ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

Abstract

A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing ␤ cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptorprogrammed death ligand 1 signaling pathway and CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.anergy ͉ programmed death-1 ͉ regulatory T cells ͉ transplantation ͉ islet transplantation

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

“…We previously demonstrated the ability of i.v.-administered Ag-SP to induce tolerance in models of autoimmunity, transplant, and allergy (4,10,12). Ag-SP uses natural tolerogenic pathways, targeting apoptotic cells to the splenic marginal zone via scavenger receptor-mediated uptake, resulting in induction of IL-10 and PD-L1 on APCs and, ultimately, T-cell anergy and regulatory T-cell (Treg) activation (10).…”

Tolerance Strategies Employing Antigen-Coupled Apoptotic Cells and Carboxylated PLG Nanoparticles for the Treatment of Type 1 Diabetes

“…In mice treated with ECDI-fixed donor leukocytes, accumulation of Tregs is seen in peri-isletinfiltrating cells in islet grafts [51,52]. Depletion of Tregs or treatment with anti-TGF-β, which has been shown to be effective in the induction of Tregs in vivo prior to or at the time treatment, abolished the protective effects of ECDI-fixed donor leukocytes [18]. However, if depletion of Tregs was induced after tolerance no graft rejection occurred, suggesting that Tregs are required for induction of tolerance, but that maintenance of tolerance was probably mediated through T cellintrinsic tolerogenic mechanisms.…”

“…Indefinite tolerance to subsequent allogeneic islet cell transplantation was established in diabetic mice by i.v. infusion of donor splenic leukocytes rendered apoptotic by fixation using ECDI, with no requirement for maintenance immunosuppression [18]. Treated mice exhibited reduced DTH responses to donor antigens, were devoid of donorspecific antibodies (Abs), and showed reduced donor-specific proliferation and IFN-γ production in mixed lymphocyte cultures.…”

“…The therapy has recently proven safe and has shown some efficacy in a magnetic resonance imagingcontrolled phase I clinical trial in relapsingremitting MS patients at the Center for Multiple Sclerosis, University of Hamburg, Germany [14]. In addition to EAE and MS, the efficacy of Ag-ECDI-SP has been demonstrated in other immunemediated inflammatory conditions, including T1D [15,16], allergy [17], and islet transplant rejection [18]. This review focuses on the use and mechanisms of tolerance induction using Ag-ECDI-SP and Ag-coupled biodegradable poly(lactide-coglycolide) (Ag-PLG) nanoparticles in experimental mouse models of T1D.…”

Nano- and micro-based systems for immunotolerance induction in multiple sclerosis

“…The administration of peptides crosslinked to splenic leucocytes demonstrated very promising results, inducing a robust antigen-specific tolerance. 26,27 Nonetheless, in order to circumvent the use of cellular components and the drawbacks associated, like cost and manipulation, researchers have been focused in the development of alternative strategies based on nanoparticulate systems. The premise is that nanoparticles crosslinked with disease-associated antigens and their epitopes can target antigen-presenting cells (APCs) capable to regulate T-cell function and simultaneously support the induction and/or expansion of regulatory T-cells (Tregs), restoring immunological tolerance.…”