Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Ma, Huihui; Lu, Chang; Ziegler, Judith; Liu, Ailing; Sepulveda, Antonia R.; Okada, Hideho; Lentzsch, Suzanne; Mapara, Markus Y.

doi:10.1172/jci43706

Cited by 68 publications

(76 citation statements)

References 67 publications

(79 reference statements)

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“…12 If STAT1 was missing in donor splenocytes, clinical GVHD signs and the disease-related mortality were significantly impaired, both in the minor and major mismatch setting. 13 Here we show that JAK1/2 inhibition by ruxolitinib potently reduced aGVHD in mice and significantly prolonged survival, even in an aggressive major mismatch model. Translating our observation into the clinic, we observed potent reduction of GVHD symptoms and serum cytokines in 6 patients with steroidrefractory aGVHD and chronic GVHD (cGVHD).…”

Section: Introductionmentioning

confidence: 62%

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Spoerl

Mathew²,

Bscheider

et al. 2014

Blood

352

296

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Key Points• We report that ruxolitinib reduces murine GVHD via increased Treg numbers.• We demonstrate the potent activity of ruxolitinib treatment in patients with corticosteroidrefractory GVHD.Graft-versus-host-disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) characterized by the production of high levels of proinflammatory cytokines. Activated Janus kinases (JAKs) are required for T-effector cell responses in different inflammatory diseases, and their blockade could potently reduce acute GVHD. We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of effector T cells and suppression of proinflammatory cytokine production in response to alloantigen in mice. In vivo JAK 1/2 inhibition improved survival of mice developing acute GVHD and reduced histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells. Mechanistically, we could show that ruxolitinib impaired differentiation of CD4 1 T cells into IFN-g-and IL17A-producing cells, and that both T-cell phenotypes are linked to GVHD. Conversely, ruxolitinib treatment in allo-HCT recipients increased FoxP3 1 regulatory T cells, which are linked to immunologic tolerance. Based on these results, we treated 6 patients with steroid-refractory GVHD with ruxolitinib. All patients responded with respect to clinical GVHD symptoms and serum levels of proinflammatory cytokines. In summary, ruxolitinib represents a novel targeted approach in GVHD by suppression of proinflammatory signaling that mediates tissue damage and by promotion of tolerogenic Treg cells. (Blood. 2014;123(24):3832-3842)

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Section: Introductionmentioning

confidence: 62%

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Spoerl

Mathew²,

Bscheider

et al. 2014

Blood

352

296

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“…STAT1 is a critical transcriptional regulator of T h 1-type pathways and has been shown to directly impact CD4 T-cell responses in GVHD. 5 However, when using bone marrow from STAT1 knockout mice (STAT1 pDCs produced less interleukin (IL)12, type I interferon, and free radicals (see figure). Not only did this impair the T h 1-driven GVHD processes when the normal T cells were later given as DLI, but the lesser free radical formation likely also diminished tissue damage so often associated with fueling the GVHD cascade.…”

Section: Bringing Out the Dcs' Softer Side In Gvhd ------------------mentioning

confidence: 99%

Bringing out the DCs’ softer side in GVHD

Murphy

2014

Blood

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“…What is the effect of type I-IFN signaling on other donor cellular subsets that affect GVHD and GVL, namely donor natural killer cells, plasmacytoid DCs, and Tregs (where STAT-1 signaling has recently been shown to be critical)? 9 Is there an effect on overall functional immune-competence? What is the effect on CD4 ϩ -mediated GVL?…”

Section: Pavan Reddy University Of Michigan Comprehensive Cancer Centermentioning

confidence: 99%

Type I-IFNs interfere with GVH responses

Reddy¹

2011

Blood

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Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Cited by 68 publications

References 67 publications

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Bringing out the DCs’ softer side in GVHD

Type I-IFNs interfere with GVH responses

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