期刊
JOURNAL OF IMMUNOTHERAPY
卷 31, 期 2, 页码 189-198出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e31815dc0e8
关键词
human; immunotoxin; RFT5-SMPT-dgA; CD25; regulatory T cell; depletion
资金
- Intramural NIH HHS [Z01 SC003811-33] Funding Source: Medline
The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25(+)CD4(+) T regulatory (T-reg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate T-reg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the T-reg-cell depleting capacity of the CD25-directed immunotoxin, RFT5-SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25(+), Foxp3-expressing CD4(+) T cells in vitro. Administration of RFT5-SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25(high) CD4(+) T cells in vivo (a 97.5% mean reduction at nadir; from 69.4 +/- 12.4cells/mu L to 1.7 +/- 0.3 cells/mu L). The reduction in FOXP3(+) CD4+ T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6 +/- 16.5 cells/mu L to 14.2 +/- 3.9 cells/mu L). This resulted in the selective persistence of a stable number of CD25(low/neg) FOXP3(+) CD4(+) T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human T-reg cells in vivo may require the ability to target and eliminate FOXP3(+) cells expressing both high and low levels of CD25.
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