Exploiting apoptosis for therapeutic tolerance induction.
Immune tolerance remains the most promising yet elusive strategy for treating immune-mediated diseases. An experimental strategy showing promise in phase 1 clinical studies is the delivery of Ag cross-linked to apoptotic leukocytes using ethylene carbodiimide. This approach originated from demonstration of the profound tolerance-inducing ability of i.v. administered Ag-coupled splenocytes (Ag-SP) in mice, which has been demonstrated to treat T cell-mediated disorders including autoimmunity, allergy, and transplant rejection. Recent studies have defined the intricate interplay between the innate and adaptive immune systems in Ag-SP tolerance induction. Innate mechanisms include scavenger receptor-mediated uptake of Ag-SP by host APCs, Ag representation, and the required upregulation of PD-L1 expression and IL-10 production by splenic marginal zone macrophages leading to Ag-specific T cell regulation via the combined effects of cell-intrinsic anergy and regulatory T cell induction. In this paper, we discuss the history, advantages, current mechanistic understanding, and clinical potential of tolerance induction using apoptotic Ag-coupled apoptotic leukocytes.
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Daniel R
DR
Getts
Derrick P
DP
McCarthy
Stephen D
SD
Miller
D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017635:Clonal Anergy; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology / Q000628:therapy*; D007108:Immune Tolerance; D007113:Immunity, Innate; D007165:Immunosuppression Therapy / Q000379:methods* / Q000639:trends; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D051116:Receptors, Scavenger / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
D000941:Antigens; D060890:B7-H1 Antigen; D051116:Receptors, Scavenger; D016753:Interleukin-10