期刊
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
卷 11, 期 2, 页码 624-640出版社
E-CENTURY PUBLISHING CORP
关键词
Jak2; cardiac transplantation; chronic rejection; regulatory T cells; allograft
资金
- National Natural Science Foundation of China [81530024, 9174920038, 81770823, 81470988]
- Ministry of Science and Technology [2017ZX-09304022, 2016YFC1305002]
- Department of Science and Technology of Hubei State [2017ACA096]
- Integrated Innovative Team for Major Human Disease Programs of Tongji Medical College, Huazhong University of Science and Technology
Chronic rejection acts as the most formidable obstacle for organ transplantation in clinical settings. Herein we demonstrated in a cardiac transplantation model that blockade of Janus kinase 2 (Jak2) provides protection for cardiac allografts against chronic rejection. Specifically, loss of Jak2 almost completely abolished the production of IFN-gamma(+) Th1 cells, while the percentage of Foxp3(+) regulatory T cells (Tregs) was significantly increased. As a result, loss of Jak2 significantly prolonged allograft survival (58 +/- 30.6 days vs. 7 +/- 0.3 days). Particularly, 4 out of 13 Jak2 deficient recipients (30%) showed long-term acceptance of allografts as manifested by the graft survival time > 100 days. Cellular studies revealed that Jak2 deficiency did not impact the intrinsic proliferative capability for CD4(+) T cells in response to nonspecific polyclonal and allogenic stimulation. Mechanistic studies documented that the impaired Th1 development was caused by the attenuated IFN-gamma/STAT1 and IL-12/STAT4 signaling along with repressed expression of Th1 transcription factors T-bet, Hlx and Runx3. However, the IL-2/STAT5 signaling remained intact, which ensured normal Treg development in Jak2(-/-) naive CD4 T cells. Together, our data support that blockade of Jak2 may have therapeutic potential for prevention and treatment of allograft rejection in clinical settings.
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