PECAM-1 Targeted Therapy in Antibody-Mediated Rejection of Solid Organ Transplants – PETTAR
End-stage vital organ failure is a life-threatening condition and the leading cause of premature death worldwide. The economic burden of vital organ failure is currently estimated at 25% of total health expenditures, in rapid expansion.
Patients with end-stage vital organ failure depend on solid organ transplantation, which represents their best therapeutic option. Progress over the last decades has failed to prolong the duration of graft function because modern immunosuppressive drugs are ineffective to prevent the generation of donor-specific antibodies (DSA) directed against the allogeneic HLA molecules expressed by the graft. As a result, antibody-mediated rejection (AMR) of graft vasculature has emerged as the first cause of graft loss. Designing innovative strategies to improve the prevention of DSA generation, and the diagnosis and the treatment of AMR, therefore represents the most straightforward and achievable approach to alleviate organ shortage.
Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a cell surface protein constitutively and exclusively expressed on endothelial cells, platelets, and T and B lymphocytes, NK cells, neutrophils, monocytes and dendritic cells, i.e. all the actors involved in AMR pathophysiology. Initially described as a member of the immunoglobulin-superfamily of cell adhesion molecules, its role has been recently revisited with the discovery that its cytoplasmic tail comprises two ImmunoTyrosine-based Inhibitory Motifs (ITIM) and the demonstration that CD31 transhomophilic engagement drives inhibitory signalling. CD31 is now considered as a major inhibitory signalling receptor, responsible for key non-redundant homeostatic role in immunity and at the vessel/blood interface.
In the present project, we propose to evaluate innovative PECAM-1 Targeted Therapies in Antibody-mediated Rejection (PETTAR). CD31 indeed represents an attractive integrated molecular target in AMR since triggering its signalling could i) block B cell activation thereby preventing DSA generation, and ii) regulate concomitantly abnormal leucocyte activation, altered vascular permeability and platelet thrombosis, the later events of antibody-mediated graft destruction (and therefore cure AMR). Its biomarker potential will also be explored to improve AMR diagnosis and stratify the risk of graft loss.
PETTAR will be conducted by a consortium gathering internationally recognised experts in CD31 biology and transplant immunology, with epidemiologists and physicians involved in the management of solid organ recipients. They will follow a translational approach involving the use of both in vitro and preclinical murine model of heart transplantation (to test innovative CD31-targeted biotherapies aiming at preventing and/or curing AMR), and analyses of human samples from large cohorts of renal and heart recipients (to evaluate the possibility to use in the clinic new CD31-based biomarkers).
This ambitious collaborative project, approved by the competitiveness cluster “Lyonbiopole” is conducted by a highly synergistic consortium that has the ambition to fill the gap between fundamental and applied biomedical researches. As an illustration of its potential, the consortium has already generated a corpus of preliminary data that supports the validity of PETTAR's hypotheses and reinforces the feasibility of the whole project.
The long-term objective of the PETTAR project is to provide a CD31-based integrated strategy to improve the clinical outcomes of AMR. The success of PETTAR project will pave the way to future clinical studies — in the frame of PHRC calls — aiming at improving the management of solid organ recipients diagnosed with AMR and thereby prolonging the duration of graft function. This would not only relieve organ shortage crisis but also reduce the morbidity/mortality of transplanted patients.
Monsieur Olivier Thaunat (U1111 - International Centre for Infectiology Research (OT))
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.
Inserm U970 UMR-S970 - Paris-Centre de recherche Cardiovasculaire (AL)
Inserm U1111 U1111 - International Centre for Infectiology Research (OT)
Inserm U1148 URMS1148 - Laboratory for Vascular Translational Science (AN)
Help of the ANR 437,400 euros
Beginning and duration of the scientific project: December 2016 - 36 Months