2006 Fiscal Year Final Research Report Summary
The establishment of bacteria antigen-specific T cell transgenic mice develop spontaneous chronic colitis, and the development of inhibitory probiotics for the treatment of inflammatory bowel diseases
| Project/Area Number |
17390215
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KANAI Takanori Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Assistant Professor, 医学部附属病院, 講師 (40245478)
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| Co-Investigator(Kenkyū-buntansha) |
AZUMA Miyuki Tokyo Medical and Dental University, Professor, 大学院医歯学総合研究科, 教授 (90255654)
HIBI Toshifumi Keio University, School of Medicine, Professor, 医学部, 教授 (50129623)
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| Project Period (FY) |
2005 – 2006
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| Keywords | intestinal bacteria / biological molecule / translational research / immunology |
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| Research Abstract |
The aim of this study is to assess the role of intestinal bacteria in the development and the persistence of colitogenic CD4^+ memory T cells in chronic colitic mice. To do it, we used a chronic colitis model induced by adoptive transfer of CD4^+CD45RB^<high> T cells into immunodeficient Rag-2^<-/-> mice. Lamina propria CD4^+ T cells obtained from colitic CD4^+CD45RB^<high> T cell-transferred mice have a characteristic of CD44^<high>CD62L^-CD69^+IL-7Ra^<high> effector T or effector-memory (T_<EM>) phenotype. SPF, but not germ free (GF), Rag-2^<-/-> mice re-transferred with these colitic LP CD4^+ T cells developed colitis showing higher histological scores and elevated production of Th1 cytokines 10 wk after retransfer. Surprisingly, however, albeit less compared with SPF Rag-2^<-/-> mice, significant number of CD4^+ TEM cells remained to reside in various sites, such as spleen, mesenteric lymph nodes, and bone marrow in GF Rag-2^<-/-> mice. Furthermore, GF→SPF, but not GF→GF, SCID mice rapidly developed colitis 2 wk after transferring to SPF condition. In another experiment, we further evaluated the role of toll-like receptor (TLR) signaling in donor CD4^+ T cells using MyD88^<-/-> mice. Interestingly, we found that the severity of colitis in MyD88^<-/-> CD4^+CD45RB^<high> T cell-transferred Rag-^<2-/-> mice was significantly decreased as compared with that in wild-type CD4^+CD45RB^<high> T cell-transferred Rag-2^<-/-> mice, indicating that donor CD4^+ T cells expressed some TLRs, and their TLR signaling tunes the maintenance of colitogenic CD4^+ memory T cells.
Collectively, We found that intestinal bacteria are critical important for the persistence of colitogenic CD4^+ memory T cells in chronic colitic mice, but not essential for the survival of these cells.
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