Mast Cell Growth Research Articles

Effective midostaurin treatment in a patient with aggressive systemic mastocytosis

Systemic mastocytosis (SM) is a rare neoplastic disease of the hematopoietic system characterized by the presence of a somatic mutation in the KIT gene, leading to excessive proliferation of pathological mast cells. This results in abnormal growth of mast cells in the skin and other organs. There are following variants of SM: SM with an associated hematological neoplasm (SM-AHN), aggressive SM (ASM) and mast cell leukemia (MCL), they all are referred to as advanced SM (AdvSM). The drug of choice in the treatment of ASM in Poland is cladribine, which, however, is not approved in this indication, unlike the multikinase inhibitor — midostaurin and imatinib. The latter drug can be used when c-KIT D816V mutation remains negative or unknown. A 61-year-old female with ASM, accompanied by pancytopenia, hepatosplenomegaly and bone marrow fibrosis with sclerotic bone lesions was reported. The patient was initially treated with cladribine, but due to lack of efficacy after 3 cycles, midostaurin was used as a second option. Initially, the patient developed neutropenia, which led to dose reduction. Treatment continuation resulted in improvement of blood counts and regression of organ changes. Finally, the patient achieved a partial response and the drug was well tolerated. Midostaurin remains a promising treatment option in a patient with ASM and cladribine ineffectiveness.

Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

Generation of mice with a conditional Il9 allele

Abstract Interleukin (IL)-9 is a pleotropic cytokine that induces cell-specific functions associated with asthma, with target cells including T cells, mast cells, eosinophils, and epithelial cells. Previous findings have demonstrated that IL-9 promotes mast cell growth and differentiation, suggesting that IL-9 contributes to mast cell-driven allergic diseases. Although studies have demonstrated the impact of IL-9 in allergic asthma and other allergic diseases, the cellular source of IL-9 in each setting remains unclear. IL-9 can be produced by several cell types including natural killer T cells, innate lymphoid cells, mast cells, and CD4+ T helper cells (Th). We speculate that T helper 9 (Th9) cells are a major source of IL-9 and that Th9-dervied IL-9 promotes mast cell expansion, activity, and function. Our hypothesis is supported by findings in patients with asthma in which IL-9 expression and Th9 cell numbers are significantly elevated. Here, we address the role of T cell–derived IL-9 in mice with an inactivation of the IL-9 gene restricted to T cells generated by CD4-Cre/loxP-mediated targeting of the IL-9 gene. Preliminary results demonstrate efficient deletion of Il9 in T cells. Il9 fl/fl CD4-Cre Th9 cultures have minimal production of IL-9. Ongoing studies will directly examine the contribution and function of TH9-derived IL-9 during models of allergic airway inflammation and future studies will define the requirement for IL-9 in other cell populations during allergic immune responses.

Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis.

Systemic mastocytosis (SM) is a hematologic neoplasm with abnormal accumulation of mast cells in various organ systems such as the bone marrow, other visceral organs and skin. So far, only little is known about epigenetic changes contributing to the pathogenesis of SM. In the current article, we provide an overview of epigenetic changes that may occur and be relevant to mastocytosis, including mutations in genes involved in epigenetic processes, such as TET2, DNMT3A and ASXL1, and global and gene-specific methylation patterns in neoplastic cells. Moreover, we discuss methylation-specific pathways and other epigenetic events that may trigger disease progression in mast cell neoplasms. Finally, we discuss epigenetic targets and the effects of epigenetic drugs, such as demethylating agents and BET-targeting drugs, on growth and viability of neoplastic mast cells. The definitive impact of these targets and the efficacy of epigenetic therapies in advanced SM need to be explored in future preclinical studies and clinical trials.

Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors.

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

Stem Cell Factor Neutralization Protects From Severe Anaphylaxis in a Murine Model of Food Allergy.

Food allergy is a growing public health problem with ~15 million people affected in the United States. In allergic food disease, IgE on mast cells bind to ingested antigens leading to the activation and degranulation of mast cells. Stem cell factor (SCF) is mast cell growth and activation factor that is required for peripheral tissue mast cells. We targeted a specific isoform of SCF, the larger 248 amino acid form, that drives peripheral tissue mast cell differentiation using a specific monoclonal antibody in a model of food allergy. Ovalbumin sensitized and intragastrically challenged mice were monitored for symptoms of anaphylaxis including respiratory distress, diarrhea, and a reduction in body temperature. During the second week of challenges, allergic mice were injected with an antibody to block SCF248 or given IgG control. Mice treated with α-SCF248 had a decreased incidence of diarrhea and no reduction in body temperature suggesting a reduction in anaphylaxis compared to IgG control treated animals. Re-stimulated mesenteric lymph nodes indicated that α-SCF248 treated mice had decreased OVA-specific Th2 cytokine production compared to IgG control treated allergic animals. The reduction of food induced anaphylaxis was accompanied by a significant reduction in gut leak. The mesenteric lymph node cells were analyzed by flow cytometry and showed a decrease in the number of type 2 innate lymphoid cells in mice injected with α-SCF248. Morphometric enumeration of esterase+ mast cells demonstrated a significant reduction throughout the small intestine. Using a more chronic model of persistent food-induced anaphylaxis, short term therapeutic treatment with α-SCF248 during established disease effectively blocked food induced anaphylaxis. Together, these data suggest that therapeutically blocking SCF248 in food allergic animals can reduce the severity of food allergy by reducing mast cell mediated disease activation.

IL-3 is essential for ICOS-L stabilization on mast cells, and sustains the IL-33-induced RORγt+ Treg generation via enhanced IL-6 induction.

SummaryIL‐33 is a member of the IL‐1 family. By binding to its receptor ST2 (IL‐33R) on mast cells, IL‐33 induces the MyD88‐dependent activation of the TAK1‐IKK2 signalling module resulting in activation of the MAP kinases p38, JNK1/2 and ERK1/2, and of NFκB. Depending on the kinases activated in these pathways, the IL‐33‐induced signalling is essential for production of IL‐6 or IL‐2. This was shown to control the dichotomy between RORγt+ and Helios+ Tregs, respectively. SCF, the ligand of c‐Kit (CD117), can enhance these effects. Here, we show that IL‐3, another growth factor for mast cells, is essential for the expression of ICOS‐L on BMMCs, and costimulation with IL‐3 potentiated the IL‐33‐induced IL‐6 production similar to SCF. In contrast to the enhanced IL‐2 production by SCF‐induced modulation of the IL‐33 signalling, IL‐3 blocked the production of IL‐2. Consequently, IL‐3 shifted the IL‐33‐induced Treg dichotomy towards RORγt+ Tregs at the expense of RORγt− Helios+ Tregs. However, ICOS‐L expression was downregulated by IL‐33. In line with that, ICOS‐L did not play any important role in the Treg modulation by IL‐3/IL‐33‐activated mast cells. These findings demonstrate that different from the mast cell growth factor SCF, IL‐3 can alter the IL‐33‐induced and mast cell‐dependent regulation of Treg subpopulations by modulating mast cell‐derived cytokine profiles.

Detection of the germline KIT S476I mutation in a kindred with familial mastocytosis associated with gastrointestinal stromal tumors

Mastocytosis represents a rare disease characterized by clonal proliferation of mast cells (MCs).1 It mostly occurs sporadically as cutaneous or systemic mastocytosis due to somatic activating KIT mutations encoding the MC growth factor receptor KIT. A positive family history is rare and partly attributed to activating germline KIT mutations. Patients with familial mastocytosis (FM) may suffer in addition from gastrointestinal stromal tumors (GISTs), cutaneous hyperpigmentation, and/or dysphagia.

Modulation of dermal equivalent of hypothalamus-pituitary-adrenal axis in mastocytosis.

IntroductionMastocytosis is a rare disease characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems and is classified as being either cutaneous mastocytosis (CM) or systemic mastocytosis (SM). In the pioneer studies of Slominski's group, a fully functional hypothalamic-pituitary-adrenal axis equivalent has been discovered in various tissues, including skin.AimIn the present study we investigated potential involvement of hypothalamus-pituitary-adrenal (HPA) cutaneous equivalent in ongoing mastocytosis.Material and methodsThe expression of HPA elements: CRH, UCN1, UCN2, UCN3, CRHR1, POMC, MC1R, MC2R and NR3C1 was assessed for their mRNA level in skin biopsies of adult patients with mastocytosis and healthy donors (n = 16 and 19, respectively), while CRH, UCN1, CRHR1, ACTH and MC1R were selected for immunostaining assay (n = 13 and 7, respectively). The expression of CRH receptor 1 (CRHR1) isomers was investigated by RT-PCR. The ELISA was used for detection of cortisol, CRH, UCN and ACTH in the serum.ResultsThe decrease in the expression of HPA element of skin equivalent was observed on both mRNA and protein levels, however quantification of immunohistochemical data was impeded due to melanin in epidermis. Furthermore, we observed infiltration of dermis with HPA elements overexpressing mononuclear cells, which is in the agreement with an in vitro study showing a high expression of HPA elements by mast cells.ConclusionsTaken together, it was confirmed that the expression elements of HPA was modulated in mastocytosis, thus the potential involvement of general and local stress responses in its pathogenesis should be postulated and further investigated.

The Monoclonal Antibody 97A6 Defines a Novel Surface Antigen Expressed on Human Basophils and Their Multipotent and Unipotent Progenitors

Basophils (Ba) and mast cells (MC) are important effector cells of inflammatory reactions. Both cell types derive from CD34(+) hematopoietic progenitors. However, little is known about the cell subsets that become committed to and give rise to Ba and/or MC. We have generated a monoclonal antibody (MoAb), 97A6, that specifically detects human Ba, MC (lung, skin), and their CD34(+) progenitors. Other mature hematopoietic cells (neutrophils, eosinophils, monocytes, lymphocytes, platelets) did not react with MoAb 97A6, and sorting of 97A6(+) peripheral blood (PB) and bone marrow (BM) cells resulted in an almost pure population (>98%) of Ba. Approximately 1% of CD34(+) BM and PB cells was found to be 97A6(+). Culture of sorted CD34(+)97A6(+) BM cells in semisolid medium containing phytohemagglutinin-stimulated leukocyte supernatant for 16 days (multilineage assay) resulted in the formation of pure Ba colonies (10 of 40), Ba-eosinophil colonies (7 of 40), Ba-macrophage colonies (3 of 40), and multilineage Ba-eosinophil-macrophage and/or neutrophil colonies (12 of 40). In contrast, no Ba could be cultured from CD34(+)97A6(-) cells. Liquid culture of CD34(+) PB cells in the presence of 100 ng/mL interleukin (IL)-3 (Ba progenitor assay) resulted in an increase of 97A6(+) cells, starting from 1% of day-0 cells to almost 70% (basophils) after day 7. Culture of sorted BM CD34(+)97A6(+) cells in the presence of 100 ng/mL stem cell factor (SCF) for 35 days (mast cell progenitor assay) resulted in the growth of MC (>30% on day 35). Anti-IgE-induced IgE receptor cross-linking on Ba for 15 minutes resulted in a 4-fold to 5-fold upregulation of 97A6 antigen expression. These data show that the 97A6-reactive antigen plays a role in basophil activation and is expressed on multipotent CD34(+) progenitors, MC progenitors, Ba progenitors, as well as on mature Ba and tissue MC. The lineage-specificity of MoAb 97A6 suggests that this novel marker may be a useful tool to isolate and analyze Ba/MC and their progenitors.

In vitro effects of histamine receptor 1 antagonists on proliferation and histamine release in canine neoplastic mast cells.

Canine mastocytomas (MCTs) are characterized by rapid proliferation of neoplastic mast cells (MCs) and clinical signs caused by MC‐derived mediators. In dogs suffering from MCT, histamine receptor 1 (HR1) antagonists are frequently used to control mediator‐related clinical symptoms. Previous studies have shown that the HR1 antagonists loratadine and terfenadine exert some growth‐inhibitory effects on neoplastic MCs. We examined whether other HR1 antagonists used in clinical practice (desloratadine, rupatadine, cyproheptadine, dimetindene, diphenhydramine) affect proliferation and survival of neoplastic MCs. Furthermore, we analysed whether these HR1 antagonists counteract IgE‐dependent histamine release from a MC line harbouring a functional IgE‐receptor. HR1 antagonists were applied on two canine MC lines, C2 and NI‐1, and on primary MCs obtained from three MCT samples. The HR1 antagonists desloratadine, rupatadine and cyproheptadine were found to be more potent in decreasing proliferation of C2 and NI‐1 cells when compared with dimetindene and diphenhydramine. Similar effects were seen in primary neoplastic MCs, except for diphenhydramine, which exerted more potent growth‐inhibitory effects than the other HR1 antagonists. Drug‐induced growth‐inhibition in C2 and NI‐1 cells was accompanied by apoptosis. Loratadine, desloratadine and rupatadine also suppressed IgE‐dependent histamine release in NI‐1 cells. However, drug concentrations required to elicit substantial effects on growth or histamine release were relatively high (>10 µM). Therefore, it remains unknown whether these drugs or similar, more potent, HR1‐targeting drugs can suppress growth or activation of canine neoplastic MCs in vivo.

The Mast Cell-SCF-CB1 Interaction Is a Key Player in Seborrheic Keratosis.

Mast cell (MC) is an important player in the development of skin diseases, including atopic dermatitis, psoriasis, and urticaria. It is reported that MC infiltration and activation are observed around various types of tumors and speculated that MCs play key roles in their pathogenesis. As MCs in human seborrheic keratosis (SK) have not been well investigated, here we focused on the MCs in SK. The number of c-Kit and tryptase-positive MCs was significantly increased around the SK compared with the marginal lesion. Degranulated MCs were also increased around the tumors. Furthermore, MC growth factor, stem cell factor (SCF), expression within the SK was significantly upregulated compared with the marginal lesion. Interestingly, one of the cognitive regulators of SCF expression, cannabinoid receptor type 1 (CB1) immunoreactivity was downregulated within the SK. Our results suggest that MCs play important roles in the pathogenesis of SK and that SCF can be also deeply involved in the development of SKs. Our current results highlight the CB1-SCF-MC interaction as a novel mechanism of SK development and this also will be utilized for developing a novel treatment.

Laboratory Tests in Diagnosis of Mastocytosis: Literature Review and Case Report

Abstract Мastocytosis is a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs) in the skin and/or other organ systems. Mastocytosis is a rare disease. The annual incidence is 5-10 cases per 1 million people. However, the majority of cases stay undiagnosed due to the lack of specific tests and a wide variety of clinical features of the disease. In mastocytosis, somatic mutations of KIT gene lead to autocrine dysregulation and constitutive c-KIT activation in the absence of its ligand SCF. Clinical symptoms of the disease are determined by MC mediator release and/or infiltration of tissues by MCs. According to the World Health Organisation classification updated in 2016 mastocytosis is divided to cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), SM with an associated hematologic (non-MC-lineage) neoplasm (SMAHN), aggressive SM (ASM), MC leukemia (MCL) and MC sarcoma (MCS). The CM and ISM prognosis is excellent with (almost) normal life expectancy, unlike aggressive forms (ASM and MCL) with poor prognosis. In this paper the key aspects of clinical features and diagnostic criteria of mastocytosis are discussed. We present a case report of a patient with mastocytosis in the skin following psoralen plus ultraviolet A (PUVA) therapy with good response.

The role of IL-9 secreting CD4+ T helper cells in promoting mast cell expansion in pulmonary models of inflammation

Abstract Mast cells are tissue resident cells with granules that contain histamine and other proinflammatory mediators. Mast cells are important effectors in immediate type I hypersensitivity reactions. In severe allergic reactions, immunoglobulin E (IgE)-mediated mast cell degranulation triggers localized and systemic anaphylaxis. In allergic asthma, mast cells and T cells interact in the generation of long-lasting inflammation. The molecular mechanisms responsible for mast cell expansion has not been fully elucidated. Because T cells are an important source of the mast cell growth factor IL-9, we are interested in understanding the role of IL-9, and IL-9-producing T cells in mast cell expansion and recruitment. We have identified a role of T helper 9 (Th9) cells in influencing mast cell number and function in pulmonary models of inflammation. Using adoptive transfer models, we have defined a contribution of Th9 cells in immediate hypersensitivity. We have demonstrated that IL-9 expands mast cell progenitor numbers in bone marrow and lung, suggesting that there are systemic effects of local IL-9 production. We hypothesize that increased mature mast cells in the pulmonary system are from recruitment and expansion of progenitor cells rather than expansion of mature cells in situ. Ongoing studies will directly examine the relative contribution and function of the two populations during models of allergic airway inflammation.

Epigenetic regulation of C-Kitlo FcɛR1a+ mast cells by cannabidiol during staphylococcal enterotoxin B-induced liver injury

Abstract Although recent studies have established cannabidiol (CBD) as a potent anti-inflammatory agent, the mechanisms governing these processes remain unclear. Our previous research demonstrated that CBD treatment induced expansion of CD11b+Gr-1+MDSC in the peritoneum, which suppressed T cell functions leading to attenuation of staphylococcal enterotoxin B (SEB)-mediated liver inflammation in mice. Using the same model, we characterize the effects of CBD administration in the liver. Briefly, mice were injected intraperitoneally (I.P.) with 50mg/kg of CBD for 4 days (d), followed by SEB challenge on d 3. Flow cytometry analysis revealed a significant reduction in Vβ8+ CD8+ T cells. In agreement with our earlier findings, mice treated with CBD displayed robust expansion of Gr-1+ MDSC in the liver, which was primarily comprised of Ly6CHI MHCIILO leukocytes. As mast cells have been found to play a role in CBD-mediated induction of MDSC via increased peroxisome proliferator-activated receptor gamma (PPARγ) signaling, we examined changes to liver mast cell populations. We discovered two distinct subsets of mast cells, C-KithiFcɛR1a+ and C-Kitlo FcɛR1a+present in the liver. CBD treatment promoted expansion of the C-Kitlo FcɛR1a+ subset. Analysis by miRNA microarray displayed enrichment of miRNAs targeting mast cell growth factor, KIT ligand (KITLG), and significant downregulation of miR-217-5p, which is conserved for the co-activator of PPARγ (PPARγC1A). Increased gene expression of PPARγ was confirmed by single-cell RNA sequencing (sc-RNAseq). Taken together, our results identify CBD induced epigenetic reduction of C-Kit expression and KITLG signaling in mast cells to favor PPARγ signaling as a novel anti-inflammatory mechanism.

Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap.

Systemic mastocytosis is a rare and heterogeneous disease characterized by mast cell proliferation and activation. KIT is a transmembrane tyrosine kinase which plays a key role in mast cell growth, differentiation and survival. After interaction with its ligand, the stem cell factor, KIT dimerizes activating downstream pathways involving multiple tyrosine kinases (PI3K, JAK/STAT, RAS/ERK). Activating mutations in KIT are detected in most cases of systemic mastocytosis, being the most common KIT D816V. Therefore, since the emergence of tyrosine kinase inhibitors, KIT inhibition has been an attractive approach when facing mastocytosis treatment. Initial reports showed that only the rare KIT D816V negative cases were responsive to tyrosine kinase inhibitors. However, the development of new tyrosine kinase inhibitors such as midostaurin or avapritinib with activity against mast cells carrying the D816V KIT mutation, has changed the landscape of this disease.

SLAM family member 8 is expressed in and enhances the growth of anaplastic large cell lymphoma

Signaling lymphocytic activation molecule family member 8 (SLAMF8) / B-lymphocyte activator macrophage expressed/CD353 is a member of the CD2 family. SLAMF8 suppresses macrophage function but enhances the growth of neoplastic mast cells via SHP-2. In this study, we found that some anaplastic large cell lymphoma (ALCL) samples were immunohistochemically positive for SLAMF8. However, we found no significant differences between SLAMF8-positive and SLAMF8-negative ALCL samples with respect to age, gender, site, or prognosis. We also identified SLAMF8 expression in ALCL cell lines, Karpas299, and SU-DHL-1. SLAMF8 knockdown decreased the activation of SHP-2 and the growth of these cell lines, and increased the apoptosis of these cell lines. In addition, we observed the interaction between SLAMF8 and SHP-2 in these cell lines using the DuoLink in situ kit. Taken together, these results suggest that SLAMF8 may enhance the growth of ALCL via SHP-2 interaction.

Dermoscopy of Urticaria Pigmentosa.

Dermoscopy of Urticaria Pigmentosa.

Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients

Background: Mast cells play an essential role in pathology of bronchial asthma. Stem cell factor (SCF) is a major mast cell growth factor, which could be involved in the local increase of mast cell number in the asthmatic airways when bind to its receptor (C-kit). Existing study aimed to evaluate role of gene expression of SCF and their receptor C-kit in development of bronchial asthma in Iraqi population. Methods: present study included 100 patients diagnostic with bronchial asthma (59 females and 41 males) their ages range from 2 to 61 years and 30 healthy individuals (14 females and 16 males) with the same age range as control group DNA extracted from whole blood samples and then subjected to real time PCR for detection of gene expression. Results: current data showed a significant correlation (p0.05) . The optimum cut-off values for gene expression of SCF and C-kit are ≥ 0.55, ≥2.328 respectively since there are associated with a perfect test for predicting asthma. In conclusion: high gene expression of SCF and C-kit associated with increase severity stage of bronchial asthma without treatment and can be reduced by treatment. How to Cite this Article Pubmed Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Web Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic http://www.sysrevpharm.org/?mno=302645230 [Access: March 29, 2021]. doi:10.5530/srp.2020.1.08 AMA (American Medical Association) Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Vancouver/ICMJE Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. (2020), [cited March 29, 2021]; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Harvard Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Turabian Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. 2020. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Chicago Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11 (2020), 51-57. doi:10.5530/srp.2020.1.08 MLA (The Modern Language Association) Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11.1 (2020), 51-57. Print. doi:10.5530/srp.2020.1.08 APA (American Psychological Association) Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08

D100 CDX-0159, AN ANTI-KIT MONOCLONAL ANTIBODY, AS A MODULATOR OF MAST CELL-RELATED DISEASES

CDX-0159 is a humanized anti-KIT IgG1 monoclonal antibody being evaluated as a modulator of mast cell (MC)-related diseases including chronic idiopathic urticaria. The receptor KIT regulates MC growth, survival, chemotaxis and degranulation, suggesting KIT inhibition as a unique approach to modulate MC activity. CDX-0159 is a re-engineered variant of CDX-0158, a potent KIT inhibitor that decreased MC numbers in several preclinical models and decreased plasma tryptase levels in cancer patients, indicating a reduction in MC numbers/activity. However, CDX-0158 was associated with infusion-related reactions. CDX-0159 was designed to improve its safety profile and increase its serum half-life.