Organ transplantation has changed the lives of hundreds of thousands of patients. In fact, it is the success of transplantation that has led to its major limitation-there simply are not enough organs to meet the demand. Thus, researchers are looking for alternative sources of organs for transplantation. A strategy thought likely to succeed is the use of animal organs to replace failed human organs, a process known as xenotransplantation. Recent developments in genetic engineering and cloning technology have raised hopes that xenotransplantation will become a successful treatment within the next few decades. The pig is the animal felt to be the most appropriate source of organs in this regard. Extracorporeal liver perfusion (ECLP) has been suggested as one of the first applications of a vascularized porcine organ for the treatment of a patient. ECLP is felt to be a reasonable first choice because patients in fulminant liver failure have a lifethreatening condition and do not have alternative temporary means of support. In addition, ECLP could be used before long-term survival of vascularized organs has been achieved in a primate model as ECLP has been shown to provide hepatic support over a short period of time that is well within the current expected survival of vascularized porcine organs in primates. One of the barriers preventing the application of ECLP is the loss of erythrocytes that occurs when human blood perfuses a porcine liver. Further investigation has demonstrated that porcine Kupffer cells are responsible for the destruction of the human erythrocytes by a mechanism involving Kupffer cell surface protein receptor recognition of foreign human sugar molecules. Such sugar recognizing proteins are called lectins. Sialic acid has been identified as a component of the carbohydrate ligand being recognized and porcine annexins I, II and IV have been identified as potential lectin receptors responsible for the binding.
Specific aims 1 and 2 propose to identify the exact sugars being recognized and to evaluate the role of porcine annexins as the receptor responsible for binding human erythrocytes.
Specific aim 3 proposes to use this new information to design a substance that will prevent the loss of human erythrocytes during liver xenoperfusion and to test this substance in a pre-clinical model of extracorporeal porcine liver perfusion. This work will advance our understanding of macrophage recognition of foreign sugars from other species and make ECLP a more useful tool in treating fulminant hepatic failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066160-02
Application #
7120634
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Serrano, Jose
Project Start
2005-09-09
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$271,719
Indirect Cost
Name
University of Toledo
Department
Urology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
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Ekser, Burcin; Burlak, Christopher; Waldman, Joshua P et al. (2012) Immunobiology of liver xenotransplantation. Expert Rev Clin Immunol 8:621-34
Brock, L G; Delputte, P L; Waldman, J P et al. (2012) Porcine sialoadhesin: a newly identified xenogeneic innate immune receptor. Am J Transplant 12:3272-82
Pierson 3rd, Richard N; Dorling, Anthony; Ayares, David et al. (2009) Current status of xenotransplantation and prospects for clinical application. Xenotransplantation 16:263-80