Β‐cell‐specific IL‐35 therapy suppresses ongoing autoimmune diabetes in NOD mice. Issue 1 (25th November 2016)

• Record Type: Journal Article
• Authors: Manzoor, Fatima; Johnson, Mark C.; Li, Chengwen; Samulski, R. Jude; Wang, Bo; Tisch, Roland
• Is Part Of: European journal of immunology. Volume 47:Issue 1(2017)
• Page Start: 144
• Page End: 154
• Publication Date: 2016-11-25
• Subjects: β cell -- Cytokine immunotherapy -- IL‐35 -- NOD mice -- Type 1 diabetes; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201646493
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract : IL‐35 expression by β cells following adeno‐associated viral vector immunotherapy inhibits proliferation and reduces islet CD4 + and CD8 + T cells, and Foxp3 + Treg; islet dendritic cells are also decreased. Islet Foxp3 + Treg selectively inhibit IFNγ production by CD4 + T cells, further limiting local inflammation and suppressing autoimmune diabetes in NOD mice. Abstract : IL‐35 is a recently identified cytokine exhibiting potent immunosuppressive properties. The therapeutic potential and effects of IL‐35 on pathogenic T effector cells (Teff) and Foxp3 + Treg, however, are ill defined. We tested the capacity of IL‐35 to suppress ongoing autoimmunity in NOD mice. For this purpose, an adeno‐associated virus vector in which IL‐35 transgene expression is selectively targeted to β cells via an insulin promoter (AAV8mIP‐IL35) was used. AAV8mIP‐IL35 vaccination of NOD mice at a late preclinical stage of type 1 diabetes (T1D) suppressed β‐cell autoimmunity and prevented diabetes onset. Numbers of islet‐resident conventional CD4 + and CD8 + T cells, and DCs were reduced within 4 weeks of AAV8mIP‐IL35 treatment. The diminished islet T‐cell pool correlated with suppressed proliferation, and a decreased frequency of IFN‐γ‐expressing Teff. Ectopic IL‐35 also reduced islet Foxp3 + Treg numbers and proliferation, and protection was independent of induction/expansion of adaptive islet immunoregulatory T cells. These findings demonstrate that IL‐35‐mediated suppression is sufficiently robust to block established β‐cell autoimmunity, and support the use of IL‐35 to treat T1D and other T‐cell‐mediated autoimmune diseases.