Nanoparticle delivery of donor antigens for transplant tolerance in allogeneic islet transplantation

Abstract

Human islet cell transplantation is a promising treatment for type 1 diabetes; however, long-term donor-specific tolerance to islet allografts remains a clinically unmet goal. We have previously shown that recipient infusions of apoptotic donor splenocytes chemically treated with 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (donor ECDI-SP) can mediate long-term acceptance of full major histocompatibility complex (MHC)-mismatched murine islet allografts without the use of immunosuppression. In this report, we investigated the use of poly(lactide-co-glycolide) (PLG) particles in lieu of donor ECDI-SP as a synthetic, cell-free carrier for delivery of donor antigens for the induction of transplant tolerance in full MHC-mismatched murine allogeneic islet transplantation. Infusions of donor antigen-coupled PLG particles (PLG-dAg) mediated tolerance in ~20% of recipient mice, and the distribution of cellular uptake of PLG-dAg within the spleen was similar to that of donor ECDI-SP. PLG-dAg mediated the contraction of indirectly activated T cells but did not modulate the direct pathway of allorecognition. Combination of PLG-dAg with a short course of low dose immunosuppressant rapamycin at the time of transplant significantly improved the tolerance efficacy to ~60%. Furthermore, altering the timing of PLG-dAg administration to a schedule that is more feasible for clinical transplantation resulted in equal tolerance efficacy. Thus, the combination therapy of PLG-dAg infusions with peritransplant rapamycin represents a clinically attractive, biomaterials-based and cell-free method for inducing long-term donor-specific tolerance for allogeneic cell transplantation, such as for allogeneic islet transplantation.

Harnessing Nanoparticles for Immune Modulation

“…For example, studies often fail to perfuse animals before tissue examination [45][46][47][48][49], making it difficult to discriminate between NPs in the bloodstream and NPs adherent to the endothelium or NPs that have gained access to the organ parenchyma. In non-perfused animals after intravenous (IV) NP administration, the high intravenous NP content in organs with large blood volumes makes assessment of biodistribution extremely difficult by most modalities and the accurate evaluation of NP interactions with specific cells in the tissue virtually impossible (D.R.…”

Cellular and molecular targeting for nanotherapeutics in transplantation tolerance

“…Significant success was observed within the context of coupling antigens to cells as a delivery vehicle, and this strategy has more recently progressed to using polymer nanoparticles as carriers for the antigen. Initial advancements with tolerance induction have been within autoimmune disease models due to the presence of distinct, identifiable antigens, though these approaches have been extended to transplantation [15-17]. The following sections describe progress and opportunities regarding the induction of transplant tolerance with nanocarriers, which offer a platform for delivering antigens of interest, the capacity for specific cell targeting by incorporation of antibodies or ligands, and an opportunity for local immunomodulation through delivery of drugs or proteins.…”

Tolerogenic Nanoparticles to Treat Islet Autoimmunity

“…The treatment was successful in producing tolerance in about 20% of recipient mice. Adding a small dose of rapamycin to the nanoparticle treatment increased that number to approximately 60% [121•]. Wang et al [102] used the previously described magnetic nanoparticles conjugated to siRNA to inhibit rejection in a kind of xenograft of human islet to NOD.Scid mice reconstituted with NOD splenocytes.…”

“…a Nanoparticles targeting APCs. Top : MARCO receptor dependent uptake of antigen-coupled and antigen-encapsulating PLG [98•, 116••, 117••, 118••, 119•, 120••, 121•, 122]. Middle : PLG encapsulating both antigen and rapamycin [109, 110].…”