(579) Integrin activation in monocytes as a novel potential test for CFTR targeted compounds in Cystic Fibrosis.

Background: Monocytes isolated from CF patients display impaired integrin activation and dependent adhesion, causing an unbalanced recruitment of phagocytes into the lung parenchyma, with exacerbated accumulation of PMNs. CF represent a novel type of leukocyte adhesion defect disease (LAD-IV), selective for monocytes, and the improvement of CFTR function by specific compounds improves LFA-1 activation (1). Then, analysis of LFA-1 activation might represent a sign of CFTR activity and can be applied to monitor the effectiveness of CFTR correcting drugs during therapy.



Methods: Peripheral venous blood samples from CF patients before and during therapy with CFTR modulators. 1) Monoclonal antibody detecting low-intermediate affinity conformational epitope of LFA-1; 2) LFA-1 activation upon chemoattractant stimulation measured by flow cytometry and adhesion assays, respectively.

Results: We analyzed monocytes from 35 CF patients treated with IVA+TEZA± ELEXA. The results show that in monocytes isolated from 21 out of 29 patients treated with IVA+TEZA+ELEXA and from 4 out of 6 patients treated with IVA+TEZA, the therapy was able to restore LFA-1 activation, and the integrin affinity measurements and the adhesion assays were reproducible. Furthermore, change in respiratory function (FEV1) is observed in all the enrolled patients but greater in those showing LFA-1 restoration, while the reduction of chloride ion concentration in sweat is entirely comparable in the two subsets.

Conclusions: We show restoration of LFA-1 activation in CF patients during therapy, and that the correction of integrin defect is correlated to FEV1 and sweat chloride ion concentration, supporting the measurement of LFA-1 activation in monocytes as a novel potential test to evaluate the clinical effectiveness of CFTR targeted compounds.

Acknowledgements: Italian FFC grants#13/2019 and 7/2021; LIFC, Associazione Veneta-Onlus, CFF Award# ASSAEL08A0.

References: 1)
Mutations of Cystic Fibrosis Transmembrane Conductance Regulator Gene Cause a Monocyte-Selective Adhesion Deficiency. Sorio C, Montresor A, Bolomini-Vittori M, Caldrer S, Rossi B, Dusi S, Angiari S, Johansson JE, Vezzalini M, Leal T, Calcaterra E, Assael BM, Melotti P, Laudanna C.Am J Respir Crit Care Med. 2016 May 15;193(10):1123-33. doi: 10.1164/rccm.201510-1922OC.PMID: 26694899