Reparative Treg and Microparticle Therapy for the Prevention of VCA Acute and Chronic Rejection
Abstract
Rationale: Vascular composite Allograft (VCA) transplantation (Tx) involves the Tx of a functional unit of multiple tissues, such as skin, muscle, tendon, nerve, and bone. This approved clinical procedure can restore function, sensation, and appearance for Wounded Warriors suffering serve wounds to their hands, limbs, and face. Despite encouraging patient and graft survival, the widespread application of the life-enhancing benefits of VCA has been hampered by the toxicity and complications associated with high-dose, multi-drug immunosuppression necessary to prevent graft rejection by the recipient’s immune system. By blunting general immune responses, immunosuppression increases infections and cancer. Immunosuppressive drugs are highly toxic and cause kidney and heart failure. Even at levels causing these side effects, immunosuppressants do not prevent or reverse fibrotic scarring and block graft vasculature that will eventually cause graft loss. Objective: Our collaboration aims to harness the mechanisms the immune system uses daily to regulate the responses of other immune cells and complete tissue repair after injury. It is known that regulatory T cells (Treg) are a type of immune cell that has a potent ability to suppress the immune responses of other immune cells. Treg are critical for preventing autoimmunity, but recent studies in experimental Tx models suggest that their suppressive functions can be redirected to support Tx tolerance, or specifically to block antigraft immune responses. Yet, recent clinical trials have found that high doses of suppressive Treg cells do not persist in the graft and have not limited donor-specific immune responses. We have recently developed a degradable, controlled-release microparticle (MP) delivery system capable of sustaining a gradient of Treg attractants. Delivery of these MP increased intra-graft Treg and prolonged VCA survival in rodents. We have also identified a unique and rare subset of Treg that, while suppressive, also support tissue repair. These reparative Treg (RepTreg) respond to signals released during injury to direct other cells to mediate tissue repair and stimulate local tissue cell proliferation and survival. We believe we can use our combined expertise in Treg biology, VCA surgery, and bioengineering of drug delivery systems to develop RepTreg cell therapy and local delivery of Treg-attracting MP as a highly effective means to induce routine Tx tolerance and reduce graft fibrotic and vascular pathology after VCA. FY20 RTRP Focus Area: Reduce the risks of VCA-associated immunosuppression Develop novel approaches for improving VCA immune tolerance Patients Impacted and Clinical/Personal/Family Benefits: There are more than 1,600 U.S. military amputees due to Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn alone. Approximately a third of these are dual amputees. It is also estimated that there are currently over 2 million U.S. citizens living with limb loss. By reducing the need for immunosuppression through tolerance induction and developing a novel immunotherapy able to address fibrosis and vasculopathy, we will help remove the medical and ethical barriers standing in the way of routine application of VCA to improve the life quality of these America’s Wounded Warriors and U.S. citizens. Our studies will establish whether Treg cell therapy can be enhanced by directing Treg to sites of the desired action. If successful, this strategy could improve on the limited clinical success of Treg cell therapy after solid organ Tx. They may reduce the number of expanded Treg needed for administration in Tx or aid ongoing Treg cell therapy clinical trials for autoimmunity or other pro-inflammatory diseases. Time to Patient-Related Outcomes: The proposed studies represent the initial investigation into the impact of RepTreg in VCA. At the end of the funding period, we will have mechanism-rich information on the effe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110896
Entities
People
- Steven R. Little
Organizations
- United States Army
- University of Pittsburgh