Long term Th2 cytokines immunotherapy beneficial for EoE pediatric patients?

Abstract

Eosinohilic esophagitis (EoE) and gastroesophageal reflux diseases (GERD) are closely related esophageal disorders, and both accumulate eosinophils in the esophagus. However, origin of both these diseases are very different. The evidence indicates that acid reflux is the main cause of GERD; whereas EoE is induced in response to food or environment allergens exposed accumulation of inflammatory cells like eosinophils, mast cells and T cell subsets. EoE is a global problem, and effect even 1 year old children to adult population. Currently, mepolizumab (anti-IL-5) neutralization therapy sdata showed reduced epithelial layer eosinophilia in EoE,^{1, 2} and most recently FDA approved FDA has also approved Dupixent (anti-IL4R and anti-IL-13) for EoE following Phase 3 randomized, double-blind, placebo-controlled trial. The efficacy and safety of Dupixent 300 mg weekly patients 12 year or older on limited patient number, 69% and 64% reduction in EoE symptoms from baseline compared to 32% and 41% for placebo (FDA, 2022). In this commentary, we raised few concerns to be considered on these therapies based on the significance of IL-5, IL-4 in maintaining the innate immunity of the young children are mostly effected by EoE that require long term immunotherapy of mepolizumab (anti-IL-5) or Dupixent (anti-IL4R and anti-IL-13).

Introduction and Long term anti-IL-5 and anti-IL-13 immunotherapies concerns.

Recently, the Phase 3 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of Dupixent (anti-IL4R and anti-IL-13) 300 mg weekly patients 12 year or older, showed that 69% and 64% reduction in EoE symptoms from baseline compared to 32% and 41% for placebo. Based on these findings FDA has approved the therapy for EoE. Earlier anti-IL-5 (mepolizumab) therapy was also used to treat EoE that raised several questions whether anti-IL-5 immunotherapy is proposed without considering the Th2 cytokines long time treatment responses and eosinophils biology and their significance in the maintenance of innate immunity. Earlier, anti-IL-5 immunotherapy was approved for the treatment of asthma and not resulted expected results as presumed. IL-5 are critical for the stimulation, differentiation, and survival of the eosinophils.³ Once eosinophils develop in bone marrow IL-5 maintain their survival in the circulation and tissues in health. Thus, it is important to understand the consequences of eosinophils depletion following anti-IL-5 therapy on human host defense. Though, young IL5 gene-deficient mice and GATA1 gene-deficient mice are lack of baseline eosinophils in circulation, but not after the induction of disease, as both these mice are having bonemarrow eosinophils precursors. Both these mice show slow breeding rate, produce low number of pups in each breeding and lose reproduction capacity much earlier then the normal mice. The age associated disease induction need to be carefully investigated in these mice. It is well established that IL-4 is critical for higher functions of the normal brain, such as memory and learning.⁴ Additionally, IL-4 expression is tightly regulated at several levels, including signaling pathways, transcription factors, epigenetic modifications, microRNA, and long noncoding RNA.⁵ Further, our own observation indicated that IL-13 is closely related to IL-5 and inhibit IL-5 levels. Therefore, inhibition of these Th2 cytokines will compromise innate immunity in developing pediatric population.

We earlier showed that eosinophils home in the gastrointestinal tract prenatally; thus, they are very different leucocyte compare to the polymorphonuclear leukocytes (PMNLs), lymphocytes, and macrophages that develop after birth in the human body.⁶ Indicating that eosinophils play a critical role even in the development biology. Eosinophils are normally found in significant numbers in the bone marrow, the thymus, the alimentary tract exclusive of esophagus, the uterus, and the mammary gland tissues of healthy individuals.^7–9 Eosinophil and its role in human health is critical, their primary role is to protect the host against invasion and disease produced by metazoan parasitic invaders. The eosinophils have capability to expel multicellular parasites from gastrointestinal tract via the release of its cytoplasmic granules like MBP, ECP, EDN, and EPO. Eosinophils have various cell surface receptors that recognize infectious agents and injured cells.¹⁰ Mesnil, et al characterize the phenotype of rEos compared to that of CD101 expressed eosinophils develops during inflammatory response (iEos) and both are functionally different in mice.¹¹ It is well accepted that IL-5 is responsible for eosinophils differentiation and required for their growth and survival. In fact, this report did not elaborate the factor responsible for the generation of rEOS. However, our finding indicated that the CD101 is not expressed on IL-5 induced in vitro generated naïve eosinophils or eosinophils present in CD2-IL-5 transgenic (rEOS. Most importantly, we provided the evidences that IL-18 has the capacity to differentiate and transform IL-5 generated naïve (rEos) eosinophils to CD101/CD274 expressed pathogenic eosinophils (iEos)¹² and IL-5 required for the maintenance and survival of both IL-5 and IL-18 generated both subsets of eosinophils.¹² Therefore, anti-IL-5 therapy will sure deplete both IL-5 responsive naïve and pathogenic eosinophils that may compromise innate immune responses. In addition, we also reported that even GATA-1 gene-deficient mice develops tissue eosinophilia in response to the rIL-18 in mice.¹³ Thus, the questions raised whether anti-IL-5 targeted therapy is legitimate, as raises several concerns, like long term effect of IL-5 depletion, antibody-dependent cytotoxicity, antibody-dependent cytotoxicity and in bone marrow the impact on eosinophil levels on the development of other leucocytes are important and need to be considered. Earlier, several reported findings showed that anti-IL-5 associated eosinophils depletion promotes epithelial cells transformation, effects mast cells granulation processes, and also yet not proven the possible effects of anti-IL-5 therapy on the status of different diseases and immunization and IL-4 role in brain and memory related development. Several alternative therapeutic strategies are reported in experimental models of EoE, like, IL-15 responsive iNKT cells neutralization or anti-IL-18 neutralization therapies, which is still not tested by human clinical trials.

In conclusion, our concern is wide use of anti-Th2 cytokines therapy on allergic diseases for children aged 12 years and above suffering with eosinophilic esophagitis (EoE) or other allergic diseases should be carefully evaluated, considering their role in eosinophils maintenance of innate immunity and central nervous system development innate immunity.