Janus Kinase Inhibitors and Cell Therapy

Assal, Amer; Mapara, Markus Y.

doi:10.3389/fimmu.2021.740847

Cited by 5 publications

(9 citation statements)

References 90 publications

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“…Janus kinases (JAKs) are tyrosine kinases related to cytokine receptors that can activate nuclear signal transducer and activator of transcription (STAT). 15 The JAK family consists of JAK-1, JAK-2, JAK-3, and tyrosine kinase. JAK/STAT1 plays a crucial role in macrophage polarization and function.…”

Section: Introductionmentioning

confidence: 99%

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose M1 macrophages can promote corneal allograft rejection (CGR). Inhibiting M1 macrophage polarization by the JAK/STAT1 pathway may be a new strategy to prevent CGR. Tofacitinib, a potent pan-JAK inhibitor, can inhibit JAK/STAT activation. Here, we investigated the inhibitory effects of tofacitinib on M1 macrophage polarization and its therapeutic effect on rat CGR. Methods Corneal allograft transplantation was performed and administrated with 0.3% tofacitinib in rats. The corneal allografts were assessed clinically. The corneas were detected for M1 macrophages, lymphatic vessels, and inflammatory cytokine expression using immunohistochemistry and real-time polymerase chain reaction (PCR). Dendritic cells (DCs) in ipsilateral cervical lymph nodes were detected by flow cytometry. The effect and mechanism of tofacitinib on macrophages were explored by real-time PCR, enzyme-linked immunoassay, and western blot analysis in vitro. Results The results showed that topical administration of 0.3% tofacitinib significantly prolonged corneal graft survival. Tofacitinib-treated corneal allografts displayed a proportionate decrease in M1 macrophages and reduced lymphatic vessel density with fewer DCs in rat ipsilateral cervical lymph nodes. Tofacitinib reduced the mRNA expression of inflammatory cytokines, including iNOS, MCP-1, TNF-α, IL-6, IL-1β, and VEGF-C, and inhibited STAT1 activation in rat corneal grafts. In addition, tofacitinib suppressed M1 macrophage polarization via STAT1 activation after IFN-γ and lipopolysaccharide stimulation in vitro. Conclusions Tofacitinib could suppress M1 macrophage polarization and subsequently delay CGR by inhibiting STAT1 activation. The data indicate that tofacitinib is an effective drug for CGR. Translational Relevance This study provided evidence that topical administration of 0.3% tofacitinib may be a novel clinical strategy to prevent CGR.

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Section: Introductionmentioning

confidence: 99%

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

et al. 2022

Trans. Vis. Sci. Tech.

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“…Further mechanistical analyses revealed, that Ruxolitinib ameliorates GVHD by disrupting Th1 and Th17 differentiation but promoting Treg differentiation via indirect STAT1 and STAT3 inhibition ( 223 ). Overall, these pre-clinical data suggested Ruxolitinib as a promising candidate for GVHD treatment, which indeed has shown remarkable results in the application for steroid refractory GVHD in various clinical studies ( 224 ).…”

Section: Potential Strategies To Target Transcription Factors Of T Helper Cell Development In Gvhdmentioning

confidence: 94%

“…Despite the advanced clinical validation of JAK/STAT inhibitors in GVHD [reviewed by Assal and Mapara, ( 224 )], few other agents of the Kinase-inhibitor group have also shown beneficial effect on GVHD in pre-clinical studies. Inhibition of the glycogen synthase kinase 3 (GSK3) by the small molecule 6-bromoindirubin 3’-oxime (BIO), prevented mice from lethal GVHD in a xenogeneic model by STAT1/3 suppression and subsequent decrease of Th1 effector cytokines ( 187 ).…”

Section: Potential Strategies To Target Transcription Factors Of T Helper Cell Development In Gvhdmentioning

confidence: 99%

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

Campe

Ullrich

2022

Front. Immunol.

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Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.

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“…IFN-γ signaling has been implicated in the mediation of tissue damage in the gastrointestinal (GI) tract ( 13 , 14 ). Therefore, IFN-γR signaling is emerging as an attractive target ( 15 – 17 ) for graft-versus-host disease (GVHD) intervention, as corroborated by clinical results using the nonselective JAK1/2 inhibitor ruxolitinib (Rux) and preclinical results with barcitinib ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 95%

IFN-γR/STAT1 signaling in recipient hematopoietic antigen-presenting cells suppresses graft-versus-host disease

Lu¹,

Ma²,

Song³

et al. 2023

Journal of Clinical Investigation

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Janus Kinase Inhibitors and Cell Therapy

Cited by 5 publications

References 90 publications

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

IFN-γR/STAT1 signaling in recipient hematopoietic antigen-presenting cells suppresses graft-versus-host disease

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