It’s Time to Bring Dendritic Cell Therapy to Type 1 Diabetes

  1. C. Garrison Fathman4
  1. 1Department of Medicine, Columbia Center for Translational Immunology and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY
  2. 2Division of Immunogenetics, Department of Pediatrics, John G. Rangos Research Center, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA
  3. 3Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL
  4. 4Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
  1. Corresponding author: C. Garrison Fathman, cfathman{at}stanford.edu.

Type 1 diabetes (T1D) is an autoimmune disease that results from a deficient induction or maintenance of tolerance to islet β-cell antigens, allowing the eventual T-cell–mediated destruction of insulin-producing β-cells within the pancreatic islets (1). Under homeostatic conditions, immune tolerance is established by various subsets of antigen-presenting cells (APCs) with tolerance-inducing/maintaining (tolerogenic) functions and reinforced by other cells with suppressor and immunomodulatory properties. T-cell tolerance manifests itself through elimination (deletion), inactivation (anergy), or suppression of self-reactive T cells (Fig. 1A). These functions may be performed by a variety of tolerogenic APCs (Table 1), some of which have the ability to induce/boost regulatory T cells (Tregs) and/or B cells (Bregs). Genetic and environmental factors that vary among different individuals contribute to the development of T1D, in part by impacting mechanisms of tolerance (Fig. 1B). Therefore, a major goal for the prevention and/or reversal of T1D is to restore effective and durable tolerance to either prevent further destruction of remaining islet β-cells, help islet β-cell regeneration, or protect islet transplants and obviate the use of nonspecific immunosuppressive drugs. The approach reviewed here consists of developing a personalized therapy using the patient’s own cells manipulated to perform as tolerogenic APCs (Fig. 1C). In this review, we will explain why dendritic cells (DCs) are the tolerogenic cells of choice to fulfill the goal of restoring immune tolerance in T1D as part of a potentially powerful and safe cellular immunotherapy, the next generation of therapies (2). We will present the clinical considerations and challenges ahead and the plans to address them, taking into account lessons learned from animal models such as the NOD mouse.

Figure 1

Tolerance to β-cell antigens: induction, loss, and restoration. A: Tolerance to β-cell antigens is induced and maintained by tolerogenic cells comprised of migratory DCs transporting antigens from peripheral to lymphoid …

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