Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in the destruction of insulin-secreting β cells of the islets of Langerhans. Allogeneic islet transplantation could be a successful treatment for T1DM; however, it is limited by the need for effective, permanent immunosuppression to prevent graft rejection. Upon transplantation, islets are rejected through non-specific, alloantigen specific, and recurring autoimmune pathways. Immunosuppressive agents used for islet transplantation are generally successful in inhibiting alloantigen rejection, but they are suboptimal in hindering non-specific and autoimmune pathways. In this review, we summarize the challenges with cellular immunological rejection and therapeutics used for islet transplantation. We highlight agents that target these three immune rejection pathways and how to package them for controlled, local delivery via biomaterials. Exploring macro-, micro-, and nano-scale immunomodulatory biomaterial platforms, we summarize their advantages, challenges, and future directions. We hypothesize that understanding their key features will help identify effective platforms to prevent islet graft rejection. Outcomes can further be translated to other cellular therapies beyond T1DM.

Keywords: Allogeneic; Allograft; Autoimmunity; Biomaterials; Controlled release; Immune rejection; Immunosuppression; Islet transplantation.

Fig. 1.

Key cellular players involved in the progression of immunological rejection of transplanted allogeneic cells and common therapeutics (A) Non-specific antigen rejection involves the release of damage associated molecular patterns (DAMPs) and alloantigens, upregulation of tissue factor (TF) expression, and blood platelet binding to initiate the instant blood mediated inflammatory cascade (IBMIR). Neutrophils recognize DAMPs and alloantigens, recruit NK cells to induce islet apoptosis, and recruit antigen presenting cells (APCs) to phagocytose, process shed cellular debris, and travel to local draining lymph nodes. (B) Upon traveling to the lymph nodes, APCs present alloantigens and co-stimulatory signals primarily to T cells. CD4⁺ T cells help activate B and CD8⁺ T cell effector functions. B cells expand and mature to secrete donor specific antibodies, which tag the donor cells for attack and phagocytosis. CD8⁺ T cell clones expand, mature, and exit the lymph node to induce their cytotoxic effect on donor islets. (C) Shedding of autoantigens initiates the reactivation and clonal expansion of β cell specific memory T and B cells, which then execute their effector functions to destroy the β cells. (D) Common therapeutics currently being studied for their immunoprotective effect of transplanted cellular grafts include biologics and small molecule drugs that target key immune cells involved in the three immunological rejection pathways.

Fig. 2.

Advantages and disadvantages of systemic versus local delivery of immunosuppressants for the protection of allogeneic islet transplants. (A) Systemic immunosuppression, while potent for clinical islet transplantation, has many disadvantages, as noted. Upon administration, most agents have poor bioavailability and distribution in systemic circulation, leading to high clearance and off target effects to other organs. Because islets are transplanted in the liver, high drug dosages can also contribute to β cell toxicity before their concentrations are reduced after first-pass metabolism. (B) Local delivery of immunosuppressants can localize the agent directly to the transplant site. This provides distinct advantages, as noted. While patient compliance is not required with an implantable device, the amount of drug in the device is finite and eventually expires. Within the graft, the drug is typically restricted to the implant site and/or the local draining lymph nodes, thereby imparting a more targeted effect.

Fig. 3.

Summary of current drug delivering devices engineered for the immunoprotection of cellular transplants categorized by scale (A) Macroscale drug delivery devices, such as porous scaffolds and hydrogels, are site retained and can house both the allogeneic islets and drug source in one location. (B) Microscale drug delivery devices hold the therapeutic agent only, can be injected with islets, and are retained at the graft site for immunoprotection of the allogeneic cells. (C) Nanoscale drug delivery devices are unique in that they can travel to local lymph nodes to directly inhibit immune rejection of the transplanted allogeneic islets. A subset of nanoparticles are liposomes and micelles, which are particularly useful for incorporating hydrophilic or hydrophobic agents, respectively. Without immune intervention via drug delivering devices, allogeneic islets can be rejected through non-specific, alloantigen specific, and recurring autoimmune rejection pathways.