title: A bispecific protein capable of engaging CTLA-4 and MHCII protects non-obese diabetic mice from autoimmune diabetes.
abstract: Crosslinking ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4) to the T cell receptor (TCR) with a bispecific fusion protein (BsB) comprised of a mutant mouse CD80 and lymphocyte activation antigen-3 (LAG-3) has been shown to attenuate TCR signaling and to direct T-cell differentiation toward Foxp3(+) regulatory T cells (Tregs) in an allogenic mixed lymphocyte reaction (MLR). Here, we show that antigen-specific Tregs can also be induced in an antigen-specific setting in vitro. Treatment of non-obese diabetic (NOD) female mice between 9-12 weeks of age with a short course of BsB elicited a transient increase of Tregs in the blood and moderately delayed the onset of autoimmune type 1 diabetes (T1D). However, a longer course of treatment (10 weeks) of 4-13 weeks-old female NOD animals with BsB significantly delayed the onset of disease or protected animals from developing diabetes, with only 13% of treated animals developing diabetes by 35 weeks of age compared to 80% of the animals in the control group. Histopathological analysis of the pancreata of the BsB-treated mice that remained non-diabetic revealed the preservation of insulin-producing β-cells despite the presence of different degrees of insulitis. Thus, a bifunctional protein capable of engaging CTLA-4 and MHCII and indirectly co-ligating CTLA-4 to the TCR protected NOD mice from developing T1D.
authors.affiliation: Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhao
authors.forename: Jozsef
authors.initials: J
authors.lastname: Karman
authors.forename: Ji-Lei
authors.initials: JL
authors.lastname: Jiang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Nathan
authors.initials: N
authors.lastname: Gumlaw
authors.forename: John
authors.initials: J
authors.lastname: Lydon
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
authors.forename: Huawei
authors.initials: H
authors.lastname: Qiu
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001216:Asparagine / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002645:Chickens; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D000941:Antigens; D060908:CTLA-4 Antigen; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins; D001216:Asparagine