Interleukin-2 and Regulatory T Cells in Graft-versus-Host Disease

作者：John Koreth, Ken‐ichi Matsuoka, Haesook T. Kim, Sean M. McDonough, Bhavjot Bindra, Edwin Pascal Alyea, Philippe A. Armand, Corey S. Cutler, Vincent T. Ho, Nathaniel Simon Treister, Don C. Bienfang, Sashank Prasad, Dmitrios Tzachanis, Robin Joyce, David Avigan, Joseph H. Antin, Jerome Ritz, Robert J. Soiffer · 发表于：New England Journal of Medicine · 年份：2011 · DOI：10.1056/nejmoa1108188 · 被引用次数：1136 · 研究领域：Hematopoietic Stem Cell Transplantation、T-cell and B-cell Immunology、Nonmelanoma Skin Cancer Studies

BACKGROUND: Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. METHODS: In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. RESULTS: A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Tr...