Journal
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
Volume 11, Issue 2, Pages 624-640Publisher
E-CENTURY PUBLISHING CORP
Keywords
Jak2; cardiac transplantation; chronic rejection; regulatory T cells; allograft
Categories
Funding
- 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
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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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