Open access peer-reviewed chapter - ONLINE FIRST

Graft-Versus-Host Disease: Pathogenesis and Treatment

Written By

Shin Mukai

Submitted: February 19th, 2022Reviewed: March 10th, 2022Published: April 29th, 2022

DOI: 10.5772/intechopen.104450

IntechOpen
Purinergic SystemEdited by Margarete Dulce Bagatini

From the Edited Volume

Purinergic System [Working Title]

Dr. Margarete Dulce Bagatini

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Abstract

Graft-versus-host disease (GVHD) is a disabling complication after allogeneic hematopoietic stem cell transplantation (HSCT) and negatively impacts patients’ quality of life. GVHD is classified into 2 forms according to clinical manifestations. Acute GVHD (aGVHD) typically affects the skin, gastrointestinal tract, and liver, whereas chronic GVHD occurs systemically and shows diverse manifestations similar to autoimmune diseases such as eosinophilic fasciitis, scleroderma-like skin disease. GVHD is induced by complicated pathological crosstalk between immune cells of the host and donor and involves various signaling pathways such as purinergic signaling. Although the past several decades have seen significant progress in the understanding of mechanisms of GVHD and several drugs have been approved by FDA for the prevention and treatment of GVHD, there is still vast scope for improvement in the therapy for GVHD. Thus, new drugs for GVHD will need to be developed. Towards this goal, this chapter succinctly summarises the pathogenic process of GVHD and emerging GVHD treatments in order to provide some insights into the mechanisms of GVHD and facilitate the development of novel drugs.

Keywords

  • inflammation
  • fibrosis
  • therapeutic targets
  • drug development

1. Introduction

Graft-versus-host disease (GVHD) is a debilitating complication that can determine the prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) and subject 40–60% of HSCT recipients to a risk of death and disability [1]. GVHD is composed of acute GVHD (aGVHD) and chronic GVHD (cGVHD). For the classification of the 2 types of GVHD, the classifier should be clinical manifestations instead of time after HSCT [2]. However, in many cases, aGVHD appears within 100 days after HSCT and causes severe inflammation mostly in the skin, gastrointestinal tract, and liver [3]. cGVHD generally occurs systemically 6 months or later after HSCT, and its symptoms are similar to those of autoimmune diseases [4]. Complex interactions between donor and host immune cells are implicated in the pathogenesis of GVHD. It is thought that aGVHD is induced primarily by donor T cells’ cytotoxic responses against host tissues through recognition of host polymorphic histocompatibility antigens [5]. On the other hand, the mechanisms of cGVHD are more complicated and still poorly understood [6]. Although the use of corticosteroids alone or in combination with immunosuppressive agents is the recommended first-line strategy for the treatment of GVHD, its efficacy is not satisfactory [3, 7]. The prevalence of allogeneic HSCT for the treatment of hematologic diseases has increased the need for the development of efficacious second-line therapies which can mitigate symptoms of GVHD without compromising a graft-versus-leukemia effect, where donor T cells eliminate host leukemia cells. To date, various signaling pathways and pathogenic events in the context of GVHD have been intensively investigated. As a result, several FDA-approved drugs for GVHD have recently emerged. This chapter concisely summarises therapeutic targets and newly emerging drugs for the 2 forms of GVHD with the goal to facilitate the development of novel GVHD treatments for human use.

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2. Clinical manifestations of GVHD

aGVHD can occur after the engraftment of donor-derived cells in the transplant recipient [8]. Symptoms of aGVHD can develop within weeks after the transplantation [9]. It has been believed that aGVHD can primarily affect the skin, gastrointestinal (GI) tract, and/or liver [10]. HSCT recipients can manifest rash, increased bilirubin, diarrhea, and vomiting [11]. Most recently, mounting evidence suggests that other organs such as the central nervous system, lungs, ovaries and testis, thymus, bone marrow, and kidney can be susceptible to aGVHD [12].

Clinical manifestations of cGVHD are different from those of acute GVHD. The onset of chronic GVHD can be divided into the following 3 cases: (1) occurring when aGVHD is present, (2) emerging after a period of resolution from aGVHD, and (3) developing de novo [13]. Immune dysregulation and absence of functional tolerance are characteristic of cGVHD, and symptoms of cGVHD are reminiscent of those of autoimmune disorders [13]. Clinical presentations of cGVHD can be as follows: (i) rash, raised or discolored areas, skin thickening or tightening, (ii) dry eye or vision changes, (iii) dry mouth, white patches inside the mouth, (iv) diarrhea and weight loss, (v) shortness of breath due to lung disorders and (vi) abnormal liver function [14]. It was challenging for clinicians to reach an agreement on the diagnosis, the timing of treatment, and how to grade cGVHD [15]. In order to overcome these difficulties, the National Institute of Health (NIH) consensus created diagnostic criteria for cGVHD in 2005 and revised the criteria in 2014 [16, 17]. The authors considered the severity of involvement of the skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint fascia, and genital tract in order to define manifestations of cGVHD in its target organs and establish a scoring system.

Corticosteroids are used with or without immunosuppressive drugs as the first-line therapy for aGVHD and cGVHD in clinical settings [3, 7, 18, 19]. However, approximately 50% of patients who receive steroid therapy will be resistant to it, although mechanisms of steroid resistance remain to be elucidated [3, 7, 18, 19]. In addition, Corticosteroid therapies also cause various undesired effects such as diabetes, obesity, osteoporosis, hypertension, glaucoma, and liver damage [20]. Thus, medical settings are in need of effective treatments of steroid-refractory aGVHD and cGVHD [3, 7, 18, 19].

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3. General GVHD biology

GVHD has a complex pathophysiology, which initially begins with damage to host tissues by chemotherapy and radiation therapy before allogeneic HSCT (Figure 1) [21]. Due to this, damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and inflammatory cytokines are released [22]. These stimuli activate host dendritic cells (DCs), leading to the expression of major histocompatibility complex class I (MHC-I) and class II (MHC-II) on the host DCs [22]. The mature host DCs activate donor-derived T cells in the graft [22]. The activated donor T cells migrate to aGVHD-susceptible organs and promote the excessive production of pro-inflammatory cytokines such as interferon (IFN)-γ and interleukin (IL)-17 [23, 24]. It results in abnormal inflammation and tissue damage [23, 24]. While it is believed that donor-derived CD4+ and CD8+ T cells play a pivotal role in mediating aGVHD [25], several other types of immune cells are reportedly involved in the pathogenic process of aGVHD [26]. Neutrophils contribute to the development of intestinal aGVHD [27]. A previous report suggests that neutrophils in the ileum migrate to mesenteric lymph nodes, presenting antigens on their MHC-II and promoting T cell expansion [28]. Donor monocyte-derived macrophages with potent immunological functions are implicated in the pathophysiology of cutaneous aGVHD by secreting chemokines, stimulating T cells, and mediating direct cytotoxicity [29, 30]. In contrast, regulatory T cells (Tregs) are thought to serve a suppressive role in aGVHD without significantly reducing the graft-versus-leukemia (GVL) effect [31, 32]. Recent reports suggest that donor-derived natural killer (NK) cells can have an inhibitory effect in aGVHD by promoting the depletion of allo-reactive T cells while showing the GVL effect [33]. A recent study indicates that the occurrence and severity of aGVHD could be associated with the disordered reconstitution of CD56high NK cells [34].

Figure 1.

The overview of aGVHD pathogenesis. The preconditioning regimen causes tissue damage. It generates DAMPs, PAMPs and proinflammatory cytokines such as TNFα, IL-1β and IL-6, which activates host APCs. The activated APCs present antigens to donor T cells, and the activated T cells infiltrate aGVHD target organs and produce an excessive amount of IFNγ and IL-17, leading to abnormal inflammation and tissue damage. This figure is created with BioRender.

While mechanisms of cGVHD are still incompletely understood, recent evidence suggests that there are several observations characteristic of cGVHD (Figure 2) [35]. The thymus is damaged due to the conditioning regimen and/or the prior occurrence of aGVHD, leading to impaired negative selection of alloreactive CD4+ T cells [36]. Alloreactive T cells are activated by antigen-presenting cells (APCs), resulting in their expansion and polarization toward type 1, type 2, and type 17 helper T (Th1, Th2, and Th17) cells [35]. These immune deviations lead to the production of proinflammatory and profibrotic inflammatory cytokines such as IFNγ, IL-6, IL-17, IL-4, and transforming growth factor β (TGFβ), which skew macrophages and fibroblasts towards proinflammatory and/or profibrotic phenotypes [35]. Consequently, inflammation and fibrosis are induced in cGVHD target organs [37]. The damaged thymic epithelial cells (required for the generation of Tregs as well as the negative selection) also cause a decrease in the number of Tregs [38]. Furthermore, the dysregulation of B cells causes autoreactive B cells to arise and produce autoreactive antibodies [39]. The emergence and activation of autoreactive B cells presumably stem from B cell exhaustion induced by aberrant levels of B cell-activating factor (BAFF) in the lymphoid microenvironment [40, 41].

Figure 2.

Overview of cGVHD pathogenesis. The thymus is damaged due to the preconditioning regimen and/or aGVHD. Due to the damage, the negative selection of alloreactive T cell is impaired. Alloreactive T cells are polarised into Th1, Th2 or Th17 cells. Th1 cells produce IFNγ, which drives macrophages to an M1-like phenotype to promote inflammation. IL-4, IL-10 and TGFβ produced by Th2 cells facilitate macrophage differentiation into an M2-like phenotype. Activation and proliferation of tissue fibrosis are induced by (i) TGFβ from Th2 cells, (ii) PDGFα and TGFβ from M2-like macrophages and (iii) IL-6 and IL-17 from Th17 cells, leading to collagen production and fibrosis. B cells are activated by IL-6 and IL-17 from Th17 cells, and the alloreactivity of B cells is presumably induced by an excessive amount of BAFF. As a result of the above events, systemic inflammation and fibrosis are induced, and autoimmune-like manifestations are observed. This figure is created with BioRender.

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4. Therapeutic targets and strategies for GVHD

4.1 TCR and BCR signaling

When the T cell receptor (TCR) interacts with an MHC-antigenic peptide complex, it induces molecular and cellular changes in T cells [42]. A wide range of signal transduction pathways in T cells is stimulated due to this interaction, leading to the activation of a variety of genes [43]. Effector enzymes such as kinases, phosphatases, and phospholipases are involved in the TCR signaling pathways, which are integrated by non-enzymatic adaptor proteins acting as a scaffold for interactions between proteins [42]. These intracellular signaling pathways can determine the features of immunity mediated by T cells [44].

The B cell receptor (BCR) complexes on inactivated B cells act as self-inhibiting oligomers [45]. The BCR signaling pathways are initiated, when BCR is bound to an antigen and induces actin-mediated nanoscale recombination of receptor clusters [46]. Due to this event, the BCR oligomers are opened and the ITAM domains are revealed, resulting in the transduction of intracellular signals which are crucial for B cell development, activation, proliferation, differentiation, and antibody production in health and disease [47].

In 2017, FDA approved ibrutinib, which targets B cells and T cells, for the treatment of cGVHD. Ibrutinib was the first FDA-approved drug for steroid-refractory cGVHD, and it was a significant milestone for GVHD research [48]. Ibrutinib is reported to modulate the functions of B cells and T cells by potently inhibiting Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) [49], which are involved in the B cell signaling and T cell signaling pathways, respectively. Treatment of cGVHD-affected recipients with ibrutinib resulted in decreased serum-autoantibodies and B-cell proliferation [50]. Data from the clinical trials show that symptoms of cGVHD improved in 67% of patients treated with ibrutinib [48].

4.2 Purinergic signaling

The Purinergic signaling pathways play a crucial role in a range of physiological systems including the immune system. In the purinergic signaling pathways, extracellular purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP) are used as signaling molecules that mediate the communication between cells through the activation of purinergic receptors [51]. There are four types of P1 (adenosine) receptors (A1, A2A, A2B, and A3). P2 receptors are subdivided into P2X and P2Y [52]. P2X receptors have seven subtypes (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7), and P2Y receptors have 8 subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) [52].

As demonstrated by several studies using mouse models of aGVHD, extracellular ATP is augmented in aGVHD-affected mice, and purinergic signaling is implicated in the pathogenic process of aGVHD (Figure 3) [53]. The conditioning regimens prior to allo-HSCT can induce tissue damage, leading to the release of DAMP molecules including ATP, which activates purinergic signaling [53]. The involvement of extracellular ATP is evidenced by the fact that the injection of the soluble ATP diphosphohydrolase (ATPDase) can reduce inflammation in aGVHD target organs and the serum level of IFNγ [53, 54].

Figure 3.

Link between GVHD and the therapeutically targetable purinergic signaling pathways. In aGVHD, ATP is produced due to tissue damage. Host APCs and donor T cells can be activated by the P2X7 receptor, which results in the progression of aGVHD. The activation of donor Tregs can also be induced by the ATP-activated P2X7 receptor, which leads to the reduction of Treg survival and the progression of aGVHD. CD39 and CD73 on donor Tregs can degrade ATP to adenosine. Adenosine can activate the A2A receptor on donor T cells, which culminates in the decrease in the number of CD4+ and CD8+ T cells and the reduction of aGVHD. In cGVHD, ATP is also released because of tissue damage and may promote fibroblast-to-myofibroblast transition through the ATP-activated P2X7 receptor, leading to the augmented collagen production and the progression of tissue fibrosis. In contrast, the ATP-activated P2Y14 receiptor may prevent cellular senescence in macrophages and mitigate cGVHD. This figure is created with BioRender.

Evidence suggests that; (i) P2X7 is a crucial P2X receptor in the development of aGVHD after the release of extracellular ATP, (ii) the expression of the P2X7 receptor is elevated in PBMCs in aGVHD patients, (iii) the liver, spleen, skin, and thymus in aGVHD-affected mice show the increased expression of the P2X7 receptor, (iv) the ATP-induced the activation of the P2X7 receptor on host APCs can facilitate the stimulation, proliferation, and survival of donor T cells during aGVHD and (v) the P2X7 activation on host APCs may be associated with the expression of microRNA mir-155 [53, 55, 56, 57].

While the host P2X7 receptor is shown to play an integral role in the development of aGVHD, the donor P2X7 receptor is also a contributor to this disease. Evidence suggests that (i) the activation and proliferation of donor CD4+ T cells and (ii) the metabolic fitness of donor CD8+ T cells are also enhanced by the activated donor P2X7 receptor [58, 59]. In addition, the activation of P2X7 on donor Tregs can reduce their suppressive ability and stability of Tregs, promoting their conversion to Th17 cells [60].

Inhibition of the P2X7 receptor is reported to mitigate aGVHD in conventional and humanised mouse models of aGVHD. Treatment of allogeneic HSCT recipient mice with the P2X7 inhibitor pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) can increase the survival rate and the number of Tregs, and reduce the serum level of IFNγ and histological aGVHD [53, 54]. Administration of the P2X7 inhibitor brilliant blue G (BBG) to allogeneic HSCT recipient mice can also prevent weight loss and reduce inflammation in the liver and the production of inflammatory cytokines [56]. Furthermore, a crystal structure of the P2X7 receptor in complex with the inhibitor AZ10606120 has been reported (PDB: 5U1W) [61], and this structural information could be useful for the design and synthesis of novel P2X7 inhibitors which can be used in clinical settings.

The P2Y2 receptor is also reported to contribute to the pathogenesis of aGVHD [22, 57]. Evidence indicates that the number of cells expressing the P2Y2 receptor is increased in the intestinal tract in aGVHD-affected mice and that the increased P2Y2 expression enhances the severity of intestinal aGVHD [62]. Of note, knock-out allogeneic HSCT recipient mice of the p2Y2 receptor show an increased survival rate and decreased cytokine levels [62]. However, in the case where the P2Y2 receptor in donor cells is knocked out, no such improvement is observed [62]. In contrast, literature precedent suggests that the activation of the P2Y2 receptor can promote the migration of Tregs to sites of inflammation and thereby mitigate aGVHD [63]. Due to the dual functions of the P2Y2 receptor, targeting the P2Y2 receptor for the treatment has been challenging and there have been no reports about systemic injection of P2Y2 inhibitors/activators for the treatment of aGVHD [64].

While ATP is released in damaged tissues in allogeneic HSCT recipients and promotes inflammation, it is also degraded to adenosine by CD39 and CD73 [53]. In particular, a murine study indicates that CD39 and CD73 are highly expressed on CD150high Tregs [65]. As shown by a study using a mouse model of aGVHD, inhibition of CD39 and CD73 with adenosine 5′-(α,β-methylene)diphosphate (APCP) leads to the increase in the number of splenic CD4+ and CD8+ T cells, the serum levels of IFNγ and IL-6, and the mortality rate [66]. These data suggest that CD39 and CD73 play an alleviatory role in aGVHD. Evidence demonstrates that the production of adenosine by CD39 and CD73 results in the activation of the adenosine A2A receptor [66, 67, 68]. The activated A2A receptor can induce the expansion of donor Tregs and thereby mitigate aGVHD-induced inflammation [66, 67, 68]. The blockade of A2A with the antagonist SCH58261 exacerbates aGVHD by elevating the levels of TNFα, IFNγ, and IL-6 and the number of CD4+ and CD8+ T cells in sera [66]. In agreement with this report, the A2A agonist ATL-146e reduced weight loss and mortality in aGVHD-affected mice by (i) increasing serum IL-10 and reducing serum IFN-γ and IL-6, (ii) precluding the activation of splenic CD4+ and CD8+ T cells, and the infiltration of T cells into GVHD target organs [67]. Other A2A agonists, ATL-370 and ATL-1223, are reported to exert similar therapeutic effects on aGVHD [68]. Moreover, a crystal structure of the A2A receptor in complex with the activator ZM241385 has been reported (PDB: 5WF5) [69], and this structural information could facilitate the creation of novel A2A activators which can enter the clinic.

Although there are few to no reports about a link between purinergic signaling and cGVHD pathogenesis, activation of the P2X7 receptor is reported to promote fibroblast-to-myofibroblast transformation and contribute to the development of fibrosis [70]. The activation of the P2X7 receptor enhances Ca2+ influx and skews fibroblasts towards a fibrogenic phenotype, leading to augmented collagen production [70]. Considering fibrosis is a significant hallmark of cGVHD, the investigation into a correlation between purinergic signaling and fibroblast activity in cGVHD could open up a new window for the elucidation of mechanisms of cGVHD and the development of novel drugs for cGVHD (Figure 3). Furthermore, stress-induced cellular senescence in immune cells is reported to play a detrimental role in the pathogenesis of ocular cGVHD [71, 72], and a murine study indicates that the P2Y14 receptor modulates stress-induced cellular senescence in hematopoietic stem/progenitor cells [73]. Given these findings, the P2Y14 receptor may be a regulator of stress-induced cellular senescence in cGVHD, and development of agonists of the P2Y14 receptor could benefit cGVHD patients.

4.3 JAK/STAT signaling

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are regarded as a central communication junction for the immune system [74]. In the JAK/STAT signaling pathways, the cytoplasmatic kinase JAKs interact with the transcription factor STATs, and more than 50 cytokines and growth factors are involved in the JAK/STAT signaling pathways [75]. Mammals have 4 JAKs (JAK1, JAK2, JAK3, JAK4) and 7 STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) [76], and the dysregulated JAK/STAT signaling pathways contribute to a variety of human diseases, which makes this signaling a promising drug target [77].

In the early phase of aGVHD, tissue damage due to the preconditioning regimen and the disease results in the release of DAMPs, leading to the increased expression of MHC on APCs at the infusion of donor cells [78]. Donor T cells are activated via direct or indirect allorecognition, and the activated donor T cells produce IFNγ to initiate the JAK/STAT signaling pathways through IFNγ receptors [78]. The resultant increase in the expression of the chemokine receptor CXCR3 on T cells enhances their migration to aGVHD target organs, which promotes tissue damage [79].

While clinical manifestations of cGVHD are different from those of aGVHD, they have similarities in some aspects of the pathogenic processes [80]. The JAK/STAT signaling pathways in the context of cGVHD have been intensively investigated [81]. Tregs play a crucial role in the reduction of cGVHD, and JAK1/JAK2 signaling pathways are thought to negatively regulate the development and proliferation of Tregs, as indicated by the fact that JAK2 inhibition can promote Treg proliferation [82, 83]. Tissue fibrosis is highly problematic in cGVHD, and M2-like macrophages producing TGF-β are presumably a key player [84]. IL-10 skews macrophages towards an M2-like phenotype through the IL-10 receptor-JAK1/STAT3 pathway [85]. Given these reports, it would be intriguing to investigate an association between macrophages and the JAK/STAT signaling pathways in the development of cGVHD-induced fibrosis.

Many researchers have focused on the development of inhibitors targeting JAK/STAT signaling pathways for the treatment of aGVHD and cGVHD [81]. As demonstrated by several preclinical data, inhibition of the JAK/STAT pathways can mitigate GVHD without affecting the GVL effect [81] Most recently, the JAK1/JAK2 inhibitor ruxolitinib has been approved by FDA for aGVHD and cGVHD. In 2019, FDA approved ruxolitinib to treat steroid-refractory aGVHD patients 12 years or older [86]. The clinical trials show that the day-28 overall response rate (ORR) was 100% for Grade 2 aGVHD, 40.7% for Grade 3 aGVHD, and 44.4% for Grade 4 aGVHD [86]. In 2021, FDA approval was also granted to ruxolitinib for the therapy of steroid-resistant cGVHD patients 12 years or older [87]. The clinical trial data demonstrate that the ORR was 70%, and the median durations of response, which were calculated from first response to progression, death, or new systemic therapies for cGVHD, were 4.2 months [87]. A crystal structure of JAK2 in complex with ruxolitinib is provided in the PDB database (PDB: 6VGL) [88], and this structural information could be useful for the design of more potent and selective JAK1/JAK2 inhibitors. Another promising JAK1 inhibitor is itacitinib [89]. Data from a phase 1 clinical trial of itacitinib shows that 70.6% of steroid-refractory cGVHD patients were treated in a satisfactory manner [90]. Furthermore, two clinical trials of itacitinib for cGVHD have recently commenced (ClinicalTrials.gov identifier: NCT04200365, NCT03584516). It is of great medical significance that novel drugs targeting the JAK/STAT signaling will continue to be developed for the treatment of aGVHD and cGVHD.

4.4 NF-κB signaling

The transcription factor nuclear factor kappa B (NF-κB) controls the expression of various genes important for the induction of inflammatory responses in innate and adaptive immune cells [91]. NF-κB is a family of heterodimers or homodimers generated from different combinations of the following 5 proteins: p65/RelA, RelB, c-Rel, p105/p50 (NF-κB1), and p100/p52 (NF-κB2) [92]. Among them, the p50/p65 complex is thought to be the most abundant form of NF-κB dimer [93]. When NF-κB is inactive, it is retained in the cytoplasm by the IκB family of inhibitors [94, 95]. In response to a wide range of stimuli such as the proinflammatory cytokines IL-1 and TNF-α, IκB kinase (IKK) is activated to phosphorylate the 2 serine residues of IκBα [96]. The phosphorylation causes the 26S proteasome to induce the ubiquitination and degradation of IKβ. Subsequently, NF-κB is translocated into the nucleus and triggers gene transcription, leading to the production of proteins necessary for immune responses [97]. Thus, NF-κB is regarded as a therapeutic target for the treatment of various inflammatory diseases.

The NF-κB signaling pathways have captured increasing attention from GVHD researchers. It has been reported that the activation of RelB in APCs contributes to the expansion of donor Th1 cells and subsequent alloreactivity, which leads to the development of aGVHD [98]. The NF-kB signaling pathways can be survival and proliferation signals and contribute to B-cell alloantibody deposition and germinal center formation, which play a critical role in the pathogenic process of cGVHD [99, 100].

Bortezomib is an FDA-approved drug for the treatment of multiple myeloma and is known to be an indirect inhibitor of NF-κB [101]. A murine study suggests that aGVHD can be prevented by treatment with bortezomib early after allogeneic HSCT [102, 103]. Bortezomib is undergoing clinical trials for aGVHD (BMT CTN 1203), and the phase1/2 study shows that bortezomib can be used in combination with tacrolimus and methotrexate in a tolerable immunosuppressive regimen after allogeneic HSCT [104]. Bortezomib can also be effective for the treatment of cGVHD. NF-κB inhibition with Bortezomib is suggested to cause apoptosis of germinal center B cells during reconstitution, leading to the decrease in donor-derived B cell numbers and BAFF expression [103]. With these promising data, clinical trials of bortezomib for the treatment of steroid-refractory cGVHD are in progress (NCT01158105). At present, there are no NF-κB inhibitors approved by FDA for aGVHD or cGVHD. Generally, direct inhibitors are superior to indirect ones in terms of selectivity. Thus, novel direct NF-κB inhibitors with high selectivity are greatly anticipated for the treatment of GVHD.

4.5 Hedgehog signaling

The Hedgehog signaling pathways are involved in the regulation of cell proliferation, survival, and differentiation [105], and its aberrant activation contributes to detrimental events such as the self-renewal and metastasis of cancer stem cells [106]. In the absence of Hedgehog ligand (Hh), the activation of Smoothened (SMO) is inhibited by Patched (PTCH) [107]. Subsequently, the activity of glioma-associated oncogene homolog (Gli) is suppressed by a protein complex mainly composed of a suppressor of fused (SUFU), which phosphorylates Gli and prevents it from entering the nucleus. In the presence of Hh, the binding of Hh to PTCH precludes the SMO inhibition mediated by PTCH [107]. Activated SMO prevents phosphorylation of Gli mediated by the SUFU complex, leading to the migration of Gli to the nucleus and the induction of downstream target gene expression [107].

Fibrosis is a highly problematic feature of cGVHD, and a profibrotic activity of Hedgehog signaling in patients and mouse models of cGVHD has been reported [108]. Overexpression of Hh, which is an inducer of the Hedgehog signaling pathways, is observed in human and murine sclerodermatous cGVHD [108]. The downstream processes of the Hedgehog signaling pathway cause overexpression of Gli-1 and Gli-2, particularly in fibroblasts [109]. The abnormal expression of Gli-1 and Gli-2 may result in the overproduction of collagen and the resultant pathologic fibrosis in cGVHD target organs [109]. Furthermore, the Hedgehog signaling is suggested to contribute to the increase of profibrotic M2-like macrophages in the c-GVHD affected skin [109].

There are several inhibitors of the Hedgehog pathways. Among others, sonidegib, vismodegib, and glasdegib are SMO inhibitors approved by FDA for the treatment of basal cell carcinoma [110]. These 3 SMO inhibitors are currently undergoing clinical trials for cGVHD therapy (NCT02086513, NCT02337517, NCT04111497). According to a report of the Phase-1 trial of sonidegib, where 17 steroid-refractory cGVHD patients participated, protein expression of hedgehog signaling pathway molecules was decreased by treatment with sonidegib as judged by immunohistochemical evaluation of the skin [111]. With respect to the creation of novel SMO inhibitors for the treatment of GVHD, Lacroix et al. found a potential SMO inhibitor by performing structure-based virtual screening of 3.2 million available, lead-like molecules against Smoothened and subsequent biological validations of the top-ranked compounds [112]. This information could benefit the design and synthesis of more potent and selective inhibitors of SMO.

4.6 Endoplasmic reticulum stress

While elucidation of mechanisms of cGVHD is still elusive, chronic inflammation is characteristic of cGVHD [113]. Senescent macrophages contribute to ocular cGVHD in mice, and gray eyebrows, skin wrinkles and conjunctival cancer are observed in human cGVHD [71, 114]. These findings suggest that ageing in donor- and recipient-derived cells is induced in cGVHD [71]. Evidence suggests that chronic inflammation and age-related diseases are associated with the elevation of endoplasmic reticulum (ER) stress [115, 116]. Mukai et al found that ER stress was increased in organs affected by cGVHD in mice [117]. Treatment of cGVHD-affected mice with the known ER stress reducer 4-phenylburyric acid (PBA) resulted in mitigation of systemic inflammation and fibrosis induced by cGVHD [117]. Of note, PBA is approved by FDA for the treatment of urea cycle disorders, and its safety was proven [118]. Investigation at the cellular level indicates that ER stress contributes to fibrosis as well as inflammation induced by cGVHD. Elevated ER stress caused (i) the dysregulation of lacrimal-gland-derived fibroblasts and (ii) abnormal production of MCP-1/CCL2, IL-6, and connective tissue growth factor (CTGF) [117]. Suppression of ER stress with PBA reduced their abnormal production of the inflammatory and fibrotic molecules [117]. In addition, ER stress induced by cGVHD skewed splenic macrophages towards an M2-like phenotype, and treatment of them with PBA promoted their differentiation into an M1-like phenotype [117]. Several reports also indicate that the augmentation of M2-like macrophages is implicated in the progression of cGVHD [84, 119, 120]. M2-like macrophages are thought to contribute to the pathogenesis of fibrosis-associated diseases [121], and it seems to be the case with cGVHD. As these analyses were performed in a bulk population, further investigation will be needed. Macrophages and fibroblasts are known to be heterogeneous populations [122, 123, 124, 125]. In particular, mounting evidence suggests that macrophage heterogeneity is multidimensional and more complex than M1/M2 classification [126]. Hence, single-cell analyses could greatly facilitate the understanding of a correlation between ER stress and macrophages/fibroblasts in the development of cGVHD and make ER stress a more compelling therapeutic target for cGVHD therapy.

4.7 Aberrant immune cell infiltration

While aGVHD and cGVHD show different clinical manifestations, one of their common features is abnormal immune cell infiltration, which results in organ damage and severe inflammation and fibrosis. Mukai et al devised a novel therapeutic strategy for both types of GVHD by targeting vascular adhesion protein-1 (VAP-1) [127], which is known to be overexpressed in inflamed organs [128]. VAP-1 is an endothelial surface glycoprotein assisting leucocyte migration from the bloodstream to tissues and possesses the following 2 functional domains: a distal adhesion domain and a catalytic amine oxidase domain [129]. For infiltration into tissues, the amino group in leukocytes undergoes a nucleophilic attack on the carbonyl group in VAP-1 [129]. The subsequent catalytic conversion of the primary amine to the corresponding aldehyde allows immune cells to squeeze into tissues through blood vessels [129, 130]. Pursuant to their study with the use of a mouse model where aGVHD shifts to cGVHD [127], (i) the protein expression of VAP-1 is increased in organs with GVHD, where the number of inflammatory cells is accordingly augmented, (ii) blockade of VAP-1 with a novel inhibitor reduced the number of tissue-infiltrating leukocytes and thereby mitigated GVHD manifestations such as inflammation and fibrosis and (iii) the VAP-1 caused few to no severe adverse effects. Collectively, inhibition of VAP-1 could be an effective all-in-one approach for the treatment of aGVHD and cGVHD.

4.8 NOTCH signaling

The Notch signaling pathways are cell-to-cell communication induced by interactions between Notch receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4) and NOTCH ligands (Jagged1 (JAG1), JAG2, Delta-like 1 (DLL1), DLL3 and DLL4) [131]. Due to these intercellular interactions, the NOTCH receptor is proteolytically activated by an ADAM family metalloprotease and subsequently by the γ-secretase complex [132]. The sequential cleavages lead to the release of the intracellular NOTCH domain (NICD), which is a transcriptionally active fragment [133]. NICD migrates to the nucleus and binds to the DNA binding CSL/RBP-Jk factor, forming a transcriptional activation complex with a mastermind-like (MAML) family coactivator [133]. This final complex triggers the transcription of target genes which are important for biological processes such as proliferation, differentiation, and survival [134].

A correlation between the Notch signaling pathways and alloimmune responses has gained interest from GVHD researchers. Studies using animal models of aGVHD suggest that; (i) the Notch signaling promotes activation, differentiation, and alloreactivity of T cells [135]) and (ii) dendritic cells with high DLL4 expression show an increase in the production of IFN-γ and IL-17 [136]. The Notch signaling is also implicated in the pathogenic process of cGVHD. A murine study shows that NOTCH1 and NOTCH2 as well as DLL1 and DLL4 serve significant functions in regulating proinflammatory cytokine production by T cells [137]. Investigation using in-vitrohuman B-cell assay systems demonstrates that abnormal activation of NOTCH2 is correlated with hyperresponsiveness of BCR on B cells from cGVHD patients [138].

GVHD treatments by targeting the Notch signaling pathway have been reported. A series of experiments using a mouse model of aGVHD reveals; (i) inhibitors of γ-secretase block e proteolytic activation of all the NOTCH receptors, but has severe toxicity in the gut epithelium, (ii) NOTCH1 inhibition using an antibody mitigates GVHD but causes serious toxicity and (iii) treatment with a combination of anti-DLL1 and anti-DLL4 reduces aGVHD without debilitating adverse effects while maintaining a GVL effect of donor T cells [139]. An anti-DLL1 antibody is also effective for the treatment of murine cGVHD in combination with an anti-DLL4 antibody [137]. Treatment with all-trans-retinoic acid (ATRA) prevents NOTCH2-induced BCR hyperresponsiveness, which plays a detrimental role in cGVHD pathogenesis [137]. It appears that NOTCH2 and DLL1/4 are promising drug targets for the treatment of the 2 types of GVHD. Therefore, it is highly anticipated that novel, selective inhibitors of NOTCH2 and DLL1/4 will be developed for use in human GVHD.

4.9 Rho/ROCK signaling

Rho-associated coiled-coil-containing protein kinases (ROCKs) are serine-threonine-specific protein kinases, and mammals have ROCK1 and ROCK2 [140]. ROCKs are downstream effector proteins of GTPase Rho, and abnormal activation of the Rho/ROCK pathways contributes to the development of various diseases [140]. In particular, ROCK2 is known to regulate (i) the balance of Th17 cells and Tregs and (ii) profibrotic pathways [141]. ROCK2 activation increases Th17 cell-specific transcription factors by promoting STAT3 phosphorylation [142]. In addition, when ROCK2 is activated by profibrotic mediators such as tumor growth factor-β (TGF-β), it causes myocardin-related transcription factors to activate profibrotic genes in fibroblasts [143, 144]. This profibrotic gene activation induces fibroblast-to-myofibroblast differentiation and the resultant increase in collagen production [143, 144].

A study using a cGVHD mouse model shows that treatment with belumosudil, which is a selective ROCK2 inhibitor, can substantially reduce cGVHD-induced fibrosis in the lung [145]. In 2021, belumosudil was approved by FDA for the treatment of cGVHD, and the clinical trial data show that the overall response rate was 75% (6% complete response and 69% partial response) [146].

ROCK1 is also thought to be involved in the development of fibrosis, and pan-ROCK inhibitors targeting ROCK1/2 are thereby expected to show better treatment outcomes for cGVHD [147]. Several pan-ROCK inhibitors have been granted approval for human use [148, 149, 150, 151] In particular, netarsudil has been approved by FDA for the treatment of glaucoma [151]. However, due to a lack of overall kinome selectivity of the reported dual ROCK1/2 inhibitors, there is still scope for improvement in pan-ROCK inhibitors [152]. Hu et al. has recently reported the synthesis and in-vitroevaluation of a novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine, and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1/2 inhibitors [152]. Their data show that some of the novel pan-ROCK inhibitors display potent inhibitory activity against ROCK1/2 and possess excellent kinome selectivity [152]. They also provided a crystal structure of ROCK2 in complex with one of the novel dual ROCK1/2 inhibitors (PDB ID: 7JNT). This structural information can be useful in the structure-based design of other new pan-ROCK inhibitors.

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5. Conclusion

While recent decades have seen significant technological and medical advances, aGVHD and cGVHD are still a major hurdle to successful allogeneic HSCT in clinical settings. Systemic corticosteroid therapy, with or without immunosuppressive agents, is the first-line treatment for GVHD, although it can cause severe adverse effects and approximately 50% of GVHD patients develop steroid-resistant GVHD. Thus, sophisticated treatments of steroid-refractory aGVHD and cGVHD were highly anticipated by medical settings. A great deal of effort has been invested in the elucidation of mechanisms of GVHD and development of safe and efficacious drugs for GVHD. Recently, several drugs have been approved by FDA for the treatment of steroid-refractory aGVHD and cGVHD. Despite this progress, there is still a need to create novel drugs with better efficacy for GVHD therapy. This chapter focused on druggable targets for the treatment of GVHD with an aim to stimulate various GVHD researchers (from medicinal chemists to biologists) to create novel drugs which can enter the clinic. While several signaling pathways have been intensively studied in the context of GVHD, there are underexplored signaling pathways. In particular, the purinergic signaling pathway is one of the understudied signaling pathways in GVHD. The P2X7, A2A, and P2Y14 receptors seem to be compelling drug targets for the treatment of GVHD, and clinical settings could benefit from safe and efficacious (i) inhibitors of the P2X7 receptor and (ii) activators of the A2A and/or P2Y14 receptors. However, the development of new drugs is a costly and time-consuming process. To overcome this setback, the use of AL/ML has captured great interest from many researchers and has been expected to substantially reduce the cost and time of drug development. A combination of AL/ML and molecular design could greatly facilitate the development of novel, effective, safe, and affordable drugs for the treatment of GVHD.

References

  1. 1.Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296-307. DOI: 10.1182/blood-2011-06-364265
  2. 2.Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem H-P, et al. Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood. 2009;114:702-708. DOI: 10.1182/blood-2009-03-208983
  3. 3.Malard F, Huang X-J, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia. 2020;34:1229-1240
  4. 4.Ceredig R. Graft-versus-host disease: Who’s responsible? Immunology and Cell Biology. 2012;90:253-254. DOI: 10.1038/icb.2011.62
  5. 5.Martin PJ, Levine DM, Storer BE, Warren EH, Zheng X, Nelson SC, et al. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood. 2017;129:791-798. DOI: 10.1182/blood-2016-09-737700
  6. 6.Lee JW. Prevention of chronic GVHD. Best Practice & Research Clinical Haematology. 2008;21:259-270. DOI: 10.1016/j.beha.2008.02.010
  7. 7.Wolff D, Fatobene G, Rocha V, Kröger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: Treatment options and patient management. Bone Marrow Transplantation. 2021;56:2079-2087
  8. 8.Sung AD, Chao NJ. Concise review: Acute graft-versus-host disease: Immunobiology, prevention, and treatment. Stem Cells Translational Medicine. 2013;2:25-32. DOI: 10.5966/sctm.2012-0115
  9. 9.Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: A comprehensive review. Anticancer Research. 2017;37:1547-1555
  10. 10.Teshima T, Reddy P, Zeiser R. Acute graft-versus-host disease: Novel biological insights. Biology of Blood and Marrow Transplantation. 2016;22:11-16
  11. 11.Ballester-Sánchez R, Navarro-Mira M, Sanz-Caballer J, Botella-Estrada R. Review of cutaneous graft-vs-host disease. Actas Dermo-Sifiliográficas. 2016;107:183-193
  12. 12.Zeiser R, Teshima T. Nonclassical manifestations of acute GVHD. Blood. 2021;138:2165-2172. DOI: 10.1182/blood.2021012431
  13. 13.Lee SJ. Classification systems for chronic graft-versus-host disease (de novo cGVHD). Blood. 2017;129:30-37. DOI: 10.1182/blood-2016-07686642
  14. 14.Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: Clinical manifestation and therapy. Bone Marrow Transplantation. 2001;28:121-129. DOI: 10.1038/sj.bmt.1703111
  15. 15.Saidu NEB, Bonini C, Dickinson A, Grce M, Inngjerdingen M, Koehl U, et al. New approaches for the treatment of chronic graft-versus-host disease: Current status and future directions. Frontiers in Immunology. 2020;11:578314. DOI: 10.3389/fimmu.2020.578314
  16. 16.Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biology of Blood and Marrow Transplantation. 2005;11:945-955
  17. 17.Pavletic SZ, Vogelsang GB, Lee SJ. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: Preface to the series. Biology of Blood and Marrow Transplantation. 2014;2014(21):387-388. DOI: 10.1016/j.bbmt.2014.12.035
  18. 18.Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133:1191-1200. DOI: 10.1182/blood-2018-04-785899
  19. 19.Rashidi A, DeFor TE, Holtan SG, Blazar BR, Weisdorf DJ, MacMillan ML. Outcomes and predictors of response in steroid-refractory acute graft-versus-host disease. Biology of Blood and Marrow Transplantation. 2019;25:2297-2302. DOI: 10.1016/j.bbmt.2019.07.017
  20. 20.What to know about corticosteroids. Available from:https://www.medicalnewstoday.com/articles/corticosteroids
  21. 21.Choi SW, Levine JE, Ferrara JLM. Pathogenesis and management of graft versus host disease. Immunology and Allergy Clinics of North America. 2010;30:75-101. DOI: 10.1016/j.iac.2009.10.001
  22. 22.Apostolova P, Zeiser R. The role of purine metabolites as DAMPs in acute graft-versus-host disease. Frontiers in Immunology. 2016;7:439
  23. 23.Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Pillars article: Two types of Murine Helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology. 1986;136:2348-2357
  24. 24.Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang Y-H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunology. 2005;6:1133-1141. DOI: 10.1038/ni1261
  25. 25.Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood. 1998;98:3192-3204
  26. 26.Reddy P, Ferrara JLM. Immunobiology of acute graft-versus-host disease. Blood Reviews. 2003;17:187-194. DOI: 10.1016/s0268-960x(03)00009-2
  27. 27.Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nature Medicine. 2014;20:648-654
  28. 28.Hülsdünker J, Ottmüller KJ, Neeff HP, Koyama M, Gao Z, Thomas OS, et al. Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood. 2018;131:1858-1869. DOI: 10.1182/blood-2017-10-812891
  29. 29.Jardine L, Cytlak U, Gunawan M, Reynolds G, Green K, Wang X-N, et al. Donor monocyte-derived macrophages promote human acute graft-versus-host disease. Journal of Clinical Investigation. 2020;130:4574-4586. DOI: 10.1172/JCI133909
  30. 30.Terakura S, Martin PJ, Shulman HM, Storer BE. Cutaneous macrophage infiltration in acute GvHD. Bone Marrow Transplantation. 2015;50:1135-1137. DOI: 10.1038/ bmt.2015.114
  31. 31.Ianni MD, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921-3928. DOI: 10.1182/blood-2010-10311894
  32. 32.Guo W-w, Su X-h, Wang M-y, Han M-z, Feng X-m, Jiang E-l. Regulatory T cells in GVHD therapy. Frontiers in Immunology. 2021;12:9676
  33. 33.Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction ofGVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood. 2010;115:4293-4301. DOI: 10.1182/blood-2009-05-222190
  34. 34.Ullrich E, Salzmann-Manrique E, Bakhtiar S, Bremm M, Gerstner S, Herrmann E, et al. Relation between acute GVHD and NK cell subset reconstitution following allogeneic stem cell transplantation. Frontiers in Immunology. 2016;7:595. DOI: 10.3389/fimmu.2016.00595
  35. 35.Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. New England Journal of Medicine. 2017;377:2565-2579. DOI: 10.1056/NEJMra1703472
  36. 36.Wu T, Young JS, Johnston H, Ni X, Deng R, Racine J, et al. Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells. Journal of Immunology. 2013;191:488-499. DOI: 10.4049/jimmunol.1300657
  37. 37.Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nature Reviews Immunology. 2012;12:443-458. DOI: 10.1038/nri3212
  38. 38.Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S, et al. Reduced frequency ofFOXP3⫹ CD4⫹CD25⫹ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106:2903-2911. DOI: 10.1182/blood-2005-03-1257
  39. 39.Kapur R, Ebeling S, Hagenbeek A. B-cell involvement in chronic graft-versus-host disease. Haematologica. 2008;93:1702-1717. DOI: 10.3324/haematol.13311
  40. 40.Pers J-O, Daridon C, Devauchelle V, Jousse S, Saraux A, Jamin C, et al. BAFF overexpression is associated with autoantibody production in autoimmune diseases. Annals of the New York Academy of Sciences. 2005;1050:34-39. DOI: 10.1196/annals.1313.004
  41. 41.Khoder A, Alsuliman A, Basar R, Sobieski C, Kondo K, Alousi AM, et al. Evidence for B cell exhaustion in chronic graft-versus-host disease. Frontiers in Immunology. 2018;8:1937. DOI: 10.3389/fimmu.2017.01937
  42. 42.Samelson LE. Signal transduction mediated by the T cell antigen receptor: The role of adapter proteins. Annual Review of Immunology. 2002;20:371-394. DOI: 10.1146/annurev.immunol.20.092601.11135
  43. 43.Cantrell DA. T-cell antigen receptor signal transduction. Immunology. 2002;105:369-374. DOI: 10.1046/j.1365-2567.2002.01391.x
  44. 44.Hwang J-R, Byeon Y, Kim D, Park S-G. Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development. Experimental & Molecular Medicine. 2020;52:750-761. DOI: 10.1038/s12276-020-0435-8
  45. 45.Wena Y, Jinga Y, Yanga L, Kanga D, Jianga P, Lib N, et al. The regulators of BCR signaling during B cell activation. Blood Science. 2019;1:119-129. DOI: 10.1097/BS9.0000000000000026
  46. 46.Fleire SJ, Goldman JP, Carrasco YR, Weber M, Bray D, Batista FD. B cell ligand discrimination through a spreading and contraction response. Science. 2006;312:738-741. DOI: 10.1126/science.1123940
  47. 47.Tsourkas PK, Das SC, Yu-Yang P, Liu W, Pierce SK, Raychaudhuri S. Formation of BCR oligomers provides a mechanism for B cell affinity discrimination. Journal of Theoretical Biology. 2012;307:174-182. DOI: 10.1016/j.jtbi.2012.05.008
  48. 48.FDA approves treatment for chronic graft versus host disease. 2017 Available from:https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-chronic-graft-versus-host-disease
  49. 49.Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243-2250. DOI: 10.1182/blood-2017-07-793786
  50. 50.Schutt SD, Fu J, Nguyen H, Bastian D, Heinrichs J, Wu Y, et al. Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft-versus-host disease in mice. PLoS One. 2015;10:e0137641. DOI: 10.1371/journal.pone.0137641
  51. 51.Praetorius HA, Leipziger J. Intrarenal purinergic signaling in the control of renal tubular transport. Annual Review of Physiology. 2009;72:377-393
  52. 52.Kong Q , Quan Y, Tian G, Zhou J, Liu X. Purinergic P2 receptors novel mediators of mechanotransduction. Frontiers in Pharmacology. 2021;12:671809
  53. 53.Wilhelm K, Ganesan J, Müller T, Dürr C, Grimm M, Beilhack A, et al. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nature Medicine. 2010;16:1434-1438
  54. 54.Koehn BH, Saha A, McDonald-Hyman C, Loschi M, Thangavelu G, Ma L, et al. Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD. Blood. 2019;134:1670-1682. DOI: 10.1182/blood.2019001950
  55. 55.Zhong X, Zhu F, Qiao J, Zhao K, Zhu S, Zeng L, et al. The impact of P2X7 receptor antagonist, brilliant blue G on graft-versus-host disease in mice after allogeneic hematopoietic stem cell transplantation. Cellular Immunology. 2016;310:71-77. DOI: 10.1016/j.cellimm.2016.07.014
  56. 56.Cuthbertson P, Adhikary SR, Geraghty NJ, Guy TV, Hadjiashrafi A, Fuller SJ, et al. Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease. Clinical Science. 2020;134:207-223. DOI: 10.1042/CS20191086
  57. 57.Chen S, Smith BAH, Iype J, Prestipino A, Pfeifer D, Grundmann S, et al. MicroRNA-155-deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation. Blood. 2015;2015:103-112. DOI: 10.1182/blood-2014-12-617258
  58. 58.Yip L, Woehrle T, Corriden R, Hirsh M, Chen Y, Inoue Y, et al. Autocrine regulation of T-cell activation by ATP release and P2X7 receptors. FASEB Journal. 2009;23:1685-1693. DOI: 10.1096/fj.08-126458
  59. 59.Silva H, Beura LK, Wang H, Hanse EA, Gore R, Scott MC, et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8 + T cells. Nature. 2018;559:264-268. DOI: 10.1038/s41586-018-0282-0
  60. 60.Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Science Signaling. 2011;4:ra12
  61. 61.Karasawa A, Kawate T. Structural basis for subtype-specific inhibition of the P2X7 receptor. eLife. 2016;5:e22153. DOI: 10.7554/eLife.22153
  62. 62.Klämbt V, Wohlfeil SA, Schwab L, Hülsdünker J, Ayata K, Apostolova P, et al. A novel function for P2Y2 in myeloid recipient-derived cells during graft-versus-host disease. Journal of Immunology. 2015;195:5795-5804. DOI: 10.4049/jimmunol.1501357
  63. 63.Dürr C, Follo M, Idzko M, Reichardt W, Zeiser R. Graft-versus-host disease reduces regulatory T-cell migration into the tumour tissue. Immunology. 2012;137:80-88. DOI: 10.1111/j.1365-2567.2012.03610.x
  64. 64.Cuthbertson P, Geraghty NJ, Adhikary SR, Bird KM, Fuller SJ, Watson D, et al. Purinergic signalling in allogeneic haematopoietic stem cell transplantation and graft-versus-host disease. International Journal of Molecular Sciences. 2021;22:8343. DOI: 10.3390/ijms22158343
  65. 65.Yang S, Sheng X, Xiang D, Wei X, Chen T, Yang Z, et al. CD150 high treg cells may attenuate graft versus host disease and intestinal cell apoptosis after hematopoietic stem cell transplantation. American Journal of Translational Research. 2019;11:1299-1310
  66. 66.Tsukamoto H, Chernogorova P, Ayata K, Gerlach UV, Rughani A, Ritchey JW, et al. Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood. 2012;119:4554-4564. DOI: 10.1182/blood-2011-09-375899
  67. 67.Lappas CM, Liu P-C, Linden J, Kang EM, Malech HL. Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation. Journal of Leukocyte Biology. 2009;87:354
  68. 68.Han KL, Thomas SVM, Koontz SM, Changpriroa CM, Ha S-K, Malech HL, et al. Adenosine A₂A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease. Journal of Immunology. 2012;190:458-468. DOI: 10.4049/jimmunol.1201325
  69. 69.White KL, Eddy MT, Gao Z-G, Han GW, Lian T, Deary A, et al. Structural connection between activation microswitch and allosteric sodium site in GPCR signaling. Structure. 2018;26:259-269. DOI: 10.1016/j.str.2017.12.013
  70. 70.Gentile D, Lazzerini PE, Gamberucci A, Natale M, Selvi E, Vanni F, et al. Searching novel therapeutic targets for scleroderma: P2X7-receptor is up-regulated and promotes a fibrogenic phenotype in systemic sclerosis fibroblasts. Frontiers in Pharmacology. 2017;8:638
  71. 71.Kawai M, Ogawa Y, Shimmura S, Ohta S, Suzuki T, Kawamura N, et al. Expression and localization of aging markers in lacrimal gland of chronic graft-versus-host disease. Scientific Reports. 2013;3:2455. DOI: 10.1038/srep02455
  72. 72.Yamane M, Sato S, Shimizu E, Shibata S, Hayano M, Yaguchi T, et al. Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans. FASEB Journal. 2020;34:10778-10800. DOI: 10.1096/fj.201900218R
  73. 73.Cho J, Yusuf R, Kook S, Attar E, Lee D, Park B, et al. Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence. Journal of Clinical Investigation. 2014;124:3159-3171. DOI: 10.1172/JCI61636
  74. 74.Villarino AV, Kanno Y, O'Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nature Immunology. 2017;18:374-384. DOI: 10.1038/ni.3691
  75. 75.Boehi F, Manetsch P, Hottiger MO. Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses. Cell Discovery. 2021;7:104
  76. 76.Schindler C, Plumlee C. Inteferons pen the JAK-STAT pathway. Seminars in Cell and Developmental Biology. 2008;19:311-318. DOI: 10.1016/j.semcdb.2008.08.010
  77. 77.Villarino AV, Kanno Y, O’Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. Journal of Immunology. 2015;194:21-27. DOI: 10.4049/jimmunol.1401867
  78. 78.Abboud R, Choi J, Ruminski P, Schroeder MA, Kim S, Abboud CN, et al. Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease. Therapeutic Advances in Hematology. 2020;11:1-13. DOI: 10.1177/2040620720914489
  79. 79.Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML, et al. IFNγR signaling mediates alloreactive T-cell trafficking and GVHD. Blood. 2012;120:4093-1043
  80. 80.Lazaryan A, Weisdorf DJ, DeFor T, Brunstein CG, MacMillan ML, Bejanyan N, et al. Risk factors for acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched sibling donors. Biology of Blood and Marrow Transplantation. 2016;22:134-140
  81. 81.Schroeder MA, Choi J, Staser K, DiPersio JF. The role of Janus kinase signaling in graft-versus-host disease and graft versus leukemia. Biology of Blood and Marrow Transplantation. 2018;24:1125-1134. DOI: 10.1016/j.bbmt.2017.12.797
  82. 82.Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832-3842. DOI: 10.1182/blood-2013-12-543736
  83. 83.Betts BC, Abdel-Wahab O, Curran SA, Angelo ETS, Koppikar P, Heller G, et al. Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen. Blood. 2011;118:5330-5339. DOI: 10.1182/blood-2011-06-363408
  84. 84.Alexander KA, Flynn R, Lineburg KE, Kuns RD, Teal BE, Olver SD, et al. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. Journal of Clinical Investigation. 2014:4266-4280. DOI: 10.1172/JCI75935
  85. 85.Lescoat A, Lelong M, Jeljeli M, Piquet-Pellorce C, Morzadec C, Ballerie A, et al. Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo perspectives for scleroderma-associated interstitial lung disease. Biochemical Pharmacology. 2020;178:114103. DOI: 10.1016/j.bcp.2020.114103
  86. 86.FDA approves ruxolitinib for acute graft-versus-host disease. 2019 Available from:https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-acute-graft-versus-host-disease
  87. 87.FDA approves ruxolitinib for chronic graft-versus-host disease. 2021 Available from:https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-chronic-graft-versus-host-disease
  88. 88.Davis RR, Li B, Yun SY, Chan A, Nareddy P, Gunawan S, et al. Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof. The Journal of Medicinal Chemistry. 2021;64:2228-2241. DOI: 10.1021/acs.jmedchem.0c01952
  89. 89.You H, Xu D, Zhao J, Li J, Wang Q , Tian X, et al. JAK inhibitors: Prospects in connective tissue diseases. Clinical Reviews in Allergy & Immunology. 2020;59:334-351. DOI: 10.1007/s12016-020-08786-6
  90. 90.Schroeder MA, Khoury HJ, Jagasia M, Ali H, Schiller GJ, Staser K, et al. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Advances. 2020;4:1656-1669. DOI: 10.1182/bloodadvances.2019001043
  91. 91.Dorrington MG, Fraser IDC. NF-κB signaling in macrophages: Dynamics, crosstalk, and signal integration. Frontiers in Immunology. 2019;10:705. DOI: 10.3389/fimmu.2019.00705
  92. 92.Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harvor Perspectives in Biology. 2009;1:a000034. DOI: 10.1101/cshperspect.a00003410.1101/cshperspect.a000034
  93. 93.Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annual Review of Cell Biology. 1994;10:405-455
  94. 94.Ghosh S, Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990;344:678-682. DOI: 10.1038/344678a0
  95. 95.Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier JL, et al. Nuclear localization of the IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm. Journal of Cell Science. 1997;110:369-378
  96. 96.Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annual Review of Immunology. 2000;18:621-663. DOI: 10.1146/annurev.immunol.18.1.621
  97. 97.Baeuerle PA, Baichwal VR. NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Advances in Immunology. 1997;65:111-137
  98. 98.MacDonald KPA, Kuns RD, Rowe V, Morris ES, Banovic T, Bofinger H, et al. Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD. Blood. 2007;109:5049-5057. DOI: 10.1182/blood-2007-01-067249
  99. 99.Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012;119:1570-1580. DOI: 10.1182/blood-2011-07-364414
  100. 100.Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, et al. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood. 2014;123:3988-3998. DOI: 10.1182/blood-2014-03-562231
  101. 101.Velcade (bortezomib) Information. Available from:https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/velcade-bortezomib-information
  102. 102.Koreth J, Kim HT, Lange PB, Poryanda SJ, Reynolds CG, Rai SC, et al. Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: Randomized phase II results. Haematologica. 2018;103:522-530. DOI: 10.3324/haematol.2017.176859
  103. 103.Pai C-C S, Chen M, Mirsoian A, Grossenbacher SK, Tellez J, Ames E, et al. Treatment of chronic graft-versus-host disease with bortezomib. Blood. 2014;124:1677-1688. DOI: 10.1182/blood-2014-02-554279
  104. 104.Martin PJ. Bortezomib for prevention of acute graft- versus-host disease: A conclusion reached. Haematologica. 2018;103:377-379. DOI: 10.3324/haematol.2018.188052
  105. 105.Babu D, Fanelli A, Mellone S, Muniswamy R, Wasniewska M, Prodam F, et al. Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD) Evidence for a pathogenic effect by functional characterization. Clinical Endocrinology. 2019;90:449-456. DOI: 10.1111/cen.13914
  106. 106.Cochrane CR, Szczepny A, Watkins N, Cain JE. Hedgehog signaling in the maintenance of cancer stem cells. Cancers. 2015;7:1554-1585. DOI: 10.3390/cancers7030851
  107. 107.Chen Y, Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. Cell. 1996;87:553-563. DOI: 10.1016/s0092-8674(00)81374-4
  108. 108.Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, et al. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood. 2012;120:2909-2917. DOI: 10.1182/blood-2012-01-403428
  109. 109.Radojcic V, Pletneva M, Lee CJ, Ivcevic S, Sarantopoulos S, Couriel D. Hedgehog blockade in steroid-refractory sclerotic chronic graft-versus-host disease. British Journal of Haematology. 2021;195:e120-e122. DOI: 10.1111/bjh.17657
  110. 110.Du F-Y, Zhou Q-F, Sun W-J, Chen G-L. Targeting cancer stem cells in drug discovery: Current state and future perspectives. World Journal of Stem Cells. 2019;11:398-420. DOI: 10.4252/wjsc.v11.i7.398
  111. 111.DeFilipp Z, Nazarian RM, El-Jawahri A, Li S, Brown J, Rio CD, et al. Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease. Blood Advances. 2017;1:1919-1922. DOI: 10.1182/bloodadvances.2017011239
  112. 112.Lacroix C, Fish I, Torosyan H, Parathaman P, Irwin JJ, Shoichet BK, et al. Identification of novel smoothened ligands using structure-based docking. PLoS One. 2016;11:e0160365. DOI: 10.1371/journal.pone.0160365
  113. 113.Presland RB. Biology of chronic graft-vs-host disease: Immune mechanisms and progress in biomarker discovery. World Journal of Transplantation. 2020;6:608-619. DOI: 10.5500/wjt.v6.i4.608
  114. 114.Mohty M, Apperley JF. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematology/The Education Program of the American Society of Hematology. 2010;2010:229-236. DOI: 10.1182/asheducation-2010.1.229
  115. 115.Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical Chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313:1137-1140. DOI: 10.1126/science.1128294
  116. 116.Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Scientific Reports. 2012;2:799. DOI: 10.1038/srep00799
  117. 117.Mukai S, Ogawa Y, Urano F, Kudo-Saito C, Kawakami Y, Tsubota K. Novel treatment of chronic graft-versus-host disease in mice using the ER stress reducer 4-phenylbutyric acid. Scientific Reports. 2017;7:41939. DOI: 10.1038/srep41939
  118. 118.Kolb PS, Ayaub EA, Zhou W, Yum V, Dickhout JG, Ask K. The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis. International Journal of Biochemistry & Cell Biology. 2015;61:45-52
  119. 119.Inamoto Y, Martin PJ, Paczesny S, Tabellini L, Momin AA, Mumaw CL, et al. Association of plasma CD163 concentration with De Novo-Onset chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation. 2017;23:1250-1256. DOI: 10.1016/j.bbmt.2017.04.019
  120. 120.Lim J-Y, Ryu D-B, Lee S-E, Park G, Min C-K. Mesenchymal stem cells (MSCs) attenuate cutaneous sclerodermatous graft-versus-host disease (Scl-GVHD) through inhibition of immune cell infiltration in a mouse model. Journal of Investigative Dermatology. 2017;137:1895-1904. DOI: 10.1016/j.jid.2017.02.986
  121. 121.Hong Y-Q , Wan B, Li X-F. Macrophage regulation of graft-vs-host disease. World Journal of Clinical Cases. 2020;8:1793-1805
  122. 122.Guerrero-Juarez CF, Dedhia PH, Jin S, Ruiz-Vega R, Ma D, Liu Y, et al. Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nature Communications. 2019;10:650. DOI: 10.1038/s41467-018-08247-x
  123. 123.LeBleu VS, Neilson EG. Origin and functional heterogeneity of fibroblasts. FASEB Journal. 2020;34:3519-3536. DOI: 10.1096/fj.201903188R
  124. 124.Gordon S, Plüddemann A, Estrada FM. Macrophage heterogeneity in tissues: Phenotypic diversity and functions. Immunological Reviews. 2014;262:36-55. DOI: 10.1111/imr.12223
  125. 125.Gordon S, Plüddemann A. Tissue macrophages: Heterogeneity and functions. BMC Biology. 2017;15:53. DOI: 10.1186/s12915-017-0392-4
  126. 126.Decano JL, Aikawa M. Dynamic macrophages: Understanding mechanisms of activation as guide to therapy for atherosclerotic vascular disease. Frontiers in Cardiovascular Medicine. 2018;5:1-12
  127. 127.Mukai S, Ogawa Y, Kawakami Y, Mashima Y, Tsubota K. Inhibition of vascular adhesion protein-1 for treatment of graft-versus-host disease in mice. FASEB Journal. 2018;32:4085-4095. DOI: 10.1096/fj.201700176R
  128. 128.Jalkanen S, Bargatze RF, Toyos J, Butcher EC. Lymphocyte recognition of high endothelium: Antibodies to distinct epitopes of an 85-95-kD glycoprotein antigen differentially inhibit lymphocyte binding to lymph node, mucosal, or synovial endothelial cells. Journal of Cell Biology. 1987;105:983-990. DOI: 10.1083/jcb.105.2.983
  129. 129.Foot JS, Yow TT, Schilter H, Buson A, Deodhar M, Findlay AD, et al. PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo. The Journal of Pharmacology and Experimental Therapeutics. 2013;347:365-374. DOI: 10.1124/jpet.113.207613
  130. 130.Bligt-Lindén E, Pihlavisto M, Szatmári I, Otwinowski Z, Smith DJ, Lázár L, et al. Novel pyridazinone inhibitors for vascular adhesion protein-1 (VAP-1): Old target-new inhibition mode. The Journal of Medicinal Chemistry. 2013;56:9837-9848. DOI: 10.1021/jm401372d
  131. 131.Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. Journal of Cell Science. 2013;126:2135-2140
  132. 132.Tian L, Wu X, Chi C, Han M, Xu T, Zhuang Y. ADAM10 is essential for proteolytic activation of Notch during thymocyte development. International Immunology. 2008;20:1181-1187. DOI: 10.1093/intimm/dxn076
  133. 133.Ianni MD, Papa BD, Baldoni S, Tommaso AD, Fabi B, Rosati E, et al. NOTCH and graft-versus-host disease. Frontiers in Immunology. 2018;9:1825. DOI: 10.3389/fimmu.2018.01825
  134. 134.Grazioli P, Felli MP, Screpanti I, Campese AF. The mazy case of Notch and immunoregulatory cells. Journal of Leukocyte Biology. 2017;102:361-368. DOI: 10.1189/jlb.1VMR1216-505R
  135. 135.Zhang Y, Sandy AR, Wang J, Radojcic V, Shan GT, Tran IT, et al. Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood. 2011;117:299-308. DOI: 10.1182/blood-2010-03-271940
  136. 136.Mochizuki K, Xie F, He S, Tong Q , Liu Y, Mochizuki I, et al. Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice. Journal of Immunology. 2013;190:3772-3782. DOI: 10.4049/jimmunol.1202820
  137. 137.Radojcic V, Paz K, Chung J, Du J, Perkey ET, Flynn R, et al. Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice. Blood. 2018;132:2188-2200. DOI: 10.1182/blood-2018-03-841155
  138. 138.Poe JC, Jia W, Su H, Anand S, Rose JJ, Tata PV, et al. An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. Blood. 2017;130:2131-2145. DOI: 10.1182/blood-2017-05-782466
  139. 139.Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J, Shan GT, et al. Blockade of individual Notch ligands and receptors controls graft-versus-host disease. Journal of Clinical Investigation. 2013;123:1590-1604. DOI: 10.1172/JCI65477
  140. 140.Julian L, Olson M F: Rho-associated coiled-coil containing kinases (ROCK). Small GTPases. 2014;5:e29846
  141. 141.Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, et al. ROCK2 inhibition with belumosudil (KD025) for the treatment of chronic graft-versus-host disease. Journal of Clinical Oncology. 2021;39:1888-1898. DOI: 10.1200/JCO.20.02754
  142. 142.Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, Chen W, Scher JU, Mo R, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:16814-16819. DOI: 10.1073/pnas.1414189111
  143. 143.Riches DWH, Backos DS, Redente EF. ROCK and Rho: Promising therapeutic targets to ameliorate pulmonary fibrosis. The American Journal of Pathology. 2015;185:909-912. DOI: 10.1016/j.ajpath.2015.01.005
  144. 144.Knipe RS, Tager AM, Liao JK. The Rho kinases: Critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacological Reviews. 2015;67:103-117. DOI: 10.1124/pr.114.009381
  145. 145.Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127:2144-2154. DOI: 10.1182/blood-2015-10-678706
  146. 146.FDA approves belumosudil for chronic graft-versus-host disease. doi:https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belumosudil-chronic-graft-versus-host-disease
  147. 147.Sternberg A: Robust Responses With ROCK2 Inhibition Are Seen in Chronic GVHD. 2020. Available fromhttps://www.targetedonc.com/view/robust-responses-with-rock2-inhibition-are-seen-in-chronic-gvhd
  148. 148.Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y. Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. The American Journal of Physiology-Cell Physiology. 2000;278:C57-C65. DOI: 10.1152/ajpcell.2000.278.1.C57
  149. 149.Naraoka M, Munakata A, Matsuda N, Shimamura N, Ohkuma H. Suppression of the Rho/Rho-kinase pathway and prevention of cerebral vasospasm by combination treatment with statin and fasudil after subarachnoid hemorrhage in rabbit. Translational Stroke Research. 2013;4:368-374. DOI: 10.1007/s12975-012-0247-9
  150. 150.Inoue T, Tanihara H. Ripasudil hydrochloride hydrate: Targeting Rho kinase in the treatment of glaucoma. Expert Opinion on Pharmacotherapy. 2017;18:1669-1673. DOI: 10.1080/14656566.2017.1378344
  151. 151.Lin C-W, Sherman B, Moore LA, Laethem CL, Lu D-W, Pattabiraman PP, et al. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. Journal of Ocular Pharmacology and Therapeutics. 2018;34:40-51. DOI: 10.1089/jop.2017.0023
  152. 152.Hu Z, Wang C, Sitkoff D, Cheadle NL, Xu S, Muckelbauer JK, et al. Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c] pyridine derivatives as potent and selective dual ROCK inhibitors. Bioorganic & Medicinal Chemistry Letters. 2020;30:127474

Written By

Shin Mukai

Submitted: February 19th, 2022Reviewed: March 10th, 2022Published: April 29th, 2022