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Study of the CD200/CD200R pathway in the pig-to-human setting to elucidate the molecular bases of xenograft rejection and develop approaches that promote xenograft survival.

Final Activity Report Summary - PORCINE CD200 (Study of the CD200/CD200R pathway in the pig-to-human setting to elucidate the molecular bases of xenograft rejection ...)

Xenotransplantation aims to provide a therapeutic solution to many patients that suffer organ or tissue dysfunction in an unlimited fashion. However, porcine xenografts transplanted into primates are rejected by humoral and cellular responses resistant to immunosuppression. Identifying the molecular bases of xenograft rejection and developing strategies to overcome them is crucial to achieve long-term graft survival.

It has become clear that innate immunity plays a major role in the rejection processes resistant to immunosuppression, as standard treatments prevent mainly the acquired response (particularly T cells). Therefore, our main goal in the present project is to study the innate immune response in xenograft rejection, particularly the participation of the CD200 / CD200R pathway. CD200 is a transmembarane protein comprising two IgSF domains than reduces monocyte / macrophage activation through CD200R engagement. Accordingly, we have cloned and analysed the porcine CD200 and CD200R. Subsequently, we have recombinantly produced fusion proteins comprising the extracellular portion of these molecules and assessed their binding capacity to their own ligands and to the human counterparts by surface plasmon resonance.

Finally, we have overexpressed CD200 on porcine endothelial cells aiming to reduce the xenogeneic myeloid response. In summary, our objectives comprise the elucidation of the molecular bases of rejection, the development of strategies that promote engraftment at the preclinical level and the potential use of xenogeneic elements as immunotherapy, with the ultimate goal it results in clinical applications.