title: Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy.
abstract: Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.
authors.affiliation: Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Khosraviani
authors.affiliation: Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Noel
authors.affiliation: Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Mohan
authors.affiliation: Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Donner
authors.affiliation: Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA. Electronic address: ahamad@jhmi.edu.
authors.forename: Abdel Rahim A
authors.initials: AR
authors.lastname: Hamad
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016753:Interleukin-10 / Q000008:administration & dosage / Q000009:adverse effects / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use*; D016688:Mice, Inbred NOD; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology / Q000628:therapy
chemical_list: C508609:IL10 protein, human; C556062:IL10 protein, mouse; D016753:Interleukin-10
keywords: Autoimmunity; B-cells; Fas pathway; Interleukin-10; gld