Targeting JAK2 and Aurora Kinase to Prevent Allograft Rejection
Abstract
Focus Area: Immune system regulation; optimizing immunosuppressive drug regimens. Service members who survive blast injuries endure significant physical and social challenges. Resultant tissue damage may require amputation or extensive reconstructive surgery. Vascular composite tissue allotransplantation (VCA) is a specialized form of transplantation that surgically replaces whole anatomic structures from cadaveric donors, such as hands, limbs, and even facial tissue. While VCA brings form and function back to severely wounded Service members, the transplanted body tissues are at high risk of rejection by the recipient s immune system. To prevent rejection, doctors use strong medications that broadly impair the recipient s immune system. Unfortunately, these medications do not fully protect the transplanted tissues. The long-term use of nonselective immune suppressants also increases the risk of serious viral infections and secondary cancers. We have developed an innovative strategy that selectively controls the recipient s immune system, without blunting their ability to fight viruses or cancer cells. Our approach uses medications to turn off inflammatory signals (called JAK2 and Aurora kinase) in the recipient s white blood cells. This directs the recipient s immune system to recognize the transplanted donor tissues as "self" and prevents rejection. To test this concept, mice lacking an immune system will be transplanted with human skin and white blood cells from a different donor to induce rejection. We will study whether blocking JAK2 and Aurora kinase together prevents tissue rejection better than either alone, without dampening normal immune function. These experiments will also reveal how blocking JAK2 and Aurora kinase affects immune recognition of foreign versus host tissues, as well as viruses. Successful completion of this work has high likelihood of overcoming the challenge of tissue rejection after VCA. We expect this approach will significantly improve outcomes after VCA and bring independence back to wounded Service members after catastrophic blast injuries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610686
Entities
People
- Brian C Betts
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army