| Research Abstract |
The aim of the project has been to elucidate the pathophysiological roles of the immune chemokines, which are mainly directed to lymphocytes and dendritic cells. The main accomplishments of this year are as follows. (1) We showed that the proinflammatory cytokines such as IL-1 and TNFα potently induced normal human epidermal keratinocytes to express LARC/CCL20, the chemokine known to selectively attracts immature dendritic cells and α4β7-positive memory/effector T cells vua CCR6. We also showed that the lesional skin of atopic dermatitis (AD) often contained epidermal keratinocytes producing LARC and extensive accumulation of CCR6+ cells beneath the epidermal layer. Furthermore, we showed that plasma samples from AD patients often contained elevated levels of LARC. Collectively, these results support an important pathologenic role of LARC in AD. (2) We showed that expression of LARC was potently induced in mucosal epithelial cells by proinflammatory cytokines such as IL-1 and TNFα. Fur
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thermore, we analysed the activation mechanism of the LARC promoter by these cytokines and showed that an NF-kB site from -96 to -87bp from the transcriptional initiation site was essential for the induction of the LARC promoter. (3) We showed that TARC/CCL17 and MDC/CCL22, both known to attract Th2-type memory/effector T cells and skin-seeking CLA+ memory/effector T cells via CCR4, were significantly evevated in the plasma of AD patients. Furthermore, we found that platelets contained TARC and its contents were dramatically elevated in platelets from AD patients. We further showed that IFN-γinduced normal human epidermal keratinocytes to express TARC and MDC. Collectively, TARC and MDC may play important roles in the pathogenesis of AD. Furthermore, IFN-γ, which is also known to be apotent inducer of Th1-attracting chemokines, may be a critical factor in AD pathogenesis by inducing a set of chemokines attracting both Th1 and Th2 cells. (4) We showed that a large fraction of mature dendritic cells produced MDC and were clustered with CCR4-expressing T cesss in chronically inflamed skin infected with Candida albicans as well as in lymph node. Thus, MDC may play an important role in DC-T cell interactions. (5) We showed that in an asthmatic model in mice induced by priming with and subsequent inhalating of ovalbumin, the treatment with anti-mTARC monoclonal antibody efficiently blocked lung infiltrating of lymphocytes and eosinophils and elevation of methacholine-induced airway resistance. Thus, TARC is likely to play an important role in asthma. (6) We showed that in patients with multiple sclerosis (MS), the frequencies of lymphocytes expressing CCR5 or CXCR3 was increased in the cerebrospinal fluid during exacerbation, while the frequencies of CCR5-expressinglymphocytes were decreased after remission. These results support the Th1-biased immune responses in the pathogenesis of MS. (7) We generated monoclonal antibodies to mouse chemokines such as MDC, LARC and SLC/CCL21 in Armenisan hamsters but could not get antibodies with neutralizing activities. (8) We have repeatedly backcrossed TARC-knockout mice and αE integrin-knockout mice into BALB/c and C57BL/6 mice and developed the syngeneic strains. Less
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