Xenoreactive Antibody

The problem of PNXAb has been approached through various selective and nonselective techniques. Plasmapheresis, a nonselective technique for antibody removal, has been employed in xenotransplantation with some success. It has proven useful for antibody removal in human ABO-in-compatible kidney transplants and for renal transplants into highly sensitized recipients. In pig-to-primate xenotransplants, Alexandre et al. Used plasmapheresis and immunosuppression in splenectomized baboons to extend porcine renal xenograft survival, with one organ surviving 22 days. Recently, we have described the ability of plasmapheresis and immunosuppression to extend cardiac xenograft survival from one hour in untreated controls to greater than two days. When we combined plasmapheresis and immunosuppression with complement depletion, xenograft survival was extended to 17.5 days. Despite these encouraging results with plasmapheresis, it is hampered by the concomitant reduction of other plasma proteins-such as clotting factors and complement system proteins-that may be essential for the recipient. The effect of plasmapheresis on the coagulation system is likely to limit its application in the peritransplant period, since bleeding complications may result. Replacement of clotting factors with fresh frozen plasma would be hazardous, since it contains high levels of xenoreactive antibodies. Another, more selective approach to remove xenoreactive antibodies is the use of immunosorbent columns. They avoid the consequences of wholesale plasma protein removal seen with plasmapheresis. Protein A and protein G effectively remove of antibodies of the IgG and IgM isotype, and have been used successfully in a variety of clinical situations. We have recently shown that columns containing polyclonal antihuman IgG or IgM antibodies conjugated to Sepharose are extremely effective for removing antipig antibody from human plasma. However, two potential disadvantages of column technologies are their nonspecific removal of all antibodies and the potential side effects of column-dependent complement activation.

The optimal approach to selective xenoreactive antibody removal may be an extracorporeal source of target xenoantigens. The crudest application of this approach is the perfusion of a donor organ, most commonly the spleen, kidney, or liver. This approach, though effective, has several disadvantages. Organ perfusion results in the sequestration of blood volume and in the activation of the complement and coagulation cascades as the perfused organ is rapidly rejected. In addition, organ perfusion is cumbersome to perform, requiring sacrifice of a donor animal to obtain target organs. A more elegant approach to selective xenoreactive antibody removal would be to use purified or synthesized target antigens. Specific columns using human ABO blood group antigens have proved successful in removing anti-A and anti-B antibodies. Similarly columns loaded with a-gal have proven effective in recovery a-gal specific XNA and extending xenograft survival. An attractive solution to the problem of xenoreactive antibodies is to selectively prevent antibody synthesis. To date, attempts to achieve selective B cell tolerance against a-gal antigens has proven unsuccessful.

0 0

Post a comment