Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen Journal Article

   

Authors:	Betts, B. C.; Abdel-Wahab, O.; Curran, S. A.; St Angelo, E. T.; Koppikar, P.; Heller, G.; Levine, R. L.; Young, J. W.
Article Title:	Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen
Abstract:	Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4+ Tregs to CD8+CD25+ effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell-stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment. © 2011 by The American Society of Hematology.
Keywords:	signal transduction; controlled study; human cell; janus kinase 2; cd8+ t lymphocyte; t lymphocyte; t-lymphocytes; interleukin 2; stat3 protein; enzyme inhibition; dendritic cell; cell differentiation; immunological tolerance; regulatory t lymphocyte; cytokines; dendritic cells; immune tolerance; lymphocyte culture test, mixed; tumor necrosis factor alpha; t-lymphocytes, regulatory; sulfonamides; cd4+ t lymphocyte; interleukin 6; cytokine production; effector cell; immunity; th17 cell; th1 cell; cd25+ t lymphocyte; alloantigen; isoantigens; t lymphocyte activation; interleukin 15; immunologic memory; pyrrolidines
Journal Title:	Blood
Volume:	118
Issue:	19
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2011-11-10
Start Page:	5330
End Page:	5339
Language:	English
DOI:	10.1182/blood-2011-06-363408
PROVIDER:	scopus
PMCID:	PMC3217413
PUBMED:	21917753
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-81055126760&partnerID=40&md5=c300694bc7f7df76b5f4dad5938faa30
Notes:	--- - "Export Date: 9 December 2011" - "CODEN: BLOOA" - "Source: Scopus"

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