BOB1 as the key regulator of lymphocytic responses in CLAD – BEELINED
Chronic lung allograft dysfunction (CLAD) is the primary cause of poor-long term outcomes after lung transplantation. CLAD pathogenesis is poorly understood, and there are no effective therapies for the prevention or treatment of CLAD. It is increasingly recognised that the balance of effector and regulatory mechanisms determines lung allograft outcome favouring rejection or tolerance. We accumulated substantial evidence that lymphocyte-specific transcription co-activator BOB1 plays a crucial role in controlling this balance: 1) a decrease in the expression of BOB1 in the blood of lung recipients predicts the development of CLAD; 2) expression of BOB1 is increased in target tissues of patients with autoimmune disorders, characterised by loss of immunological tolerance; 3) high levels of BOB.1 in B cells lead to enhanced costimulatory capacities resulting in the activation of antigen-specific T-cell responses. To functionally interrogate BOB1, we have developed a series of novel small molecule BOB1 antagonists. Our data demonstrate that interference with BOB1 function elicits a selective biological response by suppressing activated effector lymphocytes without affecting regulatory. Therefore, we propose that BOB1 is a central driver of pathogenic lymphocytic responses in CLAD. Using a translational approach - analyses of primary human lung allograft tissue by single-cell RNA sequencing and imaging mass cytometry combined with functional in vitro, ex vivo and in vivo experiments with novel BOB1 inhibitors – we aim to unravel the role of BOB1 in CLAD by 1) quantification and phenotyping of BOB1-expressing lymphocytes within the lung allograft microenvironment; 2) determining if and how selective targeting of BOB.1 modulates effector and lymphocytic regulatory responses; 3) characterisation and optimisation of BOB1 antagonists for future therapeutic interventions. Collectively, this project will validate BOB1 as novel therapeutic targets for CLAD.
Madame Sophie BROUARD (Center for Research in Transplantation and Translational Immunology)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CEISAM CHIMIE ET INTERDISCIPLINARITE : SYNTHESE, ANALYSE, MODELISATION
CR2TI Center for Research in Transplantation and Translational Immunology
PHU 2 PHU 2 - Institut du Thorax et du Système Nerveux
Help of the ANR 558,902 euros
Beginning and duration of the scientific project: December 2022 - 36 Months