Sustained-Release Microparticle-Based Antirejection Therapy Through Enhancement of Regulatory T Cells (SMARTER) Platform for VCA Immunomodulation
Abstract
Background and Rationale: The proposed study examines the RTRP topic area of vascularized composite allotransplantation (VCA). VCA 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 U.S. armed conflicts. While significant advances have been made in this field, the bane of VCA continues to be rejection of the transplant. The problem of rejection in VCA is very similar to that encountered in solid organ transplantation; however, the complications from rejection are actually exacerbated, as VCA 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 being 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 this “balanced” state of the immune system is maintained in healthy individuals in part by a group of suppressive immune cells known as regulatory T cells (Tregs). 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 has developed SMARTER novel technologies to harness the body’s own innate mechanisms to regulate immune responses and prevent VCA rejection via the recruitment and expansion of a patient’s own regulatory T cells (Treg). Approach: Our group has recently developed SMARTER controlled-release drug delivery systems consisting of synthetic microparticles that provide local, sustained release of very small amounts of a protein (called CCL22) (Recruitment-MP) and also (separately) a unique combination of suppressive factors (TGFb-MP, Rapamycin-MP, and IL-2MP) (Expansion-MP) that can influence the behavior of the body’s own regulatory cells. As such, our work suggests that subcutaneous administration of either Recruitment-MP or Expansion-MP can prevent hind-limb allograft rejection and promote donor antigen-specific tolerance to the transplanted graft. Further, the observed tolerance is likely due to the local recruitment and induction of Tregs. The studies proposed in this proposal are meant to focus on scaling this technology in large animal preclinical studies preparation for first-in-human studies. Accordingly, we propose to test this SMARTER technology in a preclinical, face transplant model in non-human primates (NHP). In addition to measuring the effectiveness of recruiting/inducing Tregs at the site of VCA, we will also explore the mechanisms by which SMARTER Recruitment-MP and TRI-MP prolong survival of the face flap in NHP. 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 VCA research. In the proposed research, we plan to demonstrate the effectiveness of the aforementioned SMARTER drug delivery systems to prevent VCA rejection in the NHP Face Transplant flap model. In the long term, we believe that the outcomes of the proposed research have the ability to substantially impact t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110933
Entities
People
- Vijay S Gorantla
Organizations
- United States Army
- Wake Forest University