Anti-4-1BB-based immunotherapy for autoimmune diabetes: lessons from a transgenic non-obese diabetic (NOD) model.
Various therapeutic strategies have been developed to tolerize autoreactive T cells and prevent autoimmune pathology in type 1 diabetes. 4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory receptor primarily expressed on activated T cells. The administration of an agonistic anti-4-1BB antibody (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Treatment with the same antibody in Fas-deficient MRL/lpr mice blocked lymphadenopathy and lupus-like autoimmune processes. Paradoxically, transgenic non-obese diabetic (NOD) mice overexpressing membrane-bound agonistic single-chain anti-4-1BB Fv in pancreatic beta cells developed more severe diabetes than their non-transgenic littermates, with earlier onset, faster diabetic processes, and higher mortality. Forty percent of transgenic mice developed diabetes by 4 weeks of age, compared with their control littermates, which first exhibited diabetes at 14 weeks. The frequency of diabetes in female transgenics reached 70% by 8 weeks of age. Most female transgenic mice died around 12 weeks. Consistent with this, transgenic mice developed earlier and more severe insulitis and showed stronger GAD-specific T-cell responses, compared with age-matched control littermates. Our results indicate an adverse effect of transgenic anti-4-1BB scFv in NOD mice and suggest a potential risk of this anti-4-1BB-based immunotherapy for autoimmune diseases.
Sytwu
Huey-Kang
HK
Department of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, 114, Taipei, Taiwan. sytwu@ndmctsgh.edu.tw
Lin
Wen-Der
WD
Roffler
Steve R
SR
Hung
Jung-Tung
JT
Sung
Hsiang-Sheng
HS
Wang
Chi-Hsien
CH
Cheng
Tian-Lu
TL
Tsou
Shey-Cherng
SC
Hsi
Sheng-Chuan
SC
Shen
Kuo-Liang
KL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D041702:BALB 3T3 Cells; D001786:Blood Glucose / Q000032:analysis; D015139:Blotting, Southern; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006580:Genetic Carrier Screening; D005822:Genetic Vectors / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000276:immunology; D006029:Glycosuria / Q000652:urine; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000494:pharmacology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007167:Immunotherapy / Q000009:adverse effects*; D007328:Insulin / Q000235:genetics; D007527:Isoenzymes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D012737:Sex Factors; D013154:Spleen / Q000166:cytology; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001786:Blood Glucose; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D007328:Insulin; D007527:Isoenzymes; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2