The humoral response to xenogeneic stimulation: Functional implications of immunoglobulin subclass
The major hurdle to transplanting porcine organs into humans is acute vascular rejection, thought to be caused by the humoral reaction of host Ab against the graft. In unsensitized individuals, this response consists mostly of Abs specific for Galα1-3Gal, a sugar expressed on the cells of lower mammals. The nature of the Ab response in individuals sensitized to porcine organs by cross perfusion, and then receiving liver transplants and immunosuppression, was studied to gain insight into humoral response which may contribute to acute vascular rejection. The anti-pig Ab response in these individuals consisted largely of IgG and IgM specific for Galα1-3Gal. These Abs activated human complement (C) on porcine cells to a significantly greater extent than anti-pig Abs from the same subjects obtained prior to cross-perfusion. The increase in C activation was disproportionate to the increase in concentration of anti-Gal Abs. The increase in C activation correlated with a shift from IgG2 to IgG1, and with an increase in avidity. These changes coincided with peak Ab levels and were sustained for at least six months. Consistent with this finding, purified human IgG1 and IgG2 anti-Gal Abs had highly disparate abilities to activate C on porcine cell surfaces. The subclass of natural anti-Gal IgG in unstimulated subjects also correlated with C activation. The IgG subclass of the anti-Gal response to xenografts may reflect the phenotype of B cells or the costimulus from T helper cells involved in such a response, and may determine the humoral-mediated tissue injury that ensues.
Yu, PB; Parker, W; Huang, WW; Platt, JL
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