Related Experiment Videos
Factors in xenograft rejection
S C Robson1, J Schulte am Esch, F H Bach
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. Srobson@bidmc.harvard.edu
Annals of the New York Academy of Sciences
|July 23, 1999
Summary
Delayed xenograft rejection (DXR) remains a major hurdle in organ transplantation, characterized by endothelial cell activation and thrombosis. Understanding molecular incompatibilities in coagulation and anticoagulation pathways is key to improving xenograft survival.
Area of Science:
- Transplantation immunology
- Xenotransplantation
- Vascular biology
- Coagulation and anticoagulation
Background:
- Hyperacute rejection (HAR) mechanisms in pig-to-primate xenografts are understood, with therapies addressing complement activation and xenoreactive natural antibody (XNA) binding.
- Delayed xenograft rejection (DXR), or acute vascular rejection (AVR), causes xenograft loss within days, involving endothelial cell (EC) perturbation, XNA localization, and thrombosis.
- Molecular incompatibilities between human coagulation factors and porcine EC anticoagulants contribute to DXR.
Purpose of the Study:
- To delineate the molecular mechanisms underlying delayed xenograft rejection (DXR) in pig-to-primate xenotransplantation.
- To identify specific incompatibilities in coagulation and anticoagulation pathways that contribute to xenograft failure.
- To inform the development of novel therapeutic strategies to prolong xenograft survival.
Main Methods:
- Analysis of molecular incompatibilities between human coagulation factors and porcine endothelial cell (EC) natural anticoagulants.
- Demonstration of porcine tissue factor pathway inhibitor (TFPI) inadequacy in neutralizing human factor Xa (FXa).
- Assessment of aberrant activation of human prothrombin and FXa by porcine EC.
- Evaluation of thrombomodulin's failure to bind human thrombin and activate human protein C.
- Investigation of porcine von Willebrand factor's interaction with human platelets.
- Examination of TFPI and vascular ATPDase/CD39 activity loss post-EC activation.
Main Results:
- Porcine TFPI cannot adequately neutralize human FXa, and porcine EC aberrantly activate human prothrombin and FXa.
- Porcine thrombomodulin fails to bind human thrombin, inhibiting human protein C activation.
- Porcine von Willebrand factor's A1 domain enhances binding to human platelets, and loss of TFPI/ATPDase/CD39 activity potentiates procoagulant changes.
Conclusions:
- Molecular incompatibilities in coagulation and anticoagulation pathways significantly contribute to DXR, leading to graft infarction and loss.
- Addressing these cross-species differences through genetic and pharmacological approaches is crucial for extending xenograft survival.
- Further research into these factors will guide the development of effective strategies for clinical xenotransplantation.