Antibody-mediated injury and rejection of kidney xenografts

Antibodies provide the most difficult barriers to xenotransplantation of the kidney. Polyreactive natural antibodies, present in all immunocompetent individuals, can bind to ischemic cells, activating the complement system, and such binding has been implicated in ischemia-reperfusion injury. Natural antibodies specific for carbohydrate antigens such as anti-blood group or anti-Gal(alpha 1-3)Gal can bind to a xenograft, causing hyperacute rejection or early antibody-mediated rejection. The elimination of carbohydrate targets of these antibodies is one thrust of genetic engineering of pigs. Antibodies generated in germinal center reactions particularly directed at polypeptide antigens are produced three or more weeks after initial exposure to foreign antigens and often have high affinity and pathogenicity. After do novo production, these antibodies cause antibody-mediated rejection. In xenotransplantation, production of the antibodies is suppressed by administration of antibodies that disrupt CD40-CD40L interaction. The capacity to produce antibodies against polypeptide antigens can be maintained over long periods of time (years or decades) by memory B cells and long-lived plasma cells. Antibodies produced by such memory responses can be present or rapidly evoked at the time of transplantation, causing hyperacute rejection or early antibody-mediated rejection, respectively. Antibody products of memory responses referred to as "presensitization" pose a significant hurdle in allotransplantation; the significance of that hurdle in xenotransplantation (denoted in gray) is unknown.