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Jiro Morimoto

Publications and source records attributed to Jiro Morimoto.

9 recordsLinked to original sources
PubMed2004

CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis.

We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of beta cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature beta cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of beta cells and resultantly increased beta cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for beta cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.

Animals↗
PubMed2004

GAD-reactive T cells were mainly detected in autoimmune-related type 1 diabetic patients with HLA DR9.

Type 1 diabetes mellitus (T1DM) is considered to be a T cell-mediated disease, and many reports suggest that some HLA types, especially HLA DR4 and DR9, convey susceptibility to T1DM in Japanese. We investigated the association between T cell reactivity against GAD and HLA types in "islet-associated autoantibody-positive" T1DM in Japanese. Blood samples were obtained from 36 "autoantibody-positive" type 1 diabetic patients with HLA DR4 or DR9 and 23 type 2 diabetic patients with HLA DR4 or DR9 as controls. They were divided into three groups, DR4/9, DR4/X, and DR9/X groups. In each HLA type group, GAD-reactive IFN-gamma-producing CD4(+) cells were assessed by means of intracellular cytokine staining for flow cytometry. Type 1 diabetic patients with HLA DR9/X had significantly higher numbers of GAD-reactive IFN-gamma-producing CD4(+) cells as compared to type 1 diabetic patients with DR4/X or DR4/9 (P < 0.05) and all type 2 diabetic patients. There was no significant difference in the number of GAD-reactive IFN-gamma-producing CD4(+) cells between type 1 diabetic and type 2 diabetic patients belonging to the DR4/X and DR4/9 groups. There was an association between T cell reactivity against GAD and HLA DR9 in Japanese type 1 diabetes.

Adult↗
PubMed2003

Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice.

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.

Age Factors↗
PubMed2003

T-cell function in anti-GAD65(+)diabetes with residual beta-cell function.

We have recently reported that in patients with anti-glutamic acid decarboxylase (GAD) 65(+)diabetes with residual beta-cell function, most with a 'high-titer' (>10U/ml) required insulin within 5 years, whereas most with a 'low-titer' (1.3-9.9U/ml) did not need insulin for over 15-20 years after the onset. We therefore examined T-cell function to evaluate the difference between the high-titer and low-titer groups. Interleukin (IL)-10 production upon polyclonal activation was significantly lower in the high-titer group than in the low-titer group. The serum level of interferon-inducible protein-10 (IP-10) was higher in the high-titer than the low-titer group. Although GAD65-reactive CD4(+)cells in the periphery were detected in both groups, a significant positive correlation between serum IP-10 level and the number of GAD65-reactive CD4(+)cells was observed only in the high-titer group. Therefore, it has been speculated that the co-existence of GAD65-reactive IFN-gamma-producing CD4(+)cells and a high serum IP-10 level may be important for rapid disease progression as seen in the high-titer group. Based upon these results, T-cell function is considered to be different between the high-titer and low-titer groups in anti-GAD65(+)diabetes with residual beta-cell function, supporting our previous findings regarding the clinical outcome of insulin-dependence in the two groups.

Adult↗
PubMed2003

Assessment of beta cell mass and oxidative peritoneal exudate cells in murine type 1 diabetes using adoptive transfer system.

Because it is controversial how the beta cell mass is reduced during the disease process in type 1 diabetes, we transferred splenocytes from Non-obese diabetic (NOD) to NOD-scid mice and evaluated the relation between the status of the pancreas in donors and the time taken to transfer diabetes to the recipients. We also evaluated the usefulness of assessment of the proportion of oxidative peritoneal exudate cells (PEC) as a novel marker of disease activity in this system. We examined the proportion of oxidative PEC, pancreatic insulin content and pancreatic histology in 16-18-week-old female NOD mice (donors), and transferred their splenocytes into 5-week-old female NOD-scid mice (recipients). After the onset of diabetes in NOD-scid recipients, we assessed the relation between insulin content (or severity of insulitis) of NOD donors and the time taken to transfer diabetes to NOD-scid recipients. The insulin content of "diabetes-prone" donors whose disease status was considered to be just before the onset of diabetes ("malignant" donors) was the same as that of diabetic mice, whereas the insulin content of "diabetes-prone" donors excluding "malignant" donors ("benign" donors) was the same as that of "non-diabetes-prone" donors. Because its proportion of oxidative PEC was inversely correlated with the severity of insulitis, we then evaluated the relation between the proportion of oxidative PEC and the time taken to transfer diabetes. "Malignant" donors had less proportion of oxidative PEC (< 10%), as compared to "benign" and "non-diabetes-prone" donors. These results suggest that a marked reduction of beta cell mass occurs at the very late prediabetic stage, and assessment of the proportion of oxidative PEC is useful to evaluate disease activity in type 1 diabetes.

Adoptive Transfer↗
PubMed2003

Relationship between beta cell mass of NOD donors and diabetes development of NOD-scid recipients in adoptive transfer system.

BACKGROUND: There is controversy about the way the beta cell mass is reduced in type 1 diabetes. One view is that a gradual fall in beta cell mass begins soon after the onset of insulitis. Another view is that a sudden wave of beta cell destruction occurs just before the onset of diabetes. To clarify how the beta cell mass is reduced, we performed adoptive transfer experiments and examined the relationship between the pancreatic status of NOD donors and the time taken to transfer diabetes into NOD-scid recipients. METHODS: We killed 18-week-old female NOD mice (n = 20), removed their spleen, and transferred splenocytes into 5-week-old female NOD-scid mice (n = 60). The relationship between the pancreatic status of donors and the time taken to transfer diabetes into recipients was assessed. As pancreatic status, we measured insulin content and severity of insulitis. RESULTS: There was no linear correlation between the pancreatic status of donors and the time taken to transfer diabetes into recipients. NOD donors who needed 7 or more weeks to transfer diabetes in NOD-scid recipients had similar levels of insulin content or severity of insulitis as those of NOD donors who could not transfer diabetes. On the other hand, NOD donors who needed 6 or less weeks to transfer diabetes in recipients had similar levels of insulin content or severity of insulitis as those of diabetic NOD mice. CONCLUSIONS: According to our observations, beta cell mass seems to be preserved until just before the onset of diabetes and decreased dramatically within a few weeks.

Adoptive Transfer↗
PubMed2003

Detection of GAD-reactive CD4+ cells in so-called "type 1B" diabetes.

OBJECTIVE: Although the majority of type 1 diabetes is considered to be type 1A, some patients with type 1 diabetes have no islet-associated autoantibody in their serum. This type of type 1 diabetes has usually been diagnosed as type 1B on the basis of islet-associated autoantibody-negativity. In this study, we tried to demonstrate the existence of islet-associated antigen-specific T cells in type 1 diabetes without islet-associated autoantibody. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 110 Japanese diabetic patients, including 15 type 2 diabetic patients. Measurement of islet-associated antigen-specific cytokine response was performed by intracellular cytokine staining for flow cytometry. RESULTS: The number of GAD-reactive IFN-gamma-producing CD4+ cells in 50,000 CD4+ cells in diabetics with type 1B (113.6 +/- 34.6, median 45), type 1A (132.4 +/- 33.3, median 25), and LADA (154.4 +/- 44.1, median 20) was higher than that in type 2 diabetics (0.3 +/- 0.3, median 0) and control subjects (3.8 +/- 2.4, median 0). When the normal upper limit of the number of GAD-reactive CD4+ cells was set at the mean + 3SD of values in control subjects, at least half (52.4%) of the so-called "type 1B" patients were positive for GAD-reactive IFN-gamma-producing CD4+ cells, a significantly larger proportion than that in type 2 diabetics (0%; p < 0.001). CONCLUSIONS: Assessment of T cell reactivity against islet-associated antigen may contribute to the diagnosis of "autoimmune-related" type 1 diabetes.

Aged↗
PubMedDate not supplied

Insulin-like growth factor-1 (IGF-1)-derived peptide protects against diabetes in NOD mice.

Spontaneous diabetes in non-obese diabetic (NOD) mice results from beta-cell destruction by autoreactive T lymphocytes. Here, we report the significance of insulin-like growth factor-1 (IGF-1) peptide as a tool for the prevention of type 1 diabetes. Female NOD mice were immunized with a subcutaneous injection of IGF-1, glutamic acid decarboxylase (GAD), insulin or IGF-1-derived peptides (residues 8-23, 24-41 or 50-70) in incomplete Freund's adjuvant (IFA) or with IFA only as the control group at 4 weeks of age, and observed up to 36-37 weeks of age. Diabetes onset was significantly suppressed and delayed in the IGF-1 group as compared to the GAD, insulin and control groups (p<0.05), and it was significantly suppressed and delayed in the (50-70)IGF-1 group as compared to the (8-23)IGF-1 and control groups (p<0.02). Although the degree of insulitis in all treated mice was not significantly different, a significant number of IL-4-producing cells in response to IGF-1 peptides were detected in (50-70)IGF-1-treated mice in intracellular cytokine assay. In conclusion, IGF-1 peptide 50-70 immunizations of NOD mice suppressed and delayed diabetes onset, probably through amplification of the Th2-type response. It was suggested that IGF-1 peptide 50-70 immunization can be used as a tool for prevention of type 1 diabetes.

Age Factors↗