Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

National Institute Of Allergy And Infectious Diseases

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Abstract

Using a cohort of more than 600 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 expanded 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 COVID19 (Espinoza et al.J Allergy Clin Immunol Pract 2022). One of the difficulties in assessing responses to clinical interventions in HES is the lack of specific measures of eosinophil-mediated disease activity. This is particularly problematic in the setting of eosinophil-depleting therapies that may lower the eosinophil count despite clinical evidence of continuing eosinophil-mediated pathogenesis. We have previously described a multiplex assay to measure eosinophil granule proteins in the blood and shown a correlation between other markers of eosinophil activation and serum levels of eosinophil-derived neurotoxin (EDN) that is independent of the blood eosinophil count (Makiya et al. J Immunol Methods 2014). In the past year, we explored the use of this assay to measure eosinophil granule proteins in the blood and urine of patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma before and after treatment with eosinophil-depleting therapies (Makiya et al. Allergy 2022). Whereas both plasma and urine measurement of EDN were elevated in patients with active disease and decreased with effective therapy, unlike plasma measurement, urine measurement is non-invasive and unaffected by cellular lysis. Moreover, the lack of correlation between AEC or prednisone dose and urine but not plasma EDN levels suggests that measurement of urine EDN may be a better biomarker of disease activity in patients with eosinophilic disorders. Targeted therapies not only provide new options for patients but provide insight into the effects of eosinophil depletion in humans and the mechanisms driving eosinophilia and eosinophil activation in HES. Ongoing studies include the use of tyrosine kinase inhibitors (imatinib and ruxolitinib) for the treatment of steroid-refractory HES, a single site study of mepolizumab for the treatment of episodic angioedema and eosinophilia, 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. We have previously described the results of our single center phase 2 placebo-controlled study of benralizumab that demonstrated efficacy of this agent in patients with treatment-refractory PDGFRA-negative HES (Kuang et al. N Engl J Med 2019). These results were instrumental in the initiation of an ongoing multicenter phase 3 study of benralizumab in HES and provided support for the safety of eosinophil-depletion in humans (Manetz et al.J Allergy Clin Immunol Pract 2020). Detailed analysis of the clinical, laboratory and histochemical findings in the 7 patients with gastrointestinal involvement suggest that residual symptoms in some patients despite complete depletion of eosinophils in the blood and tissue may reflect persistent epithelial changes and/or mast cell persistence (Kuang et al. J Allergy Clin Immunol Pract 2022). As the number of therapeutic agents that affect eosinophils, eosinophil migration and eosinophil activation increase, it is becoming increasingly important to identify predictors of response. We have previously shown that the 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). A recent multicenter study of off-label biologic use for the treatment of HES confirmed variable responsiveness to the different agents due, at least in part, to HES clinical subtype (Chen et al. J Allergy Clin Immunol Pract 2022). Other factors, including the mechanism of action of the drug and the role of other cells in disease pathogenesis are clearly also important both in determining efficacy and potential toxicity in patients with eosinophilic disorders. The latter is exemplified by the effect of dupilumab on blood eosinophilia (Wechsler et al. J Allergy Clin Immunol Pract 2022). 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). After initial studies in murine models demonstrated that the early influx of neutrophils and NK cells into the lung post-Mtb infection is eosinophil-dependent, suggesting that eosinophils may be responsible for orchestrating the pulmonary innate immune response after Mtb infection, these findings were confirmed using rhesus macaque and zebrafish models of mycobacterial infection and human tissues from patients with tuberculosis (Bohrer et al. J Exp Med 2021). In a more recent study designed to explore the mechanism and kinetics of eosinophil recruitment to the lung in Mtb infection, we used macaque and murine models to demonstrate that eosinophils are recruited to the infected lung within 1-2 weeks and interact with Mtb infected cells in the airways (Bohrer et al. Cell Rep 2022). In mice, this migration was CCR3-independent but required expression of GPR183, an oxysterol receptor present on human blood eosinophils and human eosinophils isolated from Mtb-infected lung tissue. Consistent with the in vivo murine data, in vitro human eosinophil chemotaxis to oxysterol ligands was abrogated by specific GPR183 inhibitors. These data support an early role for eosinophils in the protective immune response to Mtb infection.