Details

Autor(en) / Beteiligte

• Heiss, Judith
• Grün, Katja
• Tempel, Laura
• Matasci, Mattia
• Schrepper, Andrea
• Schwarzer, Michael
• Bauer, Reinhard
• Förster, Martin
• Berndt, Alexander
• Jung, Christian
• Schulze, P. Christian
• Neri, Dario
• Franz, Marcus

Titel

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

Ist Teil von

• European journal of clinical investigation, 2023-03, Vol.53 (3), p.e13907-n/a

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2023

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Aims 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. Methods 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). Results 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). Conclusions 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. Administration of the immunocytocine F8IL9 in mice induced with pulmonary hypertension enables a targeted transfer of IL9 into the inflamed lung tissue. Beneficial effects on PH severity were associated with a recruitment of regulatory T cells into the lung.