Stephen D. Miller, PhD

Northwestern University, USA

Title: An antigen-specific tolerance approach to therapy of autoimmune disease and tissue transplantation

Abstract:

Our previous results have shown that chronic progression of relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse (a mouse model of multiple sclerosis) is dependent on the activation of T cells to endogenous myelin epitopes released during acute disease, i.e. epitope spreading. Our laboratory is investigating antigen-specific modalities for therapy of established disease. Provided the correct autoepitope(s) are targeted, disease progression can be both prevented and treated by induction of antigen-specific tolerance using the intravenous injection of syngeneic myelin peptide-pulsed splenic antigen presenting cells (Ag-SP) fixed with the chemical cross-linker, ethylene carbodiimide (ECDI).  In the R-EAE model of MS, we have shown that tolerance can be induced to multiple myelin epitopes simultaneously by using cocktails of self peptides to prepare the Ag-SP. We have also recently used Ag-SP tolerance to demonstrate a role for epitope spreading in the pathogenesis of type 1 diabetes (T1D) in the NOD mouse. Our results indicate that the insulin B chain epitope (Ins B9-23) is the initiating diabetogenic epitope in NOD mice as tolerance induced with either intact insulin (Ins-SP) or Ins B_9-23 (InsB_9-23-SP), but not with GAD65_509-528, GAD65_524-543, or IGRP_206-214 coupled splenocytes at 4-6 weeks of age inhibits diabetes development.  In contrast, regulation of new onset diabetes in 18-20 week old NOD mice is only induced by tolerization with Ins-SP, not InsB_9-23-SP, suggesting spreading to a distinct insulin epitope. Lastly, we have demonstrated that ECDI-fixed allogeneic APCs is a powerful way to induce allo-specific tolerance for the successful long-term survival of transplanted pancreatic islet cells for the treatment of T1D without any requirement for immunosuppression. Ag-SP tolerance appears to be due primarily to an indirect mechanism involving re-presentation of apoptotic Ag-SP by host splenic APCs which induces two independent, but synergistic mechanisms of regulation - cell-intrinsic PD-1/PD-L1-mediated clonal anergy and the activation antigen-specific Foxp3+ regulatory T cells (Tregs). A critical role for the spleen in tolerance induction is indicated by the requirement for i.v. injection of Ag-SP to induce efficient unresponsiveness, the failure to induce tolerance in splenectomized hosts, and the concentration of the apoptotic Ag-Sp debris in the marginal zone of the spleen. Host APCs which are required for efficient tolerance induction appear to consist of both splenic CD8- DCs and marginal zone macrophages.  The potential role of various scavenger receptors on these cells for uptake of the apoptotic Ag-SP and the response of these APCs to engagement with Ag-SP uptake is currently under investigation.

Biography:

Stephen D. Miller, PhD, received both his undergraduate and graduate degrees from Pennsylvania State University.  After being awarded a PhD in immunology in 1975, Dr. Miller pursued a National Institutes of Health (NIH) fellowship in cellular immunology at University of Colorado Health Sciences Center in Denver.  Upon completion of his fellowship, Dr. Miller joined the faculty at University of Colorado and went on to achieve the title of assistant professor of Medicine and Microbiology-Immunology.

Dr. Miller moved to Northwestern in 1981 as an assistant professor of Microbiology-Immunology.  In 1992, he was named a full professor.  He was named the Congressman John E. Porter Professor of Biomedical Research in 2000 and was named the Judy Gugenheim Research Professor in Autoimmunity in 2007.  In addition to serving as Director of the Interdepartmental Immunobiology Center, Dr. Miller leads the Immunology and Molecular Pathogenesis Training Program.

His research focuses on understanding the cellular and molecular mechanisms of immunopathogenesis and immunoregulation of T cell-mediated autoimmune responses and the role they play in the induction and progression of autoimmunity with particular interests in animal models of multiple sclerosis (experimental autoimmune encephalomyelitis) and type 1 diabetes (diabetes in the NOD mouse).  His lab has contributed to the understanding of epitope spreading in driving progressive CNS autoimmune disease, the role of peripheral dendritic cells in presentation of endogenous CNS antigens, the mechanisms underlying induction of CNS autoimmune disease following infection with Theiler’s murine encephalomyelitis virus, and the use of specific immune tolerance for treatment of established autoimmune disease and for the prevention of rejection of tissue transplants.  His research is supported by various NIH grants, and grants from the National Multiple Sclerosis Society, the Myelin Repair Foundation, and the Juvenile Diabetes Research Foundation.

Author of more than 290 publications, Dr. Miller serves on the editorial boards of Virology, Viral Immunology, the European J. Immunology, and is Deputy Editor of Cellular Immunology.  In the past, he has served as a permanent member of the NIH Neurological Sciences 3 Study Section, the National Multiple Sclerosis Society Study Section Panel B, the Juvenile Diabetes Research Foundation Immunology Study Section, and the NIH ‘Immune Tolerance Network’ Steering Committee.  He is past Chair of the American Association of Immunologists Publications Committee, and an elected Fellow of the American Association for the Advancement of Science and the American Academy of Microbiology.