Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model

Haruei Ogino, Kazuhiko Nakamura, Tsutomu Iwasa, Eikich Ihara, Hirotada Akiho, Yasuaki Motomura, Kazuya Akahoshi, Hisato Igarashi, Masaki Kato, Kazuhiro Kotoh, Tetsuhide Ito, Ryoichi Takayanagi

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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 inthe presence of rapamycin for three 7-day rounds of stimulation. The ratio of Tregs to CD4+T cells was analyzed by flow cytometry. NaiveCD4+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 down regulation 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.

Original languageEnglish
Pages (from-to)366-376
Number of pages11
JournalJournal of gastroenterology
Volume47
Issue number4
DOIs
Publication statusPublished - Apr 1 2012

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All Science Journal Classification (ASJC) codes

  • Gastroenterology

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