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Generation of Human/Pig Hybrid Thymus to Achieve Immune Tolerance to Pig Antigens with Optimal Immune Function

M. Khosravi Maharlooei, H. Li, M. Holzl, A. Vecchione, A. Misra, A. Ruiz, R. Madley, G. Nauman, N. Danzl, G. Zhao, K. Yamada, M. Sykes

Columbia University, New York, NY

Meeting: 2019 American Transplant Congress

Abstract number: D68

Keywords: Thymic tolerance, Thymus transplantation, Tolerance

Session Information

Session Name: Poster Session D: Tolerance / Immune Deviation

Session Type: Poster Session

Date: Tuesday, June 4, 2019

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall C & D

*Purpose: Thymus transplantation is a promising approach to induce T-cell tolerance for xenotransplantation. We have previously shown that humanized mice generated with human hematopoietic stem cells (HSCs) and swine (SW) thymus grafts (SW/HU mice) are tolerant to human hematopoietic antigens. Our recent data suggests that, unlike humanized mice generated with human HSCs and autologous thymus grafts (HU/HU mice), human T cells in SW/HU mice are not tolerant to human tissue-restricted antigens (TRAs), presumably due to the lack of expression of human TRAs by SW thymic epithelial cells (TECs). While there was no significant difference between HU/HU vs SW/HU Treg suppressive capacity in auto, allo and xeno responses, we found that human CD8 and Treg cells have lower survival rates in SW/HU compared to HU/HU mice. We hypothesized that these problems and suboptimal positive selection of T-cells recognizing antigens presented by HLA might be overcome by creating a pig thymus containing human TECs.

*Methods: In order to generate a “hybrid thymus”, stromal cells of human fetal thymi (gestational age 20 weeks) were injected into freeze/thawed fetal SW thymic tissue and transplanted to NSG mice with human fetal liver CD34+ cells.

*Results: As SW thymocytes might potentially reject human thymic stromal cells, we tested strategies to deplete pig thymocytes. Ex vivo treatment of SW thymic fragments with 2 deoxy glucose (2DG), which competitively inhibits the production of glucose-6-phosphate from glucose, for 12 hours most effectively depleted the thymocytes while preserving the capacity of SW thymic tissue to support thymopoiesis. HuTEC-injected SW thymi were functional and supported human thymopoiesis. Human mTECs and cTECs were admixed with pig TECs in long-term hybrid thymi. Peripheral T-cells of mice generated with fetal TEC-injected SW thymi were hyporesponsive to human TEC donor-derived DCs. However, dynamics of T cell development in mice with hybrid thymus were closer to those in SW/HU than HU/HU mice.

*Conclusions: In conclusion, injection of human thymic stromal cells into pig thymus can generate a human/pig hybrid thymus with an impact on tolerance.

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To cite this abstract in AMA style:

Maharlooei MKhosravi, Li H, Holzl M, Vecchione A, Misra A, Ruiz A, Madley R, Nauman G, Danzl N, Zhao G, Yamada K, Sykes M. Generation of Human/Pig Hybrid Thymus to Achieve Immune Tolerance to Pig Antigens with Optimal Immune Function [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/generation-of-human-pig-hybrid-thymus-to-achieve-immune-tolerance-to-pig-antigens-with-optimal-immune-function/. Accessed June 2, 2025.

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