Regulatory T Cell-Enriching Microparticles for Promoting Vascularized Composite Allotransplant Survival
Abstract
Focus Area: Immunomodulation approaches and mechanisms, e.g., tolerance induction, chimerism/Optimizing immunosuppressive drug regimens. Background and Rationale: The proposed study examines the PRMRP topic area of composite tissue allotransplantation (CTA). CTA is an emerging field encompassing transplantation of hands, limbs and face. This is particularly relevant as extremity injuries account for the majority of combat wounds incurred during US armed conflicts. While significant advances have been made in this field, the bane of CTA continues to be rejection of the transplant. The problem of rejection in CTA is very similar to that encountered in solid organ transplantation; however, the complications from rejection are actually exacerbated as CTA involves transplantation of the skin, which is notorious for rapidly rejecting. In the clinic, the process of rejection is treated by the continuous delivery of potent anti-rejection medications that suppress a patient s immune system . While the current treatments are effective at preventing acute rejection, they do little to delay the process of long-term chronic rejection. Moreover, these drugs are associated with a host of deleterious side effects including kidney and liver failure. That said, if there were a way to locally shift the immune system to a balanced state (called "homeostasis") rather than suppress the entire immune system, it would be possible for the transplant to survive indefinitely without a lifelong regimen of anti-rejection medications. It is known that such a balanced state in the immune system is maintained in healthy individuals by a group of suppressive immune cells known as regulatory T cells (Tregs). These Tregs have the capability to secrete a number of factors that can influence the immune system. Further, it has been shown that the presence of these cells in a transplanted graft can actually prevent the process of rejection. Accordingly, our group is currently developing novel technologies to harness the body s own natural mechanisms to regulate immune responses and prevent CTA rejection via the recruitment and expansion of a patient s own regulatory T cells (Treg). Approach: Our group has developed a controlled release drug delivery system consisting of small microspheres that provide sustained release of a certain protein (called CCL22) that can attract Tregs. As such, we propose to test and optimize these microspheres in an animal model of CTA (rat hind limb transplantation). Specifically, we will inject various doses of our novel CCL22 releasing microspheres into the transplanted hind limb of rats and we will assess the ability of these microspheres to prevent rejection and promote long-term acceptance of the graft. In addition to recruiting Tregs to the site of CTA to prevent rejection, we are also going to explore the possibility of expanding numbers of Tregs in the transplanted graft. Our group has recently identified a unique combination of suppressive factors that can actually expand naturally occurring Tregs. Further, we have demonstrated that we can achieve sustained, controlled release of these factors from microspheres. Accordingly, we also propose to test this technology in both rat and swine models of CTA, with the hope of demonstrating that these factors will also be able prevent rejection of transplanted limb. This application brings together Principal Investigators from multiple departments with various backgrounds. Dr. Little brings a unique combination of scientific expertise in the development of controlled release drug systems, whereas Dr. Gorantla is a leader in the field clinical reconstructive transplantation (hand and face) and transplant immunology as it pertains to CTA research. In the proposed research, we plan to demonstrate the effectiveness of the aforementioned drug delivery systems to prevent CTA rejection. In the long term, we believe that the outcomes of this research have the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1510244
Entities
People
- Steven R. Little
Organizations
- United States Army
- University of Pittsburgh