PORCINE CD200 · 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.
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-01-25 → 2008-01-24
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IIF
Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Xenotransplantation aims to provide a therapeutic solution to many patients that suffer tissue or organ dysfunction. However, porcine xenografts transplanted into primates are rejected by humoral and cellular responses resistant to immunosuppression. Ident ifying the molecular bases of xenograft rejection and developing strategies to overcome them is crucial to achieve long-term graft survival. Accordingly, this proposal aims to study the role of innate immunity in this rejection process and particularly, th e interaction of porcine CD200 (pCD200) and the human CD200 receptor (hCD200R). It also seeks to develop strategies that promote CD200R signalling to prolong xenograft engraftment. It is known that engagement of hCD200R triggers inhibitory effects in cells of myeloid lineage. In this work, the main objective is to clone and sequence the pCD200 cDNA, characterize the protein and assess its binding to hCD200R. It also aims to study the expression pattern of pCD200 to compare it to the mouse and human counterp arts. The porcine and human CD200 will be expressed on porcine cells by genetic engineering to assess its effects on human immune responses in vitro using mixed cultures. The function of CD200 can be further evaluated in combination with other approaches s uch as CD86 blockade. Animal models will follow to explore its potential protective effect in vivo. To this end, I will develop pig-to-mouse cellular transplant models to evaluate the efficacy of systemic CD200Ig treatments and/or CD200 overexpression on t he porcine donor cell. The in vivo studies will focus on studying the cellular immune rejection by histologic examination and the humoral response by determining the elicited antibody titers. If these strategies prolong xenograft survival, this study will represent a step forward toward the clinical use of xenogeneic cells and tissues.
Original text from CORDIS.
Participants
- INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE · L'HOSPITALET DE LLOBREGATCoordinatorCity levelSpain
Links
Data: CORDIS, © European Union