Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes.

Abstract

The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-A(g7) class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamma secretion was induced in CD4(+) cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis.

• Authors: S Trembleau, G Penna, S Gregori, G Magistrelli, A Isacchi, L Adorini
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 12 Pg. 6748-55 (Dec 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 11120794 (Publication Type: Journal Article)

Chemical References

• Autoantigens
• Cytokines
• Epitopes
• Histocompatibility Antigens Class II
• I-A g7 antigen
• Isoenzymes
• Membrane Proteins
• Recombinant Proteins
• Interleukin-12
• Interferon-gamma
• PTPRN protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatases
• Ptprn protein, mouse
• Receptor-Like Protein Tyrosine Phosphatases, Class 8
• Glutamate Decarboxylase
• glutamate decarboxylase 2

Topics

• Aging (immunology)
• Animals
• Antigen Presentation
• Autoantigens (administration & dosage, immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Cells, Cultured
• Cytokines (biosynthesis)
• Diabetes Mellitus, Type 1 (etiology, immunology)
• Drug Administration Schedule
• Epitopes (immunology)
• Female
• Glutamate Decarboxylase (administration & dosage, immunology)
• Histocompatibility Antigens Class II (immunology, metabolism)
• Immunization
• Injections, Intraperitoneal
• Injections, Subcutaneous
• Interferon-gamma (metabolism)
• Interleukin-12 (administration & dosage)
• Islets of Langerhans (immunology)
• Isoenzymes (administration & dosage, immunology)
• Lymph Nodes (cytology, immunology, metabolism)
• Male
• Membrane Proteins (administration & dosage, genetics, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatases (administration & dosage, genetics, immunology)
• Receptor-Like Protein Tyrosine Phosphatases, Class 8
• Recombinant Proteins (administration & dosage, immunology)
• Spleen (cytology, immunology, metabolism)
• Th1 Cells (immunology, metabolism)