Elevated serum IP-10 levels observed in type 1 diabetes.

OBJECTIVE Although most patients with type 1 diabetes are considered to have T-cell-mediated autoimmune disease, a method of measuring of pancreatic beta-cell-specific T-cell function in cases of type 1 diabetes has yet to be established. Here, we focused on interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 (Th1) cells and measured serum IP-10 levels in patients with human type 1 diabetes, which is regarded as a Th1-mediated disease. RESEARCH DESIGN AND METHODS Serum samples were obtained from diabetic patients, and the levels of autoantibodies (GAD and insulinoma-associated protein-2 [IA-2]) and IP-10 were measured. Diabetic patients positive for either or both of the autoantibodies were classified as Ab+ type 1, and those negative for both were classified as Ab type 1. To evaluate islet antigen-specific responses, peripheral blood from patients stimulated with or without GAD was used, and intracellular cytokine staining for flowcytometry was performed. RESULTS The Ab+ and Ab- type 1 groups both showed a significantly higher serum IP-10 level than the healthy subjects (P < 0.001 and P < 0.05, respectively), and the IP-10 level in the recent-onset Ab+ subgroup was significantly higher than that in the established (longstanding) Ab+ subgroup (P < 0.002). Furthermore, there was a significant positive correlation between the serum IP-10 level and the number of GAD-reactive gamma-interferon-producing CD4+ cells in the Ab+ type 1 group (P < 0.007). CONCLUSIONS Our findings demonstrate that measurement of serum IP-10 concentrations is useful in patients with type 1 diabetes.

[1]  Y. Matsuzawa,et al.  Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus , 1999, Diabetologia.

[2]  W. Suarez-Pinzon,et al.  Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. , 1998, Biochemical pharmacology.

[3]  B. Buckingham,et al.  Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus. , 1996, Journal of immunology.

[4]  T. Saruta,et al.  High-titer autoantibodies against glutamic acid decarboxylase plus autoantibodies against insulin and IA-2 predicts insulin requirement in adult diabetic patients. , 1999, Journal of autoimmunity.

[5]  K. Matsushima,et al.  Liver-infiltrating T lymphocytes are attracted selectively by IFN-inducible protein-10. , 2000, Cytokine.

[6]  L. Harrison,et al.  Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes , 1993, The Lancet.

[7]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[8]  C. Fathman,et al.  β-Cell Destruction May Be a Late Consequence of the Autoimmune Process in Nonobese Diabetic Mice , 1996, Diabetes.

[9]  L. Groop,et al.  Antibodies to Glutamic Acid Decarboxylase Reveal Latent Autoimmune Diabetes Mellitus in Adults With a Non—Insulin-Dependent Onset of Disease , 1993, Diabetes.

[10]  Simon A. Jones,et al.  Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes , 1996, The Journal of experimental medicine.

[11]  K. Yamagata,et al.  Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. , 1993, The Journal of clinical investigation.

[12]  E. Bonifacio,et al.  Lack of Immunohistological Changes in the Islets of Nondiabetic, Autoimmune, Polyendocrine Patients With β-Selective GAD-Specific Islet Cell Antibodies , 1994, Diabetes.

[13]  Y. Tominaga,et al.  Expression of IFN-inducible protein-10 in chronic hepatitis. , 1997, Journal of immunology.

[14]  C. Fathman,et al.  Pathogenic and Protective Roles of CD45RBlow CD4+ Cells Correlate With Cytokine Profiles in the Spontaneously Autoimmune Diabetic Mouse , 1996, Diabetes.

[15]  Y. Tominaga,et al.  Cloning of the murine interferon-inducible protein 10 (IP-10) receptor and its specific expression in lymphoid organs. , 1998, Biochemical and biophysical research communications.

[16]  M. Baggiolini Chemokines and leukocyte traffic , 1998, Nature.

[17]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[18]  T. Kobayashi,et al.  Immunogenetic and Clinical Characterization of Slowly Progressive IDDM , 1993, Diabetes Care.

[19]  F. Cerutti,et al.  Evidence of Circulating Interferon‐γ in Newly Diagnosed Diabetic Children , 1984, Acta paediatrica Scandinavica.

[20]  G. Eisenbarth,et al.  Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM. , 1997, Diabetes research and clinical practice.

[21]  S. Morinaga,et al.  T-cell insulitis found in anti-GAD65+ diabetes with residual beta-cell function. A case report. , 1999, Diabetes care.

[22]  M. Rewers,et al.  Heterophile anti-mouse immunoglobulin antibodies may interfere with cytokine measurements in patients with HLA alleles protective for type 1A diabetes. , 1999, Diabetes.

[23]  M. Wadhwa,et al.  Cytokines in sera from insulin‐dependent diabetic patients at diagnosis , 1991, Clinical and experimental immunology.

[24]  H. Olsen,et al.  (IP-10) Chemokines by Human Neutrophils -Inducible Protein-10 g (I-TAC), and IFN-Chemoattractant a IFN-Inducible T Cell (MIG), g Monokine Induced by IFN-Gene Expression and Production of the , 1999 .

[25]  M. Knip,et al.  Progression to type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65). Childhood Diabetes in Finland Study Group. , 1999, Clinical immunology.

[26]  V. Gangur,et al.  Human Ip-10 Selectively Promotes Dominance of Polyclonally Activated and Environmental Antigen- Driven Ifn-g over Il-4 Responses Human Ip-10 Selectively Promotes Dominance of Polyclonally Activated and Environmental Antigen- Driven Ifn-g over Il-4 Responses. Faseb , 2022 .