Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus
碩士 === 國防醫學院 === 微生物及免疫學研究所 === 87 === Interleukin-1b (IL-1b), a potent pro-inflammatory cytokine, has been shown to mediate the autoimmune diabetic process in several animal models. Blocking IL-1b bioactivity by IL-1 receptor antagonist or recombinant soluble receptor has been reported t...
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ndltd-TW-087NDMC03800012016-07-11T04:14:09Z http://ndltd.ncl.edu.tw/handle/69903337692560062606 Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus 第一介白素b在胰島素依賴型糖尿病中所扮演的免疫病理角色之研究 Chang, Tsung -Hsien 張聰賢 碩士 國防醫學院 微生物及免疫學研究所 87 Interleukin-1b (IL-1b), a potent pro-inflammatory cytokine, has been shown to mediate the autoimmune diabetic process in several animal models. Blocking IL-1b bioactivity by IL-1 receptor antagonist or recombinant soluble receptor has been reported to inhibit the disease process on the delay onset of diabetes or the decrease of disease frequency. However, the anti-diabetic mechanism induced by blocking IL-1b activity is still unclear. In our study, we first evaluated the effect of a neutralizing anti-IL-1b mAb on the disease process in adult (10-11 wk of age) non-obese diabetic (NOD) mice which already developed insulitis and investigated the b-islet-specific autoimmune T and B cell responses, histological change and the cytokine production from the cultured splenic cells ex vivo stimulated with islet cell antigens (ICAs) or ConA. Inhibiting IL-1b activity by this anti-IL-1b mAb led to the significant decrease of diabetic frequency (30% compared to 90% in both Ig isotype-matched mAb-treated and non-injected groups). Interestingly, the mice treated with anti-IL-1b and protected from diabetes still remained the significant ICAs-specific T and B cell responses as in control groups . This will suggest the anti-diabetogenic mechanism induced by anti-IL-1b treatment is not due to the specific inhibition of ICAs-specific T and B cell responses. The similar incidence and severity of insulitis among each group indicated the anti-IL-1b-induced protection is not mediated by blocking the lymphocytic trafficking into the islets or by reversing the actively ongoing insulitis. No significant difference in IFN-g and IL-2 production from cultured cells responding to ConA among each group will suggest the anti-IL-1b mAb treatment did not induce the systemic impairment of T cell function, and no particular skewing of IL-4 or IFN-g production in each group responding to each ICA will indicated the T helper 1 (Th1) or T helper 2 (Th2) response was not disturbed during the treatment. Furthermore, we demonstrated the IL-1b upregulates the nitric oxide expression in islet cells. The iNOS mRNA was significantly reduced in NOD mice treated with IL-1ra. These results indicate that IL-1b can enhance the iNOS expression and NO production in islet cells. Our results support the idea that the dysfunction and destruction of b-islet cells in IDDM could be mediated by IL-1b-induced toxic NO, and the successful treatment with anti-IL-1b won't affect the remained T and B cell immune responses. This would provide the novel concept for the treatment of IDDM in a cytokine-specific modulation by selectively inhibiting the IL-1b activity. Sytwu, Huey-Kang 司徒惠康 1999 學位論文 ; thesis 63 zh-TW |
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碩士 === 國防醫學院 === 微生物及免疫學研究所 === 87 === Interleukin-1b (IL-1b), a potent pro-inflammatory cytokine, has been shown to mediate the autoimmune diabetic process in several animal models. Blocking IL-1b bioactivity by IL-1 receptor antagonist or recombinant soluble receptor has been reported to inhibit the disease process on the delay onset of diabetes or the decrease of disease frequency. However, the anti-diabetic mechanism induced by blocking IL-1b activity is still unclear. In our study, we first evaluated the effect of a neutralizing anti-IL-1b mAb on the disease process in adult (10-11 wk of age) non-obese diabetic (NOD) mice which already developed insulitis and investigated the b-islet-specific autoimmune T and B cell responses, histological change and the cytokine production from the cultured splenic cells ex vivo stimulated with islet cell antigens (ICAs) or ConA. Inhibiting IL-1b activity by this anti-IL-1b mAb led to the significant decrease of diabetic frequency (30% compared to 90% in both Ig isotype-matched mAb-treated and non-injected groups). Interestingly, the mice treated with anti-IL-1b and protected from diabetes still remained the significant ICAs-specific T and B cell responses as in control groups . This will suggest the anti-diabetogenic mechanism induced by anti-IL-1b treatment is not due to the specific inhibition of ICAs-specific T and B cell responses. The similar incidence and severity of insulitis among each group indicated the anti-IL-1b-induced protection is not mediated by blocking the lymphocytic trafficking into the islets or by reversing the actively ongoing insulitis. No significant difference in IFN-g and IL-2 production from cultured cells responding to ConA among each group will suggest the anti-IL-1b mAb treatment did not induce the systemic impairment of T cell function, and no particular skewing of IL-4 or IFN-g production in each group responding to each ICA will indicated the T helper 1 (Th1) or T helper 2 (Th2) response was not disturbed during the treatment. Furthermore, we demonstrated the IL-1b upregulates the nitric oxide expression in islet cells. The iNOS mRNA was significantly reduced in NOD mice treated with IL-1ra. These results indicate that IL-1b can enhance the iNOS expression and NO production in islet cells. Our results support the idea that the dysfunction and destruction of b-islet cells in IDDM could be mediated by IL-1b-induced toxic NO, and the successful treatment with anti-IL-1b won't affect the remained T and B cell immune responses. This would provide the novel concept for the treatment of IDDM in a cytokine-specific modulation by selectively inhibiting the IL-1b activity.
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author2 |
Sytwu, Huey-Kang |
author_facet |
Sytwu, Huey-Kang Chang, Tsung -Hsien 張聰賢 |
author |
Chang, Tsung -Hsien 張聰賢 |
spellingShingle |
Chang, Tsung -Hsien 張聰賢 Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
author_sort |
Chang, Tsung -Hsien |
title |
Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
title_short |
Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
title_full |
Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
title_fullStr |
Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
title_full_unstemmed |
Study the Immunopathological Role of Interleukin-1b in Insulin-Dependent Diabetes Mellitus |
title_sort |
study the immunopathological role of interleukin-1b in insulin-dependent diabetes mellitus |
publishDate |
1999 |
url |
http://ndltd.ncl.edu.tw/handle/69903337692560062606 |
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