Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy

Abstract

BackgroundAnti-interleukin (IL)-5 monoclonal antibodies as an eosinophil-depleting strategy is well established, with Mepolizumab being the first biologic approved as an adjunct treatment for severe eosinophilic asthma.Case presentationA 62-year old woman diagnosed with severe eosinophilic asthma showed poor response to Mepolizumab therapy (100 mg subcutaneous dose/monthly) and subsequent worsening of symptoms. The treatment response to Mepolizumab was monitored using both blood and sputum eosinophil counts. The latter was superior in assessing deterioration in symptoms, suggesting that normal blood eosinophil count may not always indicate amelioration or adequate control of the ongoing eosinophil-driven disease process. This perplexing situation of persistent airway eosinophilia and increased steroid insensitivity despite an anti-eosinophil therapy can be explained if the administered dose of the mAb was inadequate in comparison to the target antigen. The resultant immune complexes could act as ‘cytokine depots’, protecting the potency of the ‘bound’ IL-5, thereby sustaining the eosinophilic inflammation within the target tissue. Molecular analysis of the sputum indicated the development of a polyclonal autoimmune response as well as an increase in group 2 innate lymphoid cells, two novel observations in severe eosinophilic asthma, which were associated with indices of disease severity and progression. This case highlights the possibility of a previously unrecognised autoimmune-mediated worsening of asthma perhaps triggered by immune complexes formed due to inadequate dosing of administered monoclonal antibodies in the target tissue.ConclusionsWhile anti-IL5 mAb therapy is an exciting novel option to treat patients with severe asthma, there is the rare possibility of worsening of asthma as observed in this case study, due to local autoimmune mechanisms precipitated by potential inadequate airway levels of the monoclonal antibody.Electronic supplementary materialThe online version of this article (doi:10.1186/s13223-016-0174-5) contains supplementary material, which is available to authorized users.

Sputum autoantibodies in patients with severe eosinophilic asthma

“…To detect immunoglobulin reactivity in sputum, cell-free soluble fractions of processed sputum supernatants were subjected to immunoprecipitation (IP) with Protein A/G beads to generate IP-Igs, as described recently. 17 Anti-EPX reactivity was assessed by using an indirect ELISA 17 developed in house and expressed as absorbance at 600 nm (Abs 600 ) after background correction. An ANA Line Immunoassay strip (IMTEC-ANA-LIA-Maxx; Human Worldwide, Weisbaden, Germany) was adapted for detecting sputum ANAs by using the manufacturer's protocol (except for the initial step, where 100 mL of sputum supernatant was incubated overnight at 48C with 700 mL of diluent).…”

Immunological and hematological effects of IL‐5(Rα)‐targeted therapy: An overview

“…Still, it was speculated that in a certain group of patients with steroid unresponsive asthma, the fixed lower concentration of mepolizumab (100 mg) might be insufficient to reduce the number of eosinophils in the tissues. It was even speculated based on preliminary studies that this low concentration might lead to formation of immune complexes between IL‐5 and mepolizumab potentially activating tissue eosinophils . It was indeed found that lower concentrations of antibody were associated with lower reduction of both circulating and tissue eosinophils (Pavord et al 2012 Table ) .…”

“…One of the key questions is whether eosinophils that remain in the body during IL‐5‐targeted therapy are an intrinsically different nonresponsive subset or residual “normal” cells, supporting the view that IL‐5 is not critical in human eosinophilopoiesis. A third possibility is that residual eosinophils are found because of under dosing of the monoclonal antibodies such as recently suggested . To gather translational data on IL‐5 inhibition: A systemic literature search in PubMed was performed on October 2017 with the following query: (mepolizumab OR nucala OR reslizumab OR benralizumab OR cinqaero OR “anti‐il‐5” OR “anti‐il‐5r” OR “anti il‐5” OR “anti il 5” OR “anti interleukin 5” OR “anti‐interleukin 5” OR “anti‐interleukin‐5”).…”

Airway Inflammation and Inflammatory Biomarkers

“…27 Blood eosinophil counts that have been normalized by an anti-IL5 mAb may not reflect uncontrolled sputum eosinophilia that may be associated with poor asthma control. There is evidence that this may be a reflection of inadequate suppression of local eosinophilopoeitic processes driven, [38][39][40] by locally derived cytokines from sources such as the type-2 innate lymphoid cells (ILCs) 38,39 or local autoimmune mechanisms. 40 A raised blood eosinophil count is also not a good predictor of treatment response to anti-IL4/IL13.…”

“…There is evidence that this may be a reflection of inadequate suppression of local eosinophilopoeitic processes driven, [38][39][40] by locally derived cytokines from sources such as the type-2 innate lymphoid cells (ILCs) 38,39 or local autoimmune mechanisms. 40 A raised blood eosinophil count is also not a good predictor of treatment response to anti-IL4/IL13. 34 Wenzel et al, showed that dupilumab responders had an improvement in FEV1 and fewer exacerbations regardless of the blood eosinophil .…”