Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells

Kondo, Takumi; Ikegawa, Shuntaro; Fukumi, Takuya; Sumii, Yuichi; Sugiura, Hiroyuki; Sando, Yasuhisa; Nakamura, Makoto; Meguri, Yusuke; Iwamoto, Miki; Maeda, Yoshinobu; Matsuoka, Ken‐ichi

doi:10.4049/immunohorizons.2100042

Cited by 4 publications

(5 citation statements)

References 61 publications

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“…Mammadli et al reported that ITK-deficient donor T cells significantly reduced inflammatory cytokines leading to less GVHD intensity in the mice model (133). We recently demonstrated that pharmacological inhibition of ITK on donor T cells could ameliorate acute GVHD without sacrificing the GVT effect (134). In the study, we showed that ex-vivo graft manipulation with ITK inhibitor modulated donor CD4 + T cell differentiation towards Th1, Th2, and Th17 with sparing Tregs, resulting in the prolonged overall survival after HSCT.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 86%

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Ikegawa

Matsuoka

2021

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

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Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 86%

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Ikegawa

Matsuoka

2021

Front. Immunol.

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“…This complication poses a substantial impediment to the success of allo-HCT, highlighting the need for effective strategies to mitigate GVHD without increasing the risk of infection and relapse, thus improving patient outcomes. Recent studies using ITK-/-in T cell graft or short-term exposure of donor graft to an ITK inhibitor have suggested that targeting ITK may be a promising approach for preventing GVHD [38][39][40] . Indeed, we demonstrated in a murine aGVHD model that treatment with SQL can decrease alloreactive T cell activation and proliferation, consequently reducing the incidence of acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

Soquelitinib, A Selective Inhibitor of Interleukin-2-Inducible T Cell Kinase (ITK), is Active in Several Murine Models of T Cell-Mediated Inflammatory Disease

Hsu,

Rosenbaum,

Lindner

et al. 2023

Preprint

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Interleukin-2-inducible T cell kinase (or ITK) is a tyrosine kinase predominantly expressed by T lymphocytes. It plays a major role in T cell activation, differentiation, and receptor signaling. Studies in mouse models have established that the absence or inhibition of ITK reduces the secretion of Th2 and Th17 cytokines, while favoring the production of Th1 cytokines and the differentiation of T cells to regulatory T cells (T regs). We recently characterized the activity of soquelitinib (SQL), a selective, covalent inhibitor of ITKin vitrousing mouse or human T cells andin vivoin murine models of cancer. We hypothesized that selective pharmacologic blockade of ITK could attenuate a variety of T cell-mediated inflammatory diseases including murine models that resemble asthma, pulmonary fibrosis, systemic sclerosis, psoriasis, and acute graft versus host disease. In each model, SQL demonstrated substantial ability to ameliorate the disease process along with effects on cytokines and/or T cell subsets consistent with the reported function of ITK. Our studies demonstrate that selective inhibition of ITK by SQL is potentially a novel therapeutic approach for several forms of T cell-mediated, inflammatory diseases.

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“…Inhibition of the glycogen synthase kinase 3 (GSK3) by the small molecule 6bromoindirubin 3'-oxime (BIO), prevented mice from lethal GVHD in a xenogeneic model by STAT1/3 suppression and subsequent decrease of Th1 effector cytokines (187). Recent studies suggested the IL-2 inducible kinase (ITK) inhibitor ONO-7790500 as another potent therapeutic in GVHD, as administration inhibited Th1, Th2 and Th17 differentiation, inflammatory cytokine production and alloreactive T cell proliferation and significantly delayed GVHD onset and mortality (186). An earlier study with ITK -/donor T cells in…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

“…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 ). Recent studies suggested the IL-2 inducible kinase (ITK) inhibitor ONO-7790500 as another potent therapeutic in GVHD, as administration inhibited Th1, Th2 and Th17 differentiation, inflammatory cytokine production and alloreactive T cell proliferation and significantly delayed GVHD onset and mortality ( 186 ). An earlier study with ITK -/- donor T cells in an allo-HSCT mouse model has already reported comparable beneficial effects on GVHD and observed reduced expression of IRF4, JAK1, JAK2, and STAT3 as well as phosphorylated forms of JAK1, JAK2 and STAT3 if ITK was absent in T cells, which might explain impaired differentiation capacities observed in the ITK inhibitor study ( 226 ).…”

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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Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells

Cited by 4 publications

References 61 publications

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Soquelitinib, A Selective Inhibitor of Interleukin-2-Inducible T Cell Kinase (ITK), is Active in Several Murine Models of T Cell-Mediated Inflammatory Disease

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

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