Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice

Ćetković-Cvrlje, Marina; Roers, Bertram A.; Waurzyniak, Barbara; Liu, Xing‐Ping; Uckun, Fatih M.

doi:10.1182/blood.v98.5.1607

Cited by 56 publications

(62 citation statements)

References 33 publications

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“…As shown previously and here (Figure 1b), WHI-P131 induces apoptotic cell death in the primary cells 20 and cell lines 19 cultured for a short period of time. Our cell viability data, observed in cultures exposed to WHI-P131 after the first and second week of stimulation, are in agreement with apoptosis induction.…”

Section: Whi-p131 Allows Survival Of Isolated Cd4supporting

confidence: 84%

“…The chosen concentrations of WHI-P131 were selected based on our previously obtained results showing that doses of 5-100 mg/ml of WHI-P131 completely suppressed proliferation of a heterogeneous population of T cells. 20 Here, we show that the additions of 1.5, 3 and 6 mg/ml of WHI-P131 induced a dose-dependent, statistically significant reduction in proliferation of CD4 1 T cells compared to vehicle-exposed controls ( Figure 1a). …”

Section: Resultsmentioning

confidence: 57%

“…It has been previously shown that the JAK3 inhibitor WHI-P131 exhibits a potent dose-dependent suppression of proliferative responses of non-diabetic C57BL/6 and NOD mouse T cells induced by both mitogens 20,25 and an autoantigen, GAD65. 25 However, these studies did not confirm the effects of the JAK3 inhibitor on a particular subpopulation of T cells, such as CD4 1 T cells.…”

Section: Resultsmentioning

confidence: 99%

“…19 It has been shown that the lead compound, 4-(49-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses mitogen-and antigen-induced responses in vitro. 20,21 In vivo treatment with WHI-P131 attenuated the severity of T celldependent graft-versus-host disease post murine allogeneic bone marrow transplantation, 20,22,23 and prevented rejection of mouse allogeneic islet cell transplants. 24 Furthermore, WHI-P131 treatment prevented development of T1D in NOD mice.…”

Section: Regulatory Cd4mentioning

confidence: 99%

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Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

2012

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Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D). Pharmacological inhibition of Janus tyrosine kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-(49-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD41 T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4 1 CD25 1 FoxP3 1 phenotype. They secreted decreased amounts of IL-10, IL-4 and interferon (IFN)-c compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor (TGF)-b secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4 1 FoxP3 1 Tregs, while generating an elevated numbers of CD4 1 FoxP3 2 TGF-b-secreting T cells. In conclusion, our data suggest an induction of TGF-b-secreting CD4 1 T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.

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Section: Whi-p131 Allows Survival Of Isolated Cd4supporting

confidence: 84%

Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Regulatory Cd4mentioning

confidence: 99%

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Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

2012

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“…43 It is worth noting that another quinazoline derivate, named WHI-P131, was also able to prevent GVHD induction but its reactivity was only effective Selective elimination of alloreactivity S Morecki et al when given in combination with MTX for at least 85 days following transplantation. 44 As opposed to the short-term follow-up of the other chemical compounds, AO#349 compound proved to be efficient in inducing selective elimination of alloreactivity over a long-term follow-up without the need to expose the host to a foreign chemical compound. This means that in accordance with our observations to date, AO#349 can be utilized for the prevention of GVHD, but its application for in vivo treatment of already existing GVHD, as well as its possible application for autoimmune and other inflammatory diseases requires future investigation.…”

Section: Discussionmentioning

confidence: 99%

Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses

Morecki¹,

Gelfand²,

Yacovlev³

et al. 2011

Bone Marrow Transplant

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Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine-and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of o1 lM, a quinazoline derivative named AO#349 [2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine], was able to induce 78-90% inhibition of a selective allogeneic response while retaining 492% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for 4200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy.

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Acute Graft-vs-Host Disease

Platzbecker¹,

Deeg²

2004

Stem Cell Transplantation for Hematologic Malignancies

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Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice

Cited by 56 publications

References 33 publications

Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses

Acute Graft-vs-Host Disease

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