Mechanisms of placental mimicry cell therapy

About This Grant

SUMMARY Cell therapies are a promising alternative therapy for the treatment of type 1 diabetes, and stem cell-derived insulin secreting beta cells (sBC) have demonstrated the feasibility of restoring insulin independence in clinical models. However, this strategy has limited long-term application due to the requirement of ineffective and toxic immunosuppressive drug regimens and immune rejection, which currently limits the applicable patient pool to high-risk patients. The leading commercial entities clinically testing stem cell-derived islet replacement products are pursuing macroencapsulated cell delivery methods to overcome this critical hurdle to translation. Macroencapsulation devices can blunt immune responses to the graft and confer the safety benefit of cell delivery in a single, retrievable device. However, functional clinical success of these devices has not been demonstrated to date due in part to inevitable antigen shedding resulting in indirect antigen recognition, which results in immune destruction of encapsulated cells. Thus, synergistic immunomodulatory approaches are necessary to fully immunoprotect encapsulated cell grafts, and achieve immunological tolerance in the absence of immune suppression. The fetal-maternal interface is a robust model of immune tolerance toward allogeneic tissue, where placental trophoblasts maintain tolerance by two main approaches: (1) presenting an inert surface to maternal immune cells, a strategy akin to cell encapsulation which blocks direct antigen recognition; and (2) through secretion of tolerogenic factors which induce tolerance toward fetal antigens that escape the placenta. Our preliminary data demonstrates that a macroencapsulated tolerogenic trophoblast cell therapy can evade rejection and delay rejection of bystander macroencapsulated cell grafts in a challenging xenotransplant model. In this proposal, we aim to (1) validate our preliminary studies using translatable cell sources of sBC and trophoblasts, and (2) elucidate the immunological mechanisms of trophoblast cell therapy-induced tolerance in xeno and humanized allogeneic transplantation models. This will be addressed in three Specific Aims: (1) Identify immune mechanisms of trophoblast cell therapy-induced transplant site-dependent graft tolerance, (2) Optimize and characterize tolerogenic cell therapy dose impact on tolerance induction, and (3) Untangle the contributions of antigen-specific and non-specific mechanisms of trophoblast cell therapy tolerance induction. In this work, we expect to identify the immunological mechanisms by which tolerogenic trophoblast cell therapies delay or prevent immune rejection.