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Life-Supporting Pig Thymus Plus Kidney Transplantation Leads to Generation of New Baboon T-Cells and Swine-Specific Hyporesponsiveness

Y. Okumura1, K. Takeuchi1, Y. Ariyoshi1, T. Pomposelli1, L. Boyd1, D. Alper1, K. Miyake1, K. Okubo1, S. Arn1, D. Ayares2, M. Lorber3, M. Sykes1, D. Sachs1, K. Yamada1

1Columbia Center for Translational Immunology, Columbia University, New York, NY, 2Revivicor Inc., Blacksburg, VA, 3Lung BioTechnology PBC, Silver Spring, MD

Meeting: 2020 American Transplant Congress

Abstract number: 97

Keywords: Kidney transplantation, Preclinical trails, Thymic tolerance, Thymus transplantation

Session Information

Session Name: Xenotransplantation

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

 Presentation Time: 3:27pm-3:39pm

Location: Virtual

*Purpose: We have achieved greater than 6-month survivals in baboons that received vascularized thymus plus kidney xenotransplants (VT+K XTx). We assessed the thymic function and recipient immune responses >4 months post-transplant.

*Methods: Six baboon recipients that survived >4 months after VT+K XTx were studied. All animals underwent thymectomy and bilateral nephrectomy prior to XTx. Two received anti-CD154 mAb-based (129 and 193 days survivals) and the other four received anti-CD40 mAb-based immunosuppression (126, 154, 174 and 187 survivals). Three of the animals received grafts from GalTKO pig donors, without other transgenes, and three received grafts from hCD47+GalTKO pigs Tg for additional human complement +/- coagulation regulatory proteins. In vitro T cell responses as well as anti-donor antibodies were assessed using recipient PBMCs and kidney grafts. Graft cell infiltrates were examined with anti-CD3 and anti-FoxP3 Abs. Newly developed baboon T cells in peripheral blood were determined by anti-human CD3/CD4/CD31/CD45RA mAb.

*Results: All baboon recipients had stable renal function for the first 4 months. Some exhibited eventual increased serum creatinine (Cre) due to organ growth. No grafts showed signs of acute or chronic rejection histologically. All animals showed pig-specific hyporesponsiveness at all time points tested, including the day of euthanasia. Only one baboon, which was euthanized at POD187 due to SVC syndrome associated with MMF toxicity, developed anti-donor IgG after POD60 (PODs 90, 120 and 187), with no rise in Cre (0.6-0.9mg/dL), suggesting accommodation. The remaining five did not develop anti-pig Abs. One kidney displayed cell infiltrates around vessels without tubulitis or endothelialitis (biopsy at POD140) that were FoxP3+, consistent with Treg-rich organized lymphoid structures (TOLs). Three baboons (174, 187 and 193 days survivors) showed peripheral naïve recipient T cells, which gradually increased after POD60 post-VT+K XTx, suggesting recipient thymopoiesis in the donor pig thymus.

*Conclusions: Life-supporting porcine VT+K XTx in thymectomized baboon recipients led to new host T cell development and specific hyporesponsiveness to pig antigens, accompanied by development of FoxP3+ TOLs in the donor kidneys, without evidence of acute rejection.

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To cite this abstract in AMA style:

Okumura Y, Takeuchi K, Ariyoshi Y, Pomposelli T, Boyd L, Alper D, Miyake K, Okubo K, Arn S, Ayares D, Lorber M, Sykes M, Sachs D, Yamada K. Life-Supporting Pig Thymus Plus Kidney Transplantation Leads to Generation of New Baboon T-Cells and Swine-Specific Hyporesponsiveness [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/life-supporting-pig-thymus-plus-kidney-transplantation-leads-to-generation-of-new-baboon-t-cells-and-swine-specific-hyporesponsiveness/. Accessed May 9, 2025.

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