title: Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model.
abstract: BACKGROUND
  To provide rapid immunosuppression without side effects, we analyzed whether rapamycin alone, and regulatory T cells (Tregs) expanded ex vivo by rapamycin, suppressed colitis in a mouse model.
  
  
  METHODS
  Severe combined immunodeficiency (SCID) mice reconstituted with naive CD4(+) T cells were treated with or without intraperitoneal rapamycin. Body weight was evaluated. CD4(+) T cells were cultured in the presence of rapamycin for three 7-day rounds of stimulation. The ratio of Tregs to CD4(+) T cells was analyzed by flow cytometry. Naive CD4(+) T cells were transferred into SCID mice with CD4(+) T cells expanded in the presence or absence of rapamycin. Clinical symptoms of colitis, histological changes, and cytokine expression were investigated.
  
  
  RESULTS
  Systemic rapamycin partially prevented the development of colonic inflammation in a transfer model of colitis, but decreased body weight in control mice. With rapamycin, stimulated CD4(+) T cells expanded eightfold in 3 weeks in vitro, and the proportion of Tregs increased to about 40%. Without rapamycin, CD4(+) T cells expanded 20-fold in 3 weeks, but the proportion of Tregs remained at about 15%. CD4(+) T cells expanded with rapamycin prevented the development of colitis in a naïve CD4(+) T-cell transfer model, in association with the downregulation of Th1 and Th17 responses.
  
  
  CONCLUSIONS
  We demonstrated, for the first time, that CD4(+) T cells expanded with rapamycin in vitro suppressed colitis. Therefore, rapamycin-expanded Treg transfer therapy is expected to be efficacious for inflammatory bowel disease.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Haruei
authors.initials: H
authors.lastname: Ogino
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwasa
authors.forename: Eikich
authors.initials: E
authors.lastname: Ihara
authors.forename: Hirotada
authors.initials: H
authors.lastname: Akiho
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Motomura
authors.forename: Kazuya
authors.initials: K
authors.lastname: Akahoshi
authors.forename: Hisato
authors.initials: H
authors.lastname: Igarashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Kato
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kotoh
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D018929:Cell Culture Techniques; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D020123:Sirolimus