Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL Journal Article

   

Authors:	Hanash, A. M.; Kappel, L. W.; Yim, N. L.; Nejat, R. A.; Goldberg, G. L.; Smith, O. M.; Rao, U. K.; Dykstra, L.; Na, I. K.; Holland, A. M.; Dudakov, J. A.; Liu, C.; Murphy, G. F.; Leonard, W. J.; Heller, G.; van den Brink, M. R. M.
Article Title:	Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL
Abstract:	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 gastrointestinal 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 against A20 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.
Journal Title:	Blood
Volume:	118
Issue:	2
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2011-07-14
Start Page:	446
End Page:	455
Language:	English
DOI:	10.1182/blood-2010-07-294785
PROVIDER:	scopus
PMCID:	PMC3138694
PUBMED:	21596854
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79960533396&partnerID=40&md5=9f7c15d9d0d9c298c301dd7aff7d3385
Notes:	--- - "Export Date: 17 August 2011" - "CODEN: BLOOA" - "Source: Scopus"

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