Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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GoldiRunx and Remembering Cytotoxic Memory

Mikami, Y. and Kanno, Y.

Immunity 48 ( 4 ) 614 - 615 2018.04

ISSN 1074-7613

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Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice

Nakamoto, N., Amiya, T., Aoki, R., Taniki, N., Koda, Y., Miyamoto, K., Teratani, T., Suzuki, T., Chiba, S., Chu, P. S., Hayashi, A., Yamaguchi, A., Shiba, S., Miyake, R., Katayama, T., Suda, W., Mikami, Y., Kamada, N., Ebinuma, H., Saito, H., Hattori, M. and Kanai, T.

Cell Rep 21 ( 5 ) 1215 - 1226 2017.10

Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs) is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-beta through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance.

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Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice

Hayashi, A., Mikami, Y., Miyamoto, K., Kamada, N., Sato, T., Mizuno, S., Naganuma, M., Teratani, T., Aoki, R., Fukuda, S., Suda, W., Hattori, M., Amagai, M., Ohyama, M. and Kanai, T.

Cell Rep 20 ( 7 ) 1513 - 1524 2017.08

Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin-deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology.

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The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

Iwata, S., Mikami, Y., Sun, H. W., Brooks, S. R., Jankovic, D., Hirahara, K., Onodera, A., Shih, H. Y., Kawabe, T., Jiang, K., Nakayama, T., Sher, A., O'Shea, J. J., Davis, F. P. and Kanno, Y.

Immunity 46 ( 6 ) 983 - 991.e4 2017.06

ISSN 1074-7613

Host defense requires the specification of CD4(+) helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-gamma (IFN-gamma). IFN-gamma, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-gamma production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-gamma aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling.

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Epigenomic Views of Innate Lymphoid Cells

Sciume, G., Shih, H. Y., Mikami, Y. and O'Shea, J. J.

Front Immunol 8 1579 2017

ISSN 1664-3224

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity.

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A Single Species of Clostridium Subcluster XIVa Decreased in Ulcerative Colitis Patients

Takeshita, K., Mizuno, S., Mikami, Y., Sujino, T., Saigusa, K., Matsuoka, K., Naganuma, M., Sato, T., Takada, T., Tsuji, H., Kushiro, A., Nomoto, K. and Kanai, T.

Inflamm Bowel Dis 22 ( 12 ) 2802 - 2810 2016.12

ISSN 1078-0998

BACKGROUND: Imbalance of the intestinal microbiota is associated with gastrointestinal disease and autoimmune disease and metabolic syndrome. Analysis of the intestinal microbiota has recently progressed, and the association with inflammatory bowel disease has been reported at the species level. Such findings suggest that the recovery of homeostasis in the intestinal microbiota could cure inflammatory bowel disease. We aimed to search new probiotic candidates for inflammatory bowel disease through translational research by analysis of ulcerative colitis (UC) patients' intestinal microbiota and clarify the effects of them on inflammation. Here, we focused on Fusicatenibacter saccharivorans, which belongs to Clostridium subcluster XIVa and was successfully isolated and cultured in 2013. We analyzed the association of F. saccharivorans to UC patients' activity and inflammation for the first time. METHODS: Feces from UC patients and healthy controls were analyzed by 16S ribosomal RNA gene sequences. F. saccharivorans was administered to murine colitis model. Colitic lamina propria mononuclear cells from UC patients and mice were stimulated with F. saccharivorans. RESULTS: The whole fecal bacteria in active UC patients were less than that in quiescent UC patients. Furthermore, F. saccharivorans was decreased in active UC patients and increased in quiescent. The administration of F. saccharivorans improved murine colitis. F. saccharivorans induced interleukin 10 production by lamina propria mononuclear cells from not only colitis model mice but also UC patients. CONCLUSIONS: F. saccharivorans decreased in correlation to UC activity and suppresses intestinal inflammation. These results suggest that F. saccharivorans could lead to a novel UC treatment.

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Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality

Shih, H. Y., Sciume, G., Mikami, Y., Guo, L., Sun, H. W., Brooks, S. R., Urban, J. F., Jr., Davis, F. P., Kanno, Y. and O'Shea, J. J.

Cell 165 ( 5 ) 1120 - 1133 2016.05

ISSN 0092-8674

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4(+) T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.

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A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease

Kanai, T., Mikami, Y. and Hayashi, A.

J Gastroenterol 50 ( 9 ) 928 - 39 2015.09

ISSN 0944-1174

Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that Clostridium butyricum as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.

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Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity

Hirahara, K., Onodera, A., Villarino, A. V., Bonelli, M., Sciume, G., Laurence, A., Sun, H. W., Brooks, S. R., Vahedi, G., Shih, H. Y., Gutierrez-Cruz, G., Iwata, S., Suzuki, R., Mikami, Y., Okamoto, Y., Nakayama, T., Holland, S. M., Hunter, C. A., Kanno, Y. and O'Shea, J. J.

Immunity 42 ( 5 ) 877 - 89 2015.05

ISSN 1074-7613

Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation-sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.

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Classical Th1 cells obtain colitogenicity by co-existence of RORgammat-expressing T cells in experimental colitis

Saigusa, K., Hisamatsu, T., Handa, T., Sujino, T., Mikami, Y., Hayashi, A., Mizuno, S., Takeshita, K., Sato, T., Matsuoka, K. and Kanai, T.

Inflamm Bowel Dis 20 ( 10 ) 1820 - 7 2014.10

ISSN 1078-0998

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 (RORgammat)-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 RORgammat 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 CD4CD45RB(high) T cells obtained from wild-type, RORgammat(gfp/gfp), or RORgammat(gfp/gfp) mice into RAG-2(-/-) mice. RESULTS: RAG-2(-/-) mice receiving transfer of in vitro-manipulated RORgammat(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4CD45RB(high) T cells obtained from wild-type mice and RORgammat(gfp/gfp) mice developed colitis with a significant increase in RORgammat cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4CD45RB(high) T cells obtained from RORgammat(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated RORgammat(gfp/gfp) cTh1 cells developed colitis with a significant increase in RORgammat(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 RORgammat-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.

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Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease

Mizuno, S., Mikami, Y., Kamada, N., Handa, T., Hayashi, A., Sato, T., Matsuoka, K., Matano, M., Ohta, Y., Sugita, A., Koganei, K., Sahara, R., Takazoe, M., Hisamatsu, T. and Kanai, T.

Inflamm Bowel Dis 20 ( 8 ) 1426 - 34 2014.08

ISSN 1078-0998

BACKGROUND: Interleukin (IL)-22-producing RORgammat 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 RORgammat 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. METHODS: CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated. RESULTS: CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORgammat and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1alpha and Claudin-1 in human intestinal epithelial organoids. CONCLUSIONS: RORgammat ILCs might enhance mucosal barrier function through the upregulation of Reg1alpha through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORgammat ILCs.

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Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab

Yoneno, K., Hisamatsu, T., Matsuoka, K., Okamoto, S., Takayama, T., Ichikawa, R., Sujino, T., Miyoshi, J., Takabayashi, K., Mikami, Y., Mizuno, S., Wada, Y., Yajima, T., Naganuma, M., Inoue, N., Iwao, Y., Ogata, H., Hasegawa, H., Kitagawa, Y., Hibi, T. and Kanai, T.

Digestion 89 ( 3 ) 201 - 8 2014

ISSN 0012-2823

BACKGROUND AND AIMS: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. METHODS: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. RESULTS: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. CONCLUSIONS: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors.

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Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes

Bonelli, M., Shih, H. Y., Hirahara, K., Singelton, K., Laurence, A., Poholek, A., Hand, T., Mikami, Y., Vahedi, G., Kanno, Y. and O'Shea, J. J.

Curr Top Microbiol Immunol 381 279 - 326 2014

ISSN 0070-217X

CD4(+) helper T cells are crucial for autoimmune and infectious diseases; however, the recognition of the many, diverse fates available continues unabated. Precisely what controls specification of helper T cells and preserves phenotypic commitment is currently intensively investigated. In this review, we will discuss the major factors that impact helper T cell fate choice, ranging from cytokines and the microbiome to metabolic control and epigenetic regulation. We will also discuss the technological advances along with the attendant challenges presented by "big data," which allow the understanding of these processes on comprehensive scales.

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Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation

Mikami, Y., Mizuno, S., Nakamoto, N., Hayashi, A., Sujino, T., Sato, T., Kamada, N., Matsuoka, K., Hisamatsu, T., Ebinuma, H., Hibi, T., Yoshimura, A. and Kanai, T.

PLoS One 9 ( 1 ) e84619 2014

ISSN 1932-6203

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2(-/-) mice adoptively transferred with CD4(+)CD45RB(high) T cells; and IL-10(-/-) mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b(-)CD11c(low)PDCA-1(+) plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice in parallel with the emergence of macrophages (Mphis) and conventional DCs (cDCs). Furthermore, liver Mphi/cDCs emerging during intestinal inflammation not only promote the proliferation of naive CD4(+) T cells, but also instruct them to differentiate into IFN-gamma-producing Th1 cells in vitro. The emergence of pathological Mphi/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mphi/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.

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C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

Chu, P. S., Nakamoto, N., Ebinuma, H., Usui, S., Saeki, K., Matsumoto, A., Mikami, Y., Sugiyama, K., Tomita, K., Kanai, T., Saito, H. and Hibi, T.

Hepatology 58 ( 1 ) 337 - 50 2013.07

ISSN 0270-9139

UNLABELLED: Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9(+) macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-alpha)-producing CCR9(+) macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9(+) macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9(-/-) mice compared with wild-type (WT) mice, assessed by alpha-smooth muscle actin (alpha-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of alpha-SMA, collagen 1alpha1, transforming growth factor (TGF)-beta1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b(+) macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-beta1 mRNA expression compared with CCR9(-/-) mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b(+) macrophages from CCl4 -treated WT mice (i.e., CCR9(+) macrophages), but not CD8(+) T lymphocytes or non-CD11b(+) cells, significantly activated HSCs in vitro compared with those from CCR9(-/-) mice. TNF-alpha or TGF-beta1 antagonism attenuated CCR9(+) macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. CONCLUSION: Accumulated CD11b(+) macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice

Hayashi, A., Sato, T., Kamada, N., Mikami, Y., Matsuoka, K., Hisamatsu, T., Hibi, T., Roers, A., Yagita, H., Ohteki, T., Yoshimura, A. and Kanai, T.

Cell Host Microbe 13 ( 6 ) 711 - 22 2013.06

ISSN 1931-3128

Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80(+)CD11b(+)CD11c(int) macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura, Y., Kanai, T., Saeki, K., Takabe, M., Irie, J., Miyoshi, J., Mikami, Y., Teratani, T., Suzuki, T., Miyata, N., Hisamatsu, T., Nakamoto, N., Yamagishi, Y., Higuchi, H., Ebinuma, H., Hozawa, S., Saito, H., Itoh, H. and Hibi, T.

Am J Physiol Gastrointest Liver Physiol 304 ( 8 ) G700 - 7 2013.04

ISSN 0193-1857

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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Immune aspects of the pathogenesis of inflammatory bowel disease

Hisamatsu, T., Kanai, T., Mikami, Y., Yoneno, K., Matsuoka, K. and Hibi, T.

Pharmacol Ther 137 ( 3 ) 283 - 97 2013.03

ISSN 0163-7258

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFalpha and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.

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Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy

Takayama, T., Kanai, T., Matsuoka, K., Okamoto, S., Sujino, T., Mikami, Y., Hisamatsu, T., Yajima, T., Iwao, Y., Ogata, H. and Hibi, T.

J Crohns Colitis 7 ( 2 ) e49 - 54 2013.03

ISSN 1873-9946

BACKGROUND: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. METHODS: Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. RESULTS: Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI </= 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p = 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. CONCLUSIONS: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse.

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Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice

Handa, T., Kanai, T., Sato, T., Mikami, Y., Sujino, T., Hayashi, A., Mizuno, S., Matsumoto, A., Hisamatsu, T. and Hibi, T.

Immunol Lett 150 ( 1-2 ) 123 - 9 2013.02

ISSN 0165-2478

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 weeks) 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.

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