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.
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Acknowledgments
We thank Drs. Youhei Tokita and Masahiro Yamamoto for assistance with the real-time RT-PCR, and Ms. Akiyo Kondo for assistance with the preparation of colonic sections. This work was supported in part by Grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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Ogino, H., Nakamura, K., Iwasa, T. et al. Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J Gastroenterol 47, 366–376 (2012). https://doi.org/10.1007/s00535-011-0502-y
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DOI: https://doi.org/10.1007/s00535-011-0502-y