Regulatory T Cell-Enriching Microparticles for Promoting Vascularized Composite Allotransplant (VCA) ToleranceFisher, James (2018) Regulatory T Cell-Enriching Microparticles for Promoting Vascularized Composite Allotransplant (VCA) Tolerance. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractVascularized Composite Allotransplantation (VCA) is an emerging field encompassing transplantation of limbs and face. In clinical VCA, combination therapy with two or more immunosuppressive drugs is standard. Nonetheless, side effects associated with the administration of lifelong, high dose, multidrug immunosuppression continue to hamper wider implementation of VCA. Greater feasibility, wider acceptability and routine applicability of VCA will only be realized if the risks of transplant rejection and chronic immunosuppression are minimized. An immediate goal is the exploration of novel strategies that achieve donor-specific immune hypo-responsiveness via local immunomodulation, minimizing or eliminating the need for systemic immunosuppression. Interestingly, the cells of our bodies have evolved to utilize a host of strategies to maintain immunological homeostasis, representing a level of sophistication that dwarfs current attempts at immunosuppression. As a hallmark example, our bodies contain a subset of lymphocytes called regulatory T cells (Treg) that play a critical role in establishing and maintaining immunological homeostasis. However, because Tregs are found in low numbers throughout the body, strategies to harness them for therapeutic use have thus far focused on ex vivo expansion followed by in vivo re-administration. Though promising, the clinical implementation of these approaches is faced with numerous logistical and regulatory hurdles. To this end, our group has developed synthetic approaches utilizing cell sized, biocompatible, biodegradable microspheres composed of poly(lactide-co-glycolide) acid (PLGA) capable of releasing factors that can locally enrich for Treg. Specifically, PLGA microparticles that release the Treg recruiting chemokine CCL22 (referred to as Recruitment-MP) were fabricated and tested for their ability to prevent allograft rejection in a rodent model of hindlimb transplantation. Indeed, Recruitment-MP was able to prolong hind limb survival indefinitely and promote donor antigen-specific tolerance. Finally, an alternative strategy to locally enrich for Tregs via their induction from Naïve T cells was described. Treg Inducing microparticles (TRI-MP) that release TGF-, Rapamycin, and IL-2, were also able to promote long-term graft survival and (importantly) induce donor-specific tolerance. Taken together, the Treg enriching formulations described herein are synthetic systems that take inspiration from nature’s mechanisms for resolving inflammation and have the potential to prevent aberrant inflammation in the context of allotransplantation. Share
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