Targeting IFNGR/IL6R or downstream JAK1/JAK2 to control GvHD

Ashami, Kidist; DiPersio, John F.; Choi, Jaebok

doi:10.18632/oncotarget.26291

Cited by 12 publications

(9 citation statements)

References 9 publications

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“…While direct targeting of molecules on the Treg cell surface can induce their expansion, unintentional but clinically useful procedures in HSCT including extracorporeal photopheresis (ECP), 169 donor stem cell mobilization, 170–172 PTCy, 173,174 azacytidine, 175 JAK1/2 inhibitors 176,177 and ROCK1/2 inhibitors 178,179 also affect the Treg compartment although to a lesser extent than intentional interventions. Although Tregs have demonstrated promising results in regulating GvHD, combining their regulatory activity with other strategies being used in the clinic may further improve transplant outcomes for patients.…”

Section: Targeting Cell Surface Receptors For In Vivo Treg Expansionmentioning

confidence: 99%

“…171,172 Development of balanced JAK1/JAK2 targeted inhibitors has led to promising clinical results in aHSCT. 176 Notably, baricitinib is significantly more potent than ruxolitinib in preventing GvHD and demonstrates high Treg expansion by preserving the JAK3-STAT5 IL-2R pathway. 177 Additionally, the Rho kinase inhibitors which down-regulate ROCK1/ROCK2 inhibiting inflammation have also shown promise in suppressing GvHD.…”

Section: Targeting Cell Surface Receptors For In Vivo Treg Expansionmentioning

confidence: 99%

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The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Copsel¹,

Wolf

Komanduri

et al. 2019

Haematologica

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CD4 + FoxP3 + regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft- versus -host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft- versus -host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo . Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.

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Section: Targeting Cell Surface Receptors For In Vivo Treg Expansionmentioning

confidence: 99%

Section: Targeting Cell Surface Receptors For In Vivo Treg Expansionmentioning

confidence: 99%

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Copsel¹,

Wolf

Komanduri

et al. 2019

Haematologica

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“…However, these agents also confer an increased risk of infection and tumor relapse. JAK inhibition is one of the promising therapeutic strategies in the prevention and treatment of GvHD since pre-clinical animal studies with JAK inhibitors demonstrated a significant reduction of GvHD while maintaining or enhancing immune reconstitution compared to control groups [124,125,149,150]. Consistent with these pre-clinical studies, ruxolitinib was highly effective for steroid-refractory GvHD [151,152].…”

Section: Clinical Aspects Of Hdac Inhibitorsmentioning

confidence: 66%

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Kim

Santhanam²,

Lim

et al. 2020

IJMS

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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“…Numerous researches have reported that JAK is an excellent target for the treatment of GVHD 8 , 10 , 11 , 14 , 16 , which influences the activation and expansion of donor T cells and their chemotaxis to target organs through multiple downstream pathways. A recent phase 3 study of JAK1 inhibitor Itacitinib on aGVHD showed the overall response rates in Itacitinib and placebo groups were 74% and 66% ( P = 0.0782), respectively, and 6-month NRM also did not favor Itacitinib (NCT03139604), which suggested that balanced inhibition of JAK1/JAK2 is vital in treatment of GVHD 10 , 41 . The JAK1/2 inhibitor Ruxolitinib, the most common used JAK inhibitor in clinical practice, has been proven to be effective in the treatment of patients with aGVHD and has been approved by FDA 14 , 15 .…”

Section: Discussionmentioning

confidence: 99%

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Sun

Yang

et al. 2021

Cell Transplant

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Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

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Targeting IFNGR/IL6R or downstream JAK1/JAK2 to control GvHD

Cited by 12 publications

References 9 publications

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

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Targeting IFNGR/IL6R or downstream JAK1/JAK2 to control GvHD

Cited by 12 publications

References 9 publications

The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

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The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation