| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Inflammatory bowel disease (IBD) is not a single entity but represents a continuous spectrum of disease. While Th1 immunity is responsible for the onset of Crohn's disease (CD), intramucosal neutrophil infiltration is related to the activity of ulcerative colitis (UC). We found that there is distinct difference in the productivity of granulocyte colony-stimulating factor (G-CSF) among rat strains, in which SD and DA rats showed much lower mRNA expression levels of endogenous G-CSF in LPS-stimulated splenocytes than did Lewis, F344 and BN rats. We examined the therapeutic effects of recombinant G-CSF in the two types of TNBS (a hapten)-induced colitis of five rat strains. On day 7 after anal instillation of TNBS, SD and DA demonstrated massive lymphocyte infiltration with an IFN-γ mRNA upregulation (CD-like colitis), while Lewis, F344 and BN showed an intense submucosal neutrophil accumulation with high TNF-α mRNA levels (UC-like colitis). A 5-day course of recombinant G-CSF pretreatmen
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t (250μg/kg/day, s.c.) reduced the elevated levels of the both cytokines. The treatment improved the survival rate of DA and reduced the degree of body weight loss of SD, while not significantly influencing the weight loss of other strains. IL-10 mRNA levels were highly upregulated by recombinant G-CSF treatment on day 1 in the neutrophil-dominant lesions of F344 but not in the Th1-type lesions of SD, and IL-12p35 mRNA levels were downregulated in the both. Supply of G-CSF prevents the onset of Th1-type colitis and does not deteriorate neutrophil-dominant chronic colitis in the hosts showing higher expression of endogenous G-CSF. We tried to elucidate the influence of G-CSF productivity on the pathogenesis of IBD to analyze surgical human specimen, but the sample size was insufficient within the period of this study. As for development of new anti-inflammatory drugs by synthesizing fusion proteins of G-CSF and IL-10, any synthesized proteins did not show much more inhibition of IL-12 secretion by in vitro LPS-stimulated human leukocytes than IL-10 on a per-mol basis. We did not obtain enough volume of the synthesized proteins to measure their half-life time in vivo with the budget of this project. Less
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