Abstract
There is a severe shortage of donor organs in the United States. This shortage is even more pronounced in Pediatric patients. A possible solution to this problem may be xenotransplantation using porcine organs. However, a barrier to cross-species transplantation exists in which naturally occurring antibodies bind predominantly to Galα1-3Gal, initiating a rapid and severe rejection of the porcine graft. Even though this initial rejection may be avoided by current therapies, another complication is that the presence of Galα1-3Gal stimulates the production of a very strong elicited humoral response. The initial barrier may be smaller in young patients because natural antibodies in these patients are present in only very low levels. For this reason, xenotransplantation is thought to be more feasible for young patients. However, the presence of the predominant xenogeneic antigen, Galα1-3Gal, poses a threat even in pediatric patients, as it may stimulate the production of elicited antibodies. One possible way to alleviate the humoral barrier posed by xenotransplantation is to use pigs which possess very little Galα1-3Gal recognized by natural human antibodies. Such pigs have been found to exist naturally. Although very little antibody binds to the cells of“low-antigen” pigs, the cells were found to express normal levels of Galα1-3Gal. The mechanism underlying this surprising observation was explored using an enzyme linked dot blot assay and photodensiometric scanning to determine binding of human natural antibodies and lectins to porcine cells. Using this assay, xenoreactive IgM showed greater binding to“high-antigen” cells than low-antigen cells, while the lectin GS-I-B4, which is specific for Galα1-3Gal, bound to high-antigen cells the same as to low-antigen cells. When low-antigen platelets were digested with neuraminidase followed by β-galactosidase, greater binding to low-antigen platelets was seen, suggesting that other non-antigenic carbohydrates may hinder antibody binding to low-antigen porcine cells. The reduced immunologic response to low-antigen organs may be attributed in some degree to the arrangement of the determinant on the organ rather than a reduced amount of antigen. This information may be used to specifically modify porcine organs by transgenic technology which is already available.
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