期刊
BLOOD
卷 118, 期 2, 页码 446-455出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-07-294785
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资金
- National Institutes of Health [RO1-HL069929, RO1-CA107096, RO1-AI080455, PO1-CA33049, R01-HL095075]
- NHLBI
- Lymphoma Foundation
- Alex's Lemonade Stand
- Leukemia and Lymphoma Society
- Ryan Gibson Foundation
- Elsa U. Pardee Foundation
- Byrne Fund
- Emerald Foundation
- Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center
- Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research
IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastro-intestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity againstA20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes. (Blood. 2011; 118(2): 446-455)
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