,1 L. Wang,1 Q. Li,1 J. Li,1 H. Zhou,1 D. Eckhoff,1 A. Tector,1 D. Ayares,2 D. Cooper,1 H. Iwase.1

1Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham
2Revivicor, Blacksburg.

Meeting: 2018 American Transplant Congress

Abstract number: 90

Keywords: B cells, Immunosuppression, Xenoreactive antibodies, Xenotransplantation

Session Information

Date: Sunday, June 3, 2018

Session Name: Concurrent Session: Xenotransplantation

Session Time: 2:30pm-4:00pm

 Presentation Time: 2:42pm-2:54pm

Location: Room 602/603/604

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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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To cite this abstract in AMA style:

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 [abstract]. https://atcmeetingabstracts.com/abstract/prevention-of-an-adaptive-immune-response-by-fda-approved-immunosuppressive-agents-in-baboons-with-pig-artery-patch-xenografts/. Accessed January 18, 2021.

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