CP-690550, a Janus Kinase Inhibitor, Suppresses CD4+ T-Cell–Mediated Acute Graft-Versus-Host Disease by Inhibiting the Interferon-γ Pathway

Park, Hyung Bae; Oh, Keunhee; Garmaa, Nandin; Seo, Myung Won; Byoun, Ok Jin; Lee, Hee Yoon; Lee, Dong Sup

doi:10.1097/tp.0b013e3181f24e59

Cited by 37 publications

(25 citation statements)

References 42 publications

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“…The encouraging clinical effect in patients with corticosteroidrefractory aGVHD supports the potential therapeutic role of this drug for the treatment of GVHD. 28 The protective effect of ruxolitinib observed in our GVHD model was paralleled by increased Treg frequencies in the spleen, ileum, and colon of ruxolitinib-treated mice, and this effect could be reproduced in vitro when murine T cells were exposed to alloantigen. Consistent with the reduced T-cell expansion that we observed when luciferase transgenic T cells were transferred into allogeneic BALB/c recipients, it was previously reported that proliferation of human T cells exposed to allogeneic DCs in vitro was suppressed in the presence of ruxolitinib.…”

Section: Discussionmentioning

confidence: 84%

“…Here, in a semi-allogeneic system, Park and colleagues report that pretreatment of mice with tofacitinib reduced GVHD pathology via the suppression of both proliferation and IFN-g production by the donor CD4 1 T cells. 28 Also in a skin-specific GVHD model using expression of chicken ovalbumin in skin and mucosal epithelia under control of the keratin 14 promoter, mucocutaneous GVHD was reduced by tofacitinib. 33 Tofacitinib was shown to have efficacy in psoriasis, 34 rheumatoid arthritis, 35 and ulcerative colitis, the last sharing pathomechanistical features with acute intestinal GVHD.…”

Section: Discussionmentioning

confidence: 99%

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

Spoerl

Mathew²,

Bscheider

et al. 2014

Blood

356

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: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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

Spoerl

Mathew²,

Bscheider

et al. 2014

Blood

356

296

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“…An unanswered, yet extremely important, question concerns the role of pro-inflammatory cytokines on GVHD development in MF and the effect of JAK inhibitor therapy on the modulation, if any, of GVHD incidence and severity. CP-690550, a novel JAK inhibitor, has been shown in mice models of aGVHD to suppress donor CD4 + T cell IFN-c production and abrogate GVHDrelated mortality (Park et al, 2010). Ruxolitinib, predominantly a JAK1 and JAK2 inhibitor, has been shown to profoundly reduce pro-inflammatory cytokines.…”

Section: Graft-versus-host Diseasementioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012

et al. 2012

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SummaryMyelofibrosis (MF) is a heterogeneous disease for which long‐term, effective medical therapeutic options are currently limited. The role of allogeneic haematopoietic stem cell transplant (AHSCT) in this population, many of whom are elderly, often provides a challenge with regard to the identification of suitable candidates, timing of transplantation in the disease course and choice of conditioning regimen. This review summarizes key findings from published data concerning AHSCT in MF and attempts to provide a state of the art approach to MF‐AHSCT in 2012. In addition, we postulate on how the era of JAK inhibition might impact on transplantation for MF.

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“…This is of particular interest because JAK3 is a signaling molecule with a reported role in GVHD. 47,48 Reduced JAK3 phosphorylation upon inhibition of the common g chain by anti-CD132 is consistent with JAK3 being downstream of multiple common g-chain cytokine receptors. Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common g chain, 49 and we found that Jak3 2/2 T cells caused less severe GVHD compared with WT T cells, which is consistent with previous studies using JAK3 inhibitors to interfere with GVHD.…”

Section: Discussionmentioning

confidence: 54%

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

Hechinger¹,

Smith²,

Flynn

et al. 2015

Blood

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Key Points• Monoclonal antibody blockade of the common g chain attenuates acute and chronic GVHD.• Common g-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.The common g chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-g, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3 2/2 T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common g-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. (Blood. 2015;125(3):570-580)

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CP-690550, a Janus Kinase Inhibitor, Suppresses CD4+ T-Cell–Mediated Acute Graft-Versus-Host Disease by Inhibiting the Interferon-γ Pathway

Cited by 37 publications

References 42 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

Allogeneic Stem Cell Transplantation for Myelofibrosis in 2012

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

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