Regenerative Immunology
上皮再生・発がん免疫
Host-Microbial Interactions:
Goal: My investigative research interests are
centered around the basic cellular and molecular mechanisms involved in the
functional modulation of colonic epithelial cells (CECs) during the development
of Inflammatory Bowel Disease (IBD).
This includes identifying the key molecules which regulate the
CEC/microorganism interaction, CEC/immune cells interaction and intestinal
epithelial cell barrier function.
Brief introduction of my major research interest: A decade ago, we discovered an intestinal inflammation-induced,
upregulation of the Chitinase-3-like-1 (CHI3L1/YKL-40) molecule in CECs and
macrophages by DNA microarray analysis.
Our subsequent studies revealed that CHI3L1 upregulation is a common
factor in intestinal inflammation, as indicated by the upregulation of this
molecule in acute and chronic colitis models as well as human IBD. CHI3L1 was upregulated after pro-inflammatory
cytokine stimulation to enhance adhesion and internalization of intracellular
bacteria in CECs. Most importantly, in
vivo neutralization of CHI3L1 activity by administrating anti-CHI3L1
antibody or pan-chitinase inhibitor (e.g., caffeine) significantly suppressed
the development of acute colitis by dramatically decreasing bacterial invasion
in the intestinal mucosa. These studies
provide a novel insight into the physiological role of mammalian chitinases in
host/microbial interactions. We will expand the study of CHI3L1 to include
other members of mammalian chitinases in IBD.
This project has been awarded an NIH R01DK80070 for six years since
2009. By collaborating with Dean Jack A.
Elias and Professor Chun-Geun Lee in the Department of Molecular Microbiology
and Immunology (MMI) at Brown University School of Medicine, I plan to continue
my research project in chitinase continuously.
Fortunately, I have approved to be an adjunct associate professor in MMI
since 2016, I will be in a position to intensively re-organize a
chitin-chitinase research group in the US and Japan by continuously cooperating
with Professors Elias and Lee.
粘膜上皮免疫 （Epithelial Immunoｂiology）
研究の目的と今後の課題： 炎症性腸疾患（Inflammatory Bowel Disease: IBD）は、複数の遺伝子及び環境因子がその発症、進展に関係する多因子遺伝性疾患の一つと考えられている。非常に興味深いことに、NOD2、ATG16、IL-23R遺伝子は近年欧米人のIBD（特にクローン病）発症に深く関与している可能性が示されているが、日本人を含むアジア系人種間ではその関連性が認められていない。事実、これまでに報告された感受性遺伝子の欠失マウスに腸炎の自然発症は認められておらず、これらの事実より、遺伝的素因だけでなく腸内細菌に対する宿主細胞の反応性や環境因子が、IBDの発症に深く関与している可能性が強く示唆されている。また、先進国において、IBD（特に潰瘍性大腸炎）が気管支喘息やアトピー性皮膚炎と共に増加傾向にある事実から、この分野の更なる研究が早急に必要と考えられる。よって、今後もマウスモデルとヒト臨床検体の両者を用いることにより、IBDの発症機序の解明及び治療法の開発に努力していきたい。また、これまでの研究経験と免疫病理、細胞生物学、分子生物学、細菌感染学における幅広い知識を生かし、今後はIBDだけでなくその他のアレルギー疾患（アトピー性皮膚炎、気管支喘息など）や慢性炎症性疾患（慢性関節リウマチやI型糖尿病等など）や感染症における基礎と臨床の橋渡し研究（トランスレーショナルリサーチ）にも取り組んでいきたい。多くの研究報告によれば、腸内細菌叢のバランスの乱れ(dysbiosis)がこれらの疾患を引き起こす誘因になるだけでなく、炎症の慢性化、急性憎悪、悪性化にも強く関与している。 当研究室では、IBDおよびIBD関連性大腸がんの発症の過程における腸管上皮細胞と腸内細菌叢（特に潜在的に病因に関わるような細菌群）との相互作用に重点を置いて、新たな慢性炎症疾患の予防、診断、治療の開発のために研究を進めていく方針である。これまでの業績は、このページの下部に示す。
Chitinase (キチナーゼ）： 我々の研究室では、DNAマイクロアレイ解析法を用いて、腸管上皮細胞およびマクロファージに特異的にキチン質との結合能力を有する酵素であり哺乳類キチナーゼに属するChitinase 3-like 1 (CHI3L1)分子が、炎症の回復期に強く発現することを発見した。この分子がマウスの急性および慢性腸炎モデルだけでなく、ヒトIBD患者でも劇的に発現増強が見られることがわかった （Gastroenterology
2006:130:398）。特に、IBD関連性大腸がん患者における腸管CHI3L1のmRNA発現増強は、コントロール群（健常人）の15-20倍にも及ぶ（Am J Pathol 2011;179:1494）。その後の精力的かつ継続した研究成果により、腸管上皮細胞上に発現するCHI3L1がPotentially pathogenic bacteria （常在腸内細菌叢内に存在する潜在的に病気を引き起こし得る細菌群）であるサルモネラ菌、Adherent Invasive Escherichia coli (AIEC)、セラチア菌などの上皮細胞への接着、侵入を約3-5倍程度増大させることを明らかにした。特に、AIECの細菌性キチナーゼ内に存在するキチン結合部位の特定のアミノ酸モチーフとCHI3L1分子が特異的に結合することによって、これらの細菌と上皮細胞との結合性と侵入性を増強させる事を発見した（Gastroenterology 2013:145:602）。また、CHI3L1のグリコシル化（糖鎖形成）が両者の結合性に不可欠であることも確認した。さらに、キチナーゼ全般に阻害作用を持つカフェインやCHI3L1を特異的に阻害する抗CHI3ｌ１抗体が、マウスの急性腸炎を著明に抑制することから、キチナーゼ阻害剤の炎症性疾患における臨床的治療法に応用できる可能性が強く示唆された。（Gastroenterology 2006:130:398；Inflamm Bowel
Dis 2012;18:1698; J Gastroenterol 2014;49:1206）。また、米国ブラウン大学 (Providence, RI)の Jack A. Elias医学部長とChun-Geun Lee教授のラボでは、キチナーゼが気管支喘息や慢性閉塞性肺疾患（COPD）の発症に関与し、抗キチナーゼ抗体の投与によって気管支の攣縮および過敏性反応の両方を完全に抑制できることをマウスモデルで証明した(Science 2004;304:1673)。現在も継続して両教授との共同研究を継続させ、また、2016年よりブラウン大学分子細菌免疫学講座の非常勤准教授に就任し、より活発に哺乳類および細菌キチナーゼのアレルギー疾患や慢性炎症疾患全般における免疫病態機序の解明に向けて研究に全力を注いで行く所存である。この興味深いプロジェクトにより、NIH の大型グラント（Ｒ01）を2009年から2015年までの6年間獲得し、今後も国内外で研究費を申請してキチナーゼによる慢性炎症発症の予防、診断、治療と多方面の研究を展開していきたい。
Chitin (キチン): キチン質は、甲殻類、昆虫、寄生虫、ダニ等の細胞骨格を形成する主要成分の多糖体であるが、ヒトやマウスを含めた哺乳類には存在しない。このため、キチン質は、哺乳類の持つ抗原提示細胞(樹状細胞、マクロファージ) に異物として認識され、強い免疫反応（アレルギー）を誘導する危険性がある。興味深いことに、上記のように哺乳類はキチン質をもたないにもかかわらず、これを分解する能力を有する酵素であるキチナーゼを合成し分泌することが出来る。しかし、我々が今回同定したCHI3L1は、キチナーゼの中でも酵素活性を持たず、キチン質との強い結合能力のみが保存されているため、Chi-lectin（カイレクチン）と呼ばれている。この、キチナーゼと強い結合能を持つキチンはサイズ依存性に異なる機能を持つ。例えば、40-70μmの中等度キチンは、マクロファージにおけるTNFやIL-1b等の炎症性サイトカインの産生能を増強させる。一方、1-10μmのchitin micro-particles (キチン微粒子）は、マクロファージに効率よく取り込まれた後、インターフェロンやIL-10等の制御（調節）性サイトカインの産生を促進することが報告されている。我々は、Florida
Atlantic University (Boca Raton, FL)のYoshimi Shibata 教授との共同実験によって10μm以下のキチン微粒子を幼少時から予防的に投与することにより、急性期と慢性期の動物腸炎モデルの両方を抑制できることを証明した（Inflamm Bowel Dis 2012;18:1698)。今後もShibata教授との共同実験を継続し、キチン微粒子による慢性腸炎やアレルギー疾患への臨床応用を展開して行く予定である。
TNFレセプター：腸管上皮細胞は、炎症時に、TNFレセプタータイプ１(TNFR1)とタイプ２(TNFR２)を発現することが知られている。TNFR1は正常状態でも常時発現するが、TNFR2は正常時には発現せず、非常に活性化された状態の上皮細胞表面に特異的にその発現が誘導される。T細胞とマクロファージに於いては、このTNFR1とTNFR2が、細胞死（アポトーシス）と細胞増殖という相反する２つのシグナル経路を活性化することが分かっている。我々の研究グループは、これらの細胞だけでなく、腸管上皮細胞にも急性および慢性炎症時に、炎症性サイトカインの濃度に依存してTNFR2が強く発現してくることを発見した（Gastroenterology 200２:122:134；Gastroenterology 2003;125:148)。また、最近の研究の結果、TNF/TNFR2のシグナルが上皮細胞の増殖を亢進させ、炎症の増強および遷延化を助長する重要な因子であることを証明した。同時に、TNF/TNFR1のシグナルが、上皮のバリア機構の強化とアポトーシスシグナルを制御することにより、炎症を抑制していることも証明した。現在、臨床では、抗TNF抗体による治療が、リウマチやクローン病等で広く使われているが、感染を含む重篤な副作用を引き起こす例もあり、治療に際しては細心の注意が必要である。これは、抗TNF抗体がTNF/TNFR1の重要な抑制的経路までも阻害するためと考えられ、我々のグループは、骨髄キメラマウスのモデルを用いてこの機序を論理的に証明した（Gastroenterology, 2008;134:470）。 これらのデーターは腸管上皮細胞特異的にTNFR2を介するシグナルを阻害する必要性が強く示唆している。このプロジェクトは、NIH
K08 (2003-2009)グラントによる6年間のサポート後、2009年以降は一時中断していたが、今後更に研究を再開していく予定である。
教育に関する実績： 教育面に関しては，マサチューセッツ総合病院にて、約25名の学生および卒後研究生（ポストドクトラルフェロー）の指導を行ってきた。また、卒後研究生と共に、ほぼ毎年、数多くの研究成果を学会発表し、インパクトファクターの高い医学系英文紙に論文を数多く掲載してきた。2006年以降は、corresponding authorとして、実験結果の全てに責任を負い、主席研究員としての地位を確立することに尽力してきた。2014年1月に行った卒後研究生の募集には、計156件の応募があり（全18カ国）、現在の研究が世界的に高く評価されていることが伺える。直接の研究指導者（Primary Mentor）として、研究結果をほぼ毎日確認および検討すると共に、研究補助金の申請書作成指導等を直接行い、多くの大学院生や卒後研究生のキャリアの向上にも多大に貢献してきた。また、国際的なプロジェクトにも積極的に参加し、日本学術振興会
海外研究助成金、上原財団海外留学助成金、中国政府助成金，National Research Foundation
Fellowship（韓国）, A*STAR Fellowship Award (シンガポール) によるサポートで卒後研究生を受け入れてきた。更に、2007年度より夏季研究実習生を当研究室に受け入れ、NIHやその他のファウンデーション(CCFA, AGA等)のサポートのもと、将来の基礎研究を担うであろう学生数名にサイエンスの基礎を一からきめ細かく指導してきた。久留米大学着任後も意欲的に学生やリサーチフェローの教育と指導に携わって行きたい。
公的貢献：これまで、J Exp Med, J Clin Invest, PNAS, Nature Communications, Scientific
Reports, Mucosal Immunologyを含む60の科学雑誌の査読、PLoS ONEやWorld J Gastroenterolを含む１１の科学雑誌のAcademic Editor、多くの論文の査読員、欧米諸国の数々の研究助成金審査委員を務めてきた。 2012年以降は、TME, GMPB Study SectionsでのNIH グラント審査員として公的に貢献してきた。これらの経験を基に、久留米大学の教育レベルが世界的医学研究レベルに達する事と、国家試験合格率向上を二大目標として尽力したい。:
研究業績
米国ハーバード大学医学部でPIに昇進後の業績(2006-2016)：
Mizoguchi E. Chitinase 3-like-1 exacerbates intestinal
inflammation by enhancing bacterial adhesion and invasion in colonic epithelial
cells. Gastroenterology
2006;130:398-411.
Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN,
Claypool SM, Kaser A, Nagaishi T, Higgins DE, Mizoguchi E, Wakatsuki Y Roopenian DC, Mizoguchi A, Lencer WI,
Blumberg RS. Neonatal Fc
receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 2006,116:2142-2151.
Mizoguchi
A, Ogawa A, Takedatsu H, Sugimoto K, Shimomura Y, Shirane K, Nagahama K,
Nagaishi T, Mizoguchi E,
Blumberg RS, Bhan AK. Dependence of
intestinal granuloma formation on unique myeloid DC-like cells. J Clin Invest 2007,117:605-615.
Nguyen
DD, Maillard MH, Cotta-de-almeida V, Mizoguchi
E, Klein C, Fuss I, Nagler C, Mizoguchi A, Bhan AK, Snapper SB. Lymphocyte-dependent and Th2
cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome
protein. Gastroenterology,
2007,133:1188-1197.
Sugimoto
K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, and Mizoguchi A. A novel function of IL-22, a Th17 cytokine,
in intestinal inflammation. J Clin
Invest, 2008, 118:534-544.
Shimomura
Y, Mizoguchi E, Sugimoto
K, Kibe R, Benno Y, Mizoguchi A, Bhan AK.
Regulatory role of B-1 B cells in chronic colitis. Int Immunol, 2008;20:729-737.
Kawada
M, Chen CC, Arihiro A, Nagatani K, Watanabe T, Mizoguchi E. Chitinase
3-like-1 enhances bacterial adhesion to colonic epithelial cells through the
interaction with bacterial chitin-binding protein. Lab Invest, 2008, 88:883-895.
Shimomura Y, Ogawa
A, Sugimoto K, Kawada M, Mizoguchi E,
Shi H-N, Pillai S, Bhan AK, and Mizoguchi A.
A unique B-2 B cell subset in the intestine. J
Exp Med, 2008, 205:1343-1355.
Matharu
K, Mizoguchi E, Alonso C, Mingle B, Iweala OI, Nguyen D, Prioult G,
Haigis KM, Bhan AK, Murakami H, Mizoguchi A, Reinecker HC, Nagler CR. TLR4 mediated protection against spontaneous
colitis in IL-10 deficient mice. Gastroenterology, 2009, 137: 1380-1390.
Parekkadan
B, Upadhyay R, Dunham J, Iwamoto Y, Mizoguchi E, Mizoguchi A, Weissleder
R, Yarmush ML. Bone marrow stromal cell
transplants prevent experimental enterocolitis and require host CD11b(+)
splenocytes. Gastroenterology, 2011, 140:966-975.
Kogiso
M, Nishiyama A, Shinohara T, Nakamura M, Mizoguchi E, Misawa Y, Guinet
E, Nouri-Shirazi M, Dorey CK, Henriksen RA, Shibata Y. Chitin particles induce
size-dependent but carbohydrate-independent innate eosinophilia. J Leuk
Biol, 2011; 90:167-176.
Chen
CC, Llado V, Eurich K, Tran HT, Mizoguchi E. Carbohydrate-binding motif in chitinase
3-like-1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in
colonic epithelial cells. Clin Immunol,
2011; 140:268-275.
Wang
S, Villablanca E, Gomes D, Nguyen D, Mizoguchi E, Kagan J, Reinecker HC,
Hacohen N, Nagler C, Xavier R, Rossi-Bergman B, Chen YB, Blomhoff R, Snapper S,
Mora R. MyD88-dependent TLR1/2 signals
educate dendritic cells with gut-specific imprinting properties. J
Immunol, 2011, 187:141-150.
Chen
CC, Pekow J, Llado V, Kanneganti M, Lau CW, Mizoguchi A, Mino-Kenudson M,
Bissonnette M, Mizoguchi E.
Chitinase 3-like 1 (CHI3L1/YKL-40) expression in colonic epithelial
cells as a potentially novel marker for colitis-associated neoplasia. Am J
Pathol, 2011, 179:1494-1503.
Aomatsu
T, Imaeda H, Matsumoto K, Kimura E, Yoden A, Tamai H, Fijiyama Y, Mizoguchi
E, Andoh A. Fecal chitinase 3-like 1
is a novel biological marker for disease activity in pediatric inflammatory
bowel disease patients. Aliment Pharmacol Ther, 2011;34:941-948.
van
Driel B, Liao G, Romero X, O’Keeffe MS, Wang G, Faubion WA, Berger SB, Magelky
EM, Manocha M, Azcutia V, Grisham M, Luscinskas FW, Mizoguchi E, de Waal
Malefty R , Reinecker HC, Bhan AK, Wang N, Terhorst C. Signaling lymphocytes activation molecule
regulates development of colitis in mice.
Gastroenterology,
2012;143:1544-1554.
Nishida
A, Lau CW, Zhang M, Andoh A, Shi HN, Mizoguchi E, Mizoguchi A. A membrane-bound mucin Muc1 serves as a
negative feedback in colitis-associated Th17 responses. Gastroenterology,
2012;142:865-874.
Nagatani
K, Wang S, Llado V, Lau CW, Li Z, Mizoguchi A, Nagler CR, Shibata Y, Reinecker HC, Mora JR, Mizoguchi E. Chitin-microparticles for the control of
intestinal inflammation. Inflamm Bowel Dis 2012; 18:1698-1710.
Conway
KL, Goel G, Sokol H, Manocha M, Mizoguchi E, Terhorst C, Bhan AK, Gardet
A, Xavier RJ. P40phox
expression regulates neutrophil recruitment and function during the resolution
phase of intestinal inflammation. J Immunol, 2012;189:3631-3540.
Low
D, Tran HT, Lee IA, Dreux N, Reinecker HC, Darfeuille-Michaud A, Barnich N, Mizoguchi
E. Chitin-bindingdomains of Escherichia coli chiA mediate
interactions with intestinal epithelial cells in mice with colitis. Gastroenterology,
2013;145:602-612.
Yamamoto S, Nakase H, Honzawa Y, Matsumura K, Norimitsu
U, Yamaguchi Y, Mizoguchi E, Chiba T.
Heparan
sulfate on intestinal epithelial cells plays a critical role in intestinal
crypt homeostasis via Wnt/β-catenin signaling.
Am J Physiol,
2013;305:G241-249.
Lee IA, Low D, Kamba A, Llado V, Mizoguchi E. Oral caffeine administration ameliorates acute colitis
by suppressing chitinase 3-like 1 expression in intestinal epithelial cells. J Gastroenterol, 2014; 49:1206-1216.
Liao
G, van Driel B, Magelky E, O’Keeffe MS, de Waal Malefyt R, Engel P, Herzog RW, Mizoguchi
E, Bhan AK, Terhorst C.
Glucocorticoid-induced TNF receptor family related protein ligand
regulates the migration of monocytes to the inflamed intestine. FASEB
Journal, 2014;28:474-484.
Tran
HT, Lee IA, Low D, Kamba A, Coyle AJ, Mizoguchi A, Shi HN, Lee CG, Elias JA, Mizoguchi
E. Chitinase 3-like 1
synergistically activates IL-6-mediated STAT3 phosphorylation in intestinal
epithelial cells in murine models of infectious colitis. Inflamm
Bowel Dis, 2014;20:835-846.
Low
D, Subramaniam R, Lin L, Aomatsu T, Mizoguchi A, DeGruttola A, Lee CG, Elias
JA, Andoh A, Mino-Kenudson M, Mizoguchi E. Chitinase 3-like 1 induces survival and
proliferation of intestinal epithelial cells during chronic inflammation and
colitis-associated cancer by regulating S100A9.
Oncotarget, 2015;6:36535-36550.
Low
D, Poltrak A, DeGruttola AK, Mizoguchi A, Mino-Kenudson M, Mizoguchi E. High endogenous expression of Chitinase
3-like 1 and excessive epithelial proliferation with colonic tumor formation in
MOLF/EiJ mice. PLoS ONE,
2015;10:e0139149 .
米国ハーバード大学医学部でPIに昇進前の業績(1992-2006)：
Maruiwa M,
Mizoguchi A, Russell GJ, Narula N, Storonska M, Mizoguchi E, Rabb H,
Arnaout MA, Bhan AK: Anti-KCA-3, a monoclonal antibody reactive with a rat
complement C3 receptor, distinguishes Kupffer cells from other
macrophages. J Immunol 1993;150:4019-4030.
Mombaerts P, Mizoguchi
E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S: Spontaneous development of inflammatory bowel disease in
T cell receptor mutant mice. Cell
1993;75:275-282.
Mombaerts
P, Mizoguchi E, Ljunggren H-G, Iacomini J, Ishikawa H, Wang L, Grusby
MJ, Glimcher LH, Winn HJ, Bhan AK, Tonegawa S:
Peripheral lymphoid development and function in TCR mutant mice. Int Immunol 1994;6:1061-1070.
Castigli
E, Alt FW, Davidson L, Bottaro A, Mizoguchi
E, Bhan AK, Geha RS: CD40-deficient mice generated by recombination-
activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci USA
1994;91:12135-12139
Russell
GJ, Parker CM, Cepek KL, Mandelbrot DA, Sood A, Mizoguchi E, Ebert EC,
Brenner MB, Bhan AK: Distinct structural
and functional epitopes of the aEb7 integrin.
Eur J Immunol 1994;24:2832-2841。
Hollander
GA, Simpson SJ, Mizoguchi E, Nichogiannopoulou A, She J, Gutierrez-Ramos
J-C, Bhan AK, Burakoff SJ, Wang B, Terhorst C:
Severe colitis in mice with abberrant thymic selection. Immunity 1995;3:27-38.
Simpson
SJ, Mizoguchi E, Allen D, Bhan AK, Terhorst C: Evidence
that CD4+, but not CD8+ T cells are responsible for murine
interleukin-2-deficient colitis. Eur J Immunol 1995;25:2618-2629.
Russell
GJ, Parker CM, Sood A, Mizoguchi E, Ebert EC, Bhan AK, Brenner MB: p126
(CDw101), a costimulatory molecule preferentially expressed on mucosal T
lymphocytes. J Immunol 1996;157:3366-3374.
Mizoguchi,
A, Mizoguchi E, Chiba C, Spiekermann G, Tonegawa S, Nagler-Anderson C,
Bhan AK: Cytokine imbalance and autoantibody production in T cell receptor-alpha
mutant mice with inflammatory bowel disease.
J Exp Med 1996; 183:847-856.
Russell
GJ, Parker CM, Sood A, Mizoguchi E, Ebert EC, Bhan AK, Brenner MB: p126 (CDw101), a costimulatory molecule
preferentially expressed on mucosal T lymphocytes.
J Immunol 1996;157:3366-3374
Mizoguchi,
A, Mizoguchi E, Chiba C, Spiekermann G, Tonegawa S, Nagler-Anderson C,
Bhan AK: Cytokine imbalance and autoantibody production in T cell receptor-alpha
mutant mice with inflammatory bowel disease.
J Exp Med 1996; 183:847-856.
Mizoguchi A, Mizoguchi E,
Tonegawa S, Bhan AK: Alteration of polyclonal to an oligoclonal immune response
to cecal aerobic bacterial antigens in TCR-alpha mutant mice with inflammatory
bowel disease. Int Immunol
1996;8:1387-1394.
Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK: Role of appendix in the development of
inflammatory bowel disease in TCR-alpha mutant mice. J Exp Med 1996;184:707-715.
Lerner A, Clayton LK, Mizoguchi E, Ghendler Y, van Ewijk W, Koyasu S,
Bhan AK, Reinherz EL: Cross-linking of T cell receptors on double-positive
thymocytes induces a cytokine-mediated stromal activation process linked to
cell death. EMBO J
1996;15:5876-5887.
Schulz R-J, Parkes A, Mizoguchi E,
Bhan AK, Koyasu S. Development of CD4- CD8- abTCR+ NK1.1+ T lymphocytes.
Thymic selection by self antigen.
J Immunol 1996;157:4379-4389.
Young
F, Mizoguchi E, Bhan AK, Alt FW.
Constitutive Bcl-2 expression during immunoglobulin heavy chain-promoted
B cell differentiation expands a novel precursor B cell population. Immunity 1997;6:23-33.
Simpson
SJ, Hollander GA, Mizoguchi E, Allen D, Bhan AK, Wang B, Terhorst
C. Expression of pro-inflammatory
cytokines by TCRab
and TCRgd T cells
in an experimental model of colitis. Eur
J Immunol 1997;27:17-25.
Clayton
LK, Ghendler Y, Mizoguchi E, Patch R, Ocain TD, Orth K, Bhan AK, Dixit
VM, Reinherz EL. T cell receptor
ligation by peptide/major histocompatibility complex ligand induces activation
of a caspase in immature thymocytes: The molecular basis of negative
selection. EMBO J
1997;16:2282-2293.
Ghendler
Y, Hussey RE, Witte T, Mizoguchi E,
Clayton LK, Bhan AK, Koyasu S, Chang H-C, Rheinherz EL. Double positive TCRhigh thymocytes are resistant to peptide/MHC
ligand-induced negative selection. Eur
J Immunol 1997;27:2279-2289.
Keates
S, Keates AC, Mizoguchi E, Bhan AK, Kelly CP. Enterocytes are the primary source of the
chemokine ENA-78 in normal colon and in
ulcerative colitis. Am J Physiol
1997;273 (Gastrointest. Liver Physiol.
36):G75-G82.
Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI,
Bhan AK. Suppressive role of
B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med 1997;186:1749-1756.
Spergel
JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous
sensitization with protein antigen induces localized allergic dermatitis and
hyperresponsiveness to methacholine after single exposure to aerosolized
antigen in mice. J. Clin Invest
1998;101:1614-1622.
Hollander
GA, Zuklys S, Morel C, Mizoguchi E, Mobisson K Simpson S, Terhorst C,
Wishart W, Golan DE, Bhan AK, Burakoff SJ.
Monoallelic Expression of the interleukin-2 locus. Science 1998;279:2118-2121.
Simpson
SJ, Shah S, Comisky M, de Jong YP, Wang B, Mizoguchi E, Bhan AK,
Terhorst C. T cell-mediated pathology in
two models of experimental colitis depends predominantly on the interleukin
12/signal transducer and activator of transcription (Stat)-4 pathway, but is
not conditional on interferong expression by T cells. J Exp Med 1998;187:1225-1234.
Simpson
SJ, de Jong YP, Shah SA, Comiskey M, , Wang B, Spielman JA, Podack ER, Mizoguch E, Bhan AK, Terhorst C. Consequence of Fas ligand and perforin
expression by colon T cells in a mouse
model of inflammatory bowel disease. Gastroenterology
1998;115:849-855.
Snapper
SB, Rosen FS, Mizoguchi E, Cohen P, Khan W, Liu C-H, Hagemann TL, Kwan
S-P, Davidson L, Bhan AK, Alt FW.
Wiskott-Aldrich Syndrome Protein-deficient mice reveal a role for WASP
in T but not B cell activation. Immunity
1998;9:81-91.
Mackay
F, Browning JL, Lawton P, Shah S, Cominskey M, Bhan AK, Mizoguchi E, Terhorst C, Simpson SJ. Both the lymphotoxin and tumor necrosis
factor pathways are involve in experimental murine models of colitis. Gastroenterology 1998;115:1464-1475.
Levelt
CN, Mizoguchi E, Huang X,
Zacks R, Bhan AK, Tonegawa S. Inhibition
of intrathymic T cell development by expression of a transgenic antagonist
peptide. Proc Natl Acad Sci USA
1998;95:14349-54.
Mizoguchi A, Mizoguchi E, Bhan AK. The critical role of IL-4 but not
interferon gamma in the pathogenesis of chronic colitis in T cell receptor alpha
mutant mice. Gastroenterology
1999;116:320-326.
Morales
VM, Christ A, Watt SM, Kim HS, Johnson KW, Utku N, Texieira, AM, Mizoguchi A, Mizoguchi
E, Russell GJ, Russell SE, Bhan AK, Freeman GJ, Blumberg RS. Regulation of human intestinal
intraepithelial lymphocyte cytolytic function by billiary glycoprotein (CD66a). J Immunol 1999;163:1363-1370.
Mizoguchi E, Mizoguchi A,
Preffer FI, Bhan AK. Regulatory
role of mature B cells via costimulatory pathway in a murine model of
inflammatory bowel disease. Int Immunol 2000;12:597-605.
Mizoguchi
A, Mizoguchi E, Saubermann LJ, Higaki K, Blumberg RS, Bhan AK. Limited CD4 T-cell diversity associated with
colitis in T-cell receptor a mutant mice requires a T helper 2 environment. Gastroenterology
2000;119:983-995.
Andres
PG, Beck PL, Mizoguchi E, Mizoguchi A, Bhan AK, Dawson T, Kuziel, WA,
Maeda N, MacDermott RP, Podolsky DK, Reinecker H-C. Mice with a selective deletion of the
chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated
colitis: Lack of CC chemokine receptor 5 expression results in a NK1.1+
lymphocyte-associated Th-2 type immune response in the intestine. J Immunol 2000;164:6303-6312.
de
Jong YP, Comiskey M, Kalled SL, Mizoguchi E, Flavell RA, Bhan AK,
Terhorst C. Chronic murine colitis is
dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154
administration. Gastroenterology 2000;119:715-723.
Zhu
X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L, Wang Y, Robert C, Wu
B, Smith PD, Lencer WI, Blumberg RS. MHC
class I-related Fc receptor for IgG is functionally expressed in monocytes,
intestinal macrophages and dendritic cells.
J Immunol 2001;166:3266-3276.
Woodward
AL, Spergel JM, Alenius H, Mizoguchi E, Bhan AK, Castigli E, Brodeur SR,
Ottgen HC, Geha RS. An obligate role for
T-cell receptor ab+
T cells but not T cell receptor gd T cells, B cells or CD40/CD40L interaction
in a mouse model of atopic dermatitis. J
Allergy Clin Immunol 2001;107:359-366.
de
Jong YP, Abadia-Molina AC, Satoskar AR, Clarke K, Rietdijk S, Faubion WA, Mizoguchi
E, Metz CN, Al Sahli M, ten Hove T, Keates AC, Lubetsky JB, Farrell RJ,
Michetti P, van Deventer SJ, Lolis E, David JR, Bhan AK, Terhorst C. Development of chronic colitis is dependent
on the cytokine MIF. Nature Immunol
2001;2:1061-1066.
Mizoguchi E, Mizoguchi A,
Takedatsu H, Cario E, de Jong YP, Ooi CJ, Xavier RJ, Terhorst C, Podolsky DK,
Bhan AK. Role of tumor necrosis factor
receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal
inflammation in mice. Gastroenterology
2002;122:134-144.
Mizoguchi
A, Mizoguchi E, Takedatsu H,
Blumberg RS, Bhan AK. Chronic intestinal
inflammatory condition generates IL-10 producing regulatory B cell subset
characterized by CD1d upregulation. Immunity
2002;16:219-230.
Neurath
MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H, Mizoguchi A, Mizoguchi
E, Mudter J, Galle PR, Bhan AK, Autschbach F, Sullivan BM, Szabo SJ,
Glimcher LH, Blumberg RS. The
transcription factor T-bet regulates mucosal T cell activation in experimental
colitis and Crohn’s disease. J Exp
Med 2002;195:1129-1143.
Jabara
HH, Laouini D, Tsitsikov E, Mizoguchi E, Bhan AK, Castigli E, Dedeoglu
F, Pivniouk V, Brodeur SR, Geha RS. The
binding site for TRAF2 and TRAF3, but not for TRAF6, is essential for CD40
Mediated immunoglobulin class switching. Immunity 2002;17:265-276.
Mizoguchi E, Xavier RJ,
Reinecker HC, Uchino H, Bhan AK, Podolsky D, Mizoguchi A. Colonic epithelial functional phenotype
varies with type and phase of experimental colitis. Gastroenterology 2003;125:148-61.
Brodeur S, Angelini F, Bacharier LB, Blom AM, Mizoguchi
E, Fujiwara H, Plebani A, Notarangelo LD, Dahlback B, Tsitsikov E, Geha
RS. C4b-binding protein
(C4BP) activates B cells through the CD40 receptor. Immunity 2003;18:837-848.
Mizoguchi
A, Mizoguchi E, de Jong YP,
Takedatsu H, Preffer FI, Terhorst C, Bhan AK.
Role of the CD5 molecule on TCRgd T cell-mediated immune functions:
development of germinalcenters and chronic intestinal inflammation. Int Immunol 2003;15:97-108.
Colgan
SP, Pitman RS, Nagaishi T, Mizoguchi A, Mizoguchi E, Mayer LF, Shao L, Sartor RB, Subjeck JR, Blumberg
RS. Intestinal heat shock protein 110
regulates expression of CD1d on intestinal epithelial cells. J Clin Invest 2003;112:745-54.
Beck
PL, Xavier R, Wong J, Ezedi I, Mashimo H, Mizoguchi A, Mizoguchi E, Bhan AK, Podolsky
DK. Paradoxical roles of different
nitric oxide synthase isoforms in colonic injury. Am J Physiol gastrointest Liver Physiol
2004;286:G137-47.
Castigli
E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, Mizoguchi E, Geha RS.
Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acd Sci USA
2004;101:3903-3908.
Hokama
A, Mizoguchi E, Sugimoto
K, Shimomura Y, Tanaka Y, Yoshida M, Rietdijk ST, de Jong YP, Snapper SB,
Terhorst C, Blumberg RS, Mizoguchi A.
Induced reactivity of intestinal CD4+ T cells with an epithelial cell
lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity 2004;20:681-693.
Yoshida
M, Claypool SM, Wagner JS, Mizoguchi
E, Mizoguchi A, Roopenian DC, Lencer WI, Blumberg RS. Human neonatal Fc receptor mediates transport
of IgG into luminal secretions foe delivery of antigens to mucosal dendritic
cells. Immunity 2004;20:769-783.
久留米大学免疫学講座大学院時代の業績(1990-1992)：
Futagami-Mizoguchi E, Yamada A,
Mizoguchi A, Imai Y, Yokoyama MM: LFA-1 expression on exocrine glands as a
potential novel marker of malignant disease.
Am J Pathol 1993; 143:672-677.
総説：
Subramaniam
R, Mizoguchi A, Mizoguchi E. Mechanisms of mucosal signaling in colitis-associated cancer. Can Res
Frontiers, 2016, in press.
DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current
understanding of dysbiosis in human and animal models. Inflamm
Bowel Dis, 2016, in press.
Mizoguchi A, Takeuchi T, Himuro H, Okada T, Mizoguchi E. Genetically engineered mouse models for
inflammatory bowel disease. J Pathol, 2016;238:205-219.
Lee IA, Kamba A, Low D, Mizoguchi E. Novel methyxanthine
derivative-mediated anti-inflammatory effects in inflammatory bowel
disease. World J Gastroenterol, 2014;20:1127-1138.
Low
D, Mino-Kenudson M, Mizoguchi E. Recent advances in understanding
colitis-associated tumorigenesis. Inflamm Bowel Dis, 2014;20: 2115-2123.
Kamba
A, Lee IA, Mizoguchi E. Potential
linkage between TLR4 and chitinase 3-like 1 (CHI3L1/YKL-40) signaling on
colonic epithelial cells in inflammatory bowel disease and colitis-associated
cancer. Current Molecular Medicine, 2013;13:1110-1121.
Low D, Mizoguchi A, Mizoguchi E. DNA methylation in
inflammatory bowel disease and beyond. World J Gastroenterol,
2013;19:5238-5249.
Low D, Nguyen DD, Mizoguchi E. Animal
models of ulcerative colitis and their application in drug
research. Drug Design, Development and Therapy, 2013;7:1341-1357.
Kanneganti
M, Kamba A, Mizoguchi E. Role
of chitotriosidase (chitinase 1) under normal and disease conditions. J Epithel Biol Pharmacol, 2012,5:1-9.
Kanneganti M, Mino-Kenudson M, Mizoguchi E. Animal models of
colitis-associated carcinogenesis. J Biomed Biotechnol, 2011;
2011:342637, 23 pages.
Tran
HT, Barnich N, Mizoguchi E. Potential role of
chitinases and chitin-binding proteins in host-microbial interactions during
the development of intestinal inflammation.
Histology & Histopathology,
2011;26:1453-1464.
Mizoguchi A, Mizoguchi E. Animal models of IBD:
linkage to human disease. Current Opinions in
Pharmacology, 2010;10:578-587.
Eurich
K, Segawa M, Toei-Shimizu S, Mizoguchi E. Potential role of chitinase 3-like-1
(CHI3L1/YKL-40) in inflammation-associated carcinogenic change of epithelial
cells. World J Gastroenterol, 2009;15:5249-5259.
Hokama A, Mizoguchi E, Mizoguchi A. Roles of galectins in inflammatory bowel disease. World J
Gastroenterol, 2008, 14:5133-5137.
Mizoguchi
A, Mizoguchi E. IBD: past, present, and future: lessons from
the
Mizoguchi E,
Mizoguchi A. Is the sugar always sweet
in intestinal inflammation? Immunologic Research 2007, 37:47-60.
Kawada M, Hachiya Y, Arihiro A, Mizoguchi E. Role of mammalian chitinases
Mizoguchi A, Mizoguchi E, Bhan AK. Immune networks in animal models of
inflammatory bowel disease. Inflamm
Bowel Dis 2003;9:246-259.
Bhan
AK, Mizoguchi E, Smith RN, Mizoguchi A.
Spontaneous chronic colitis in TCRa mutant mice; an
experimental model of human ulcerative colitis.
Intern Rev Immunol 2000;19:123-138.
Bhan AK,
Mizoguchi E, Smith RN, Mizoguchi A.
Colitis in transgenic and knockout animals as models of human
inflammatory bowel disease. Immunol
Rev 1999;169:195-207.
Bhan AK,
Mizoguchi E, Smith RN, Mizoguchi A.
Lessons for human inflammatory bowel disease from experimental
models. Current Opinions in
Gastroenterology 1999;15:285-290.
Bhan A
K, Mizoguchi E, Mizoguchi A. New
models of chronic intestinal inflammation.
Current Opinions in Gastroenterology 1994;10:633-638.
和文総説：
溝口充志, 溝口恵美子：IBDの病態を理解するための腸管粘膜バリア機構の基礎知識、IBD Research 10:1,2016.
溝口充志, 溝口恵美子：診療に必要な炎症性腸疾患の病態の知識、日本医師会雑誌 144:23-27, 2015。
溝口恵美子：腫瘍壊死因子（TNF)の炎症生腸疾患における役割、G.I. Research 19:55-63, 2011.
下村泰代，杉本健，長濱清隆，溝口恵美子，溝口充志：腸管肉芽腫形成のための新しい腸管樹状細胞、分子消化器病, 13:97-103, 2007
本、チャプター：
Nishida A, Lau CW, Mizoguchi E, Mizoguchi A. Regulatory B cells in mouse models
of intestinal inflammation. Methods in
Molecular Biology, 2014, 1190:227-241.
Kamba A, Shibata Y, Mizoguchi E.
Potential
roles of chitin in mucosal inflammation.
In: Microbial pathogens and strategies for combating them: science,
technology and approved education. Formatex Microbiology Book Series (2013
Edition), Corchero R (Editor), Formatex Research Center Publisher, Badajoz,
Spain, 2013. Chapter 56, page 1853-1863.
Mizoguchi E, Mizoguchi A, Bhan AK. Insight from recent advances in animal
models of inflammatory bowel disease. In Molecular genetics of inflammatory
bowel disease. D’Amato M, Rioux J
(Eds.). Springer Science Publishers,
Inc, 2012. Part I-3, page 45-86.
Mizoguchi E, Kawada M.
Role of chitinase in gastroenterology.
In: Binomium chitin-chitinase: Recent issues. Musumeci S, Paoletti MG (Eds.). Nova Science Publishers, Inc, 2009. Chapter 21, page 359-381.
Hollander
GA, Simpson SJ, Mizoguchi E, Bhan AK, Wang B, Terhorst C. The role
of T cells in the pathogenesis of IBD:
Lessons from novel experimental models.
In: Inflammatory Bowel Diseases
and Recurrent Chronic Pain in Children.
Hadziselimovic F, Herzog B (Eds.).
Kluwer Press 1996; 82-107.
Simpson
SJ, Hollander GA, Mizoguchi E, Bhan AK, Wang B, Terhorst C. Defects in T cell Regulation: Lessons for
Inflammatory Bowel Disease. In: Essentials of Mucosal Immunology. M. Kagnoff and H. Kiyono (Eds.). Academic Press, 1996;291-304.