Document text
Principal Investigator: Amy Klion
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $2,075,838
Funding agency: National Institute of Allergy and Infectious Diseases
Using a cohort of more than 700 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia and to explore responses to targeted therapies with the goal of increasing our understanding of the role of eosinophils in homeostasis and disease pathogenesis. We have also continued our collaborative studies examining the role of eosinophils in the immune response to microbial infections, including M. tuberculosis, and the role of eosinophils in the clinical manifestations of COVID-19.
As the number of therapeutic agents that affect eosinophils, eosinophil migration and eosinophil activation increase, it is becoming increasingly important to understand the mechanisms driving eosinophilia and eosinophil activation in patients presenting with hypereosinophilic syndromes. We have previously shown that the clinical subtype of HES is an important predictor of response to conventional and targeted therapies (Kuang et al. J Allergy Clin Immunol Pract 2018; Khoury et al. J Allergy Clin Immunol Pract 2018). Episodic angioedema and eosinophilia (EAE) is a rare type of HES defined by cycling of serum peripheral blood eosinophil counts and symptoms. In a prior study, we demonstrated that most, if not all, patients have clonal and phenotypically aberrant lymphocyte populations characteristic of lymphocytic variant HES and cyclic elevations in serum IL-5 levels and neutrophils that precede the increase in absolute eosinophil count (AEC) (Khoury et al. Haematologica 2015). To explore the role of IL-5 driven eosinophilia in this condition, we conducted a single site pilot study of mepolizumab. The study was terminated after enrollment of 5 patients due to the lack of improvement in clinical symptoms, despite reduction in serum IL-5 levels and eosinophil counts (Khoury et al. J Allergy Clin Immunol 2024). Whether this is due to incomplete abrogation of eosinophil activation in the tissue and/or involvement of IL-5–independent lineages or pathways is currently under study.
Our group has a long-standing interest in treatment-refractory hypereosinophilic syndromes. Targeted therapeutics not only provide potentially less toxic, more effective treatment options but contribute to our understanding of underlying pathogenesis. This is perhaps most clearly demonstrated by early studies of imatinib in HES (Klion et al. Blood 2003), which led to the discovery of the FIP1L1::PDGFRA fusion gene, and studies of benralizumab which demonstrated failure of eosinophil depletion in patients with the myeloid form of HES (Kuang et al. N Engl J Med 2019). More recently, we have begun to explore the effects of dupilumab, a monoclonal antibody that blocks the IL-4 receptor, in treatment refractory hypereosinophilic syndromes, including eosinophilic fasciitis (Wang et al. Ann Allergy Asthma Immunol 2024). Whereas dupilumab has been shown to reduce tissue eosinophilia by inhibiting eotaxin-mediated chemotaxis, this can lead to increased peripheral eosinophilia and rare eosinophilic complications (Wechsler et al. J Allergy Clin Immunol Pract 2022) that may be accentuated by increased bone marrow production of eosinophils as seen in patients with HES (Ezekwe et al. J Allergy Clin Immunol 2024, AB61). Ongoing studies of targeted therapies in HES include the use of tyrosine kinase inhibitors (imatinib and ruxolitinib) for the treatment of steroid-refractory HES, a multicenter phase 3 trial of benralizumab for HES, as well as long-term followup studies of HES patients enrolled on investigator-initiated trials of benralizumab and dexpramipexole.
Historically, eosinophils have been viewed as effector cells with primary roles in the response to helminth infection and allergens. Consistent with this, recent studies in our group have focused on the role of eosinophils and eosinophil activation in the clinical manifestations and post-treatment reactions in filariasis (Herrick et al. Clin Infect Dis 2020; Legrand et al. Clin Infect Dis 2017; Legrand et al. Clin Infect Dis 2021). Over the past decade, however, there has been increasing interest in the role of eosinophils in the modulation of responses to non-helminth pathogens. To address this issue, we initiated a collaboration with Dr. Katrin Mayer-Barber to examine the role of eosinophils in the host immune response to pulmonary infection with Mycobacterium tuberculosis (Mtb) and, more recently, SARS-CoV2. Our initial data demonstrated that eosinophils are recruited to the lungs within the first few weeks of infection in a CCR3-independent, GPR183-dependent manner (Bohrer et al. Cell Rep 2022). Ongoing studies in murine models suggest that pulmonary eosinophilia is also a feature of COVID-19 infection but that recruitment occurs via CCR3. A recent study of serum markers of eosinophil recruitment and activation in humans with COVID-19 infection (in collaboration with Dr. Gail Gauvreau at McMaster University) demonstrated increased levels of eotaxins despite decreases in blood eosinophil counts, consistent with this hypothesis (Ranjbar et al. Int J Mol Sci 2024).
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Affect><After Care><After-Treatment><Aftercare><Allergens><Allergic><Allergy><Angioedema><Angioneurotic Edema><Asthma><Automobile Driving><Autoregulation><B Cell Differentiation Factor I><B Cell-Activating Factor Receptor><B cell growth factor 2><B-Cell Growth Factor-II><BCGF-II><BCGF2><Barbering><Benign><Blocking Antibodies><Blood><Blood Eosinophil><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bronchial Asthma><CCL11 protein><CD124 Antigens><CD140A><CDw124 Antigen><COVID-19><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Cell Body><Cells><Chemotaxis><Clinical><Clinical Treatment Moab><CoV-2><CoV2><Collaborations><Coronavirus Infectious Disease 2019><Cyclicity><Data><Disease><Disorder><Disseminated eosinophilic collagen disease><Effector Cell><Enrollment><Eo-CSF><Eosinophil Chemotactic Protein><Eosinophil Differentiation Factor><Eosinophilia><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Eosinophilic leukemia><Eotaxin><Failure><Fasciitis><Filariasis><Filarioidea Infections><Follow-Up Studies><Followup Studies><Giant Urticaria><Goals><Homeostasis><Human><Hypereosinophilic Syndrome><Hypersensitivity><IL-4 Receptors><IL-5><IL4 Receptors><IgA enhancing factor><Imatinib><Immune response><Immunological response><Infection><Interleukin 4 Receptor><Interleukin 5 Precursor><Interleukin-4 Receptor Alpha><Interleukin-5><Long-term Follow-up><Longterm Follow-up><Lung><Lung Respiratory System><Lung infections><Lymphatic cell><Lymphocyte><Lymphocytic><M tb><M tuberculosis><M. tb><M. tuberculosis><Marrow Eosinophil><Marrow Neutrophil><Mediating><Modern Man><Monoclonal Antibodies><Mycobacterium tuberculosis><Myelogenous><Myeloid><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ><Orphan Disease><PDGFR2><PDGFRA><PDGFRA gene><PTK Inhibitors><Pathogenesis><Pathway interactions><Patients><Periodicity><Peripheral><Peripheral Blood Eosinophilia><Phenotype><Physiological Homeostasis><Pilot Projects><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population Characteristics><Production><Protein Tyrosine Kinase Inhibitors><Pulmonary Eosinophilia><Quincke's Edema><Rare Diseases><Rare Disorder><Reaction><Refractory><Rhythmicity><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serum><Serum Markers><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Small Inducible Cytokine A11><Steroid Compound><Steroids><Study of serum><Symptoms><T cell replacing factor><T-Cell Replacing Factor><TK Inhibitors><Therapeutic Agents><Tissues><Tyrosine Kinase Inhibitor><Universities><Variant><Variation><Wuhan coronavirus><clinical subtypes><cohort><conventional therapy><conventional treatment><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><diagnostic tool><driving><effective therapy><effective treatment><enroll><eosinophil><eotaxin-1><filarial disease><filarial infection><fusion gene><hCoV19><helminth infection><helminthic infection><host response><human disease><immune system response><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with helminth><infected with severe acute respiratory syndrome coronavirus 2><interest><investigator-initiated trial><long-term followup><longterm followup><lymph cell><mAbs><mepolizumab><microbial><migration><monoclonal Abs><mouse model><mtb><murine model><nCoV2><neoplastic><neutrophil><new diagnostics><next generation diagnostics><novel><novel diagnostics><orphan disorder><participant enrollment><pathogen><pathway><patient enrollment><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><peripheral blood><phase 3 trial><phase III trial><pilot study><post treatment><predict responsiveness><predicting response><pulmonary><pulmonary infections><recruit><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment>