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H2020Individual fellowship2020–2023

DABAT · DNA-sensing by AIM2 in activated B cells: novel targets to improve allogeneic haematopoietic stem cell transplantation

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2020-10-01 → 2023-09-30
EU contribution
€275,620
Participants
2
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

DNA-sensing by AIM2 in activated B cells: novel targets to improve allogeneic haematopoietic stem cell transplantation

Allogeneic haematopoietic cell transplantation (allo-HCT) is the standard therapy for several haematological cancers and diseases, with more than 30,000 allo-HCTs carried out annually worldwide. In allo-HCT, the recipient receives a new immune system to correct an immune deficiency or to cure a leukaemia. Most of the allo-HCT are performed with a donor who presents genetic disparities with the recipient. These genetic disparities activate the new immune system which attacks recipient’s organs and tissues. This process is called chronic graft-vs-host disease (cGVHD). Among immune cells, T cells are required for cGVHD to occur. However, B cells also play a central role by producing pathogenic antibodies. The therapeutic strategies currently available for cGVHD are limited and need to be improved. Our overarching hypothesis is that, after allo-HCT, tolerance checkpoints in pathological B cells are dysregulated via B cell intrinsic mechanisms. Our overarching goal is to understand intrinsic B cell pathways that drive altered B cell homeostasis post-transplantation, so that we can develop new therapeutic strategies to improve transplantation outcomes.

Data: CORDIS, © European Union

Project objective

A recent paradigm shift is that B cells are pivotal in chronic graft-versus-host-disease (cGVHD), which is the most relevant cause of late non-relapse morbidity and mortality after allogeneic haematopoietic stem cell transplantation. DABAT’s project hypothesis is that 1) DNA-sensing by AIM2 supports cGVHD pathological B cells through autocrine regulations and that 2) their DNase1L3 expression modulates DNA-sensing by AIM2. Doctor Sarantopoulos (Duke University, US, supervisor for the outgoing phase) recently performed a single cell RNA-Sequencing experiment showing that AIM2 is upregulated in cGVHD patient B cells. Upon DNA binding, the AIM2 protein induces AIM2 inflammasome formation that triggers pro-inflammatory cytokines secretion. The survival and function of pathological B cells in cGVHD seem to be based on similar mechanisms to those of marginal zone (MZ) B cells. Doctor Sisirak (Bordeaux University, France, supervisor for the incoming phase) showed that DNase1L3, a major enzyme regulating extracellular DNA exposure, could play a pivotal role in MZ B cells development. The researcher will conduct the DABAT project under the supervision of these two internationally recognized experts in cGVHD B cells and DNase1L3. He will study AIM2 and DNase1L3 in human B cells and in mouse models. This fellowship will provide him with advanced technical training in B cell studies, flow cytometry, transcriptomic, histopathology and animal handling. He could identify intrinsic molecular programs underpinning B cell pathobiology, so that agents targeting B cell can be developed to treat cGVHD. He will be the main spokesperson of the project to a large audience. This fellowship will be a crucial step to extend his knowledge, to develop his communication, management and leadership skills, and to enlarge his international professional network. He will then become a mature and independent researcher enriching EU expertise and networking in Immunology and Transplant Immunology.

Original text from CORDIS.

Participants

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Data: CORDIS, © European Union