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Enrichment of Suppressive Lymphocytes via Biomimetic Constructs Promotes Immune Tolerance in Vascularized Composite Allotransplantation
James D. Fisher, BS, Riccardo Schweizer, MD, Jignesh Unadkat, MD, Chiaki Komatsu, MD, Sinan Oksuz, MD, Mario Solari, MD, Vijay Gorantla, MD, Steven Little, PhD.
University of Pittsburgh, Pittsburgh, PA, USA.
BACKGROUND:
Vascularized composite allotransplantation (VCA)_encompassing transplantation of hands/limbs and face is an emerging field with potential to restore the appearance and function of damaged tissue. Clinically, the process of rejection is suppressed via systemic immunosuppression, which is associated with a host of deleterious side effects.1 An alternative approach to prevent rejection is to harness the homeostatic mechanisms intrinsic to the immune system.2 To this end our group has recently developed controlled release microparticle (MP) systems capable of enriching suppressive lymphocytes (known as Regulatory T Cells or Tregs) at given location via synthetic constructs referred to as Expansion MP.3 Accordingly, we hypothesized that Treg enriching systems that release key cytokines, and immunosuppressive agents, can promote long term graft survival in preclinical VCA models.
METHODS:
Following fabrication, Expansion MP was tested in an allogeneic rat hind limb transplant model. Animals received two subcutaneous doses of Expansion MP at postoperative days 0 and 18. Grafts were monitored daily for rejection using the BANNFF Classification.
RESULTS:
Following subcutaneous injection of microparticles, rodent hind limbs survived indefinitely (>300 days) with control animals reliably rejecting their limbs by postoperative day 40. Secondary skin grafts and MLRs in the rodent model demonstrate that ExpansionMP treatment appears to confer donor specific tolerance to recipients.
CONCLUSIONS:
Given these promising results, we believe that this technology has the potential to dramatically impact the field of VCA and reconstructive transplantation. Future work will be devoted to optimization of the microparticle treatment in both large and small animal models with the ultimate goal of submitting an IND application to the FDA.
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