Targeted Interleukin-9 delivery in pulmonary hypertension: Comparison of immunocytokine formats and effector cell study.

Abstract

Pulmonary hypertension (PH) is accompanied by pulmonary vascular remodelling. By targeted delivery of Interleukin-9 (IL9) via the immunocytokine F8IL9, beneficial effects could be demonstrated in a mouse model of PH. This study aimed to compare two immunocytokine formats (single-chain Fv and full IgG) and to identify potential target cells of IL9. The Monocrotaline mouse model of PH (PH, n= 12) was chosen to evaluate the treatment effects of F8IL9F8 (n= 12) and F8IgGIL9 (n= 6) compared with sham-induced animals (control, n= 10), the dual endothelin receptor antagonist Macitentan (MAC, n= 12) or IL9-based immunocytokines with irrelevant antigen specificity (KSFIL9KSF, n= 12; KSFIgGIL9 n= 6). Besides comparative validation of treatment effects, the study was focused on the detection and quantification of mast cells (MCs) and regulatory T cells (Tregs). There was a significantly elevated systolic right ventricular pressure (104± 36 vs. 45± 17 mmHg) and an impairment of right ventricular echocardiographic parameters (RVbasal: 2.52± 0.25 vs. 1.94± 0.13 mm) in untreated PH compared with controls (p< 0.05). Only the groups treated with F8IL9, irrespective of the format, showed consistent beneficial effects (p< 0.05). Moreover, F8IL9F8 but not F8IgGIL9 treatment significantly reduced lung tissue damage compared with untreated PH mice (p< 0.05). There was a significant increase in Tregs in F8IL9-treated compared with control animals, the untreated PH and the MAC group (p< 0.05). Beneficial treatment effects of targeted IL9 delivery in a preclinical model of PH could be convincingly validated. IL9-mediated recruitment of Tregs into lung tissue might play a crucial role in the induction of anti-inflammatory and anti-proliferative mechanisms potentially contributing to a novel disease-modifying concept.