Tango Handa

Keio University, Edo, Tōkyō, Japan

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Publications (6)20.33 Total impact

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    ABSTRACT: Background: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (ROR gamma t)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without ROR gamma t expression in the pathogenesis of colitis remains poorly understood. Methods: We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4(+)CD45RB(high) T cells obtained from wild-type, ROR gamma t(gfp/gfp), or ROR gamma t(gfp/+) mice into RAG-2(-/-) mice. Results: RAG-2(-/-) mice receiving transfer of in vitro-manipulated ROR gamma t(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4+CD45RB(high) T cells obtained from wild-type mice and ROR gamma t(gfp/gfp) mice developed colitis with a significant increase in ROR gamma t(gfp/gfp) cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4(+)CD45RB(high) T cells obtained from ROR gamma t(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated ROR gamma tg(fp/gfp) cTh1 cells developed colitis with a significant increase in ROR gamma t(gfp/gfp) cTh1 cell numbers. Conclusions: These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of ROR gamma t-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.
    Inflammatory Bowel Diseases 08/2014; 20(10). DOI:10.1097/MIB.0000000000000149 · 5.48 Impact Factor
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    ABSTRACT: Interleukin (IL)-22-producing RORγt innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORγt ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD.
    Inflammatory Bowel Diseases 07/2014; 20(8). DOI:10.1097/MIB.0000000000000105 · 5.48 Impact Factor
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    ABSTRACT: Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP(+) BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration. 72h after administration, recipient C57BL/6 mice showed acute diarrhea, and administration of BMDCs (once weekly for 3 wk) induced intestinal inflammation with increased numbers of recipient macrophages and CD4(+) T cells exhibiting a Th2-mediated immune response. These results demonstrate that DCs actively communicate across the intestinal barrier, and highlight a potential technique for controlling colonic immune tolerance. (119 words).
    Immunology letters 01/2013; DOI:10.1016/j.imlet.2013.01.010 · 2.37 Impact Factor
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    ABSTRACT: Retinoid-related orphan receptor (ROR) γt-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-γ and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORγt(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORγt-sufficient Rag-2(-/-) mice. RORγt-deficient Rag-2(-/-) mice developed more severe DSS-induced colitis accompanied with lower expression of REG3β and REG3γ in the colon, but with a lower ratio and absolute number of IFN-γ-producing ILC1 cells as compared to control RORγt-sufficient Rag-2(-/-) mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis.
    Biochemical and Biophysical Research Communications 09/2012; 427(4). DOI:10.1016/j.bbrc.2012.09.091 · 2.28 Impact Factor
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    ABSTRACT: Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9(-/-) mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9(-/-) mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9(-/-) mice subjected to CLP compared with WT mice, this was normalized in CCR9(-/-) mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection.
    Immunology letters 07/2012; 147(1-2):75-9. DOI:10.1016/j.imlet.2012.06.006 · 2.37 Impact Factor
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    ABSTRACT: Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high) T cells into ccr9(-/-)×rag-2(-/-) mice. We showed that CCL25, a counterpart chemokine for CCR9, is constitutively expressed in the SI but not the colon and spleen of rag-2(-/-) or ccr9(-/-)×rag-2(-/-) mice before or after transfer of CD4(+)CD45RB(high) T cells. The ccr9(-/-)×rag-2(-/-) mice did not develop spontaneous intestinal inflammation in the SI and colon. Mice of both genotype where CD4(+)CD45RB(high) T cells were transferred developed colitis. However, the ccr9(-/-)×rag-2(-/-) mice also developed ileitis with marked infiltration of Th1 cells. These results suggest that CCR9(+) pDCs are possibly small, regulatory, antigen-presenting cells of the intestine that suppress intestinal inflammation.
    Immunology letters 05/2012; 146(1-2):64-9. DOI:10.1016/j.imlet.2012.05.001 · 2.37 Impact Factor