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.
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 July 7, 2020.
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