The aim of this study was to deplete baboons of anti-(alpha)galactosyl (alphaGal] antibody and attempt to maintain depletion by pharmacologic immunosuppressive therapy (PI). In 12 experiments, involving nine baboons, repeated extracorporeal immunoadsorption (EIA) was carried out by plasma perfusion through immunoaffinity columns of synthetic alphaGal trisaccharide type 6. Five of the baboons were immunologically naive and four had undergone various procedures at least 6 months previously. All, however, had recovered lymphohematopoietic function and (with one exception) had levels of anti-alphaGal antibody within the normal range. Eleven protocols included continuous i.v. cyclosporine (to maintain whole blood levels of approximately 1,600 ng/ml). In addition, in ten protocols, the baboon received one or more of the following drugs: cyclophosphamide (1-20 mg/kg/day), mycophenolate mofetil (70-700 mg/ kg/day), brequinar sodium (1-12 mg/kg/day), prednisolone (1 mg/kg/day), melphalan (0.15-0.6 mg/kg/day), methylprednisolone (125 mg/day x3), and antilymphocyte globulin (ATG) (50 mg/kg/day x3). EIA was carried out on 1-9 occasions in each study and was temporarily successful in removing all antibody. When no PI was administered, antibody returned close to pre-EIA levels within 48 hr. Cyclosporine alone delayed the rate of antibody return only slightly. While EIA was continuing on a daily or alternate day schedule, antibody levels (both IgM and IgG) were maintained at 20-45% of pre-EIA levels. Once EIA was discontinued but PI maintained, IgM rose to 40-90% and IgG to 30-60% of pre-EIA levels. In vitro testing demonstrated significant cytotoxicity to pig cells at these antibody levels. We conclude that i) EIA utilizing columns of alphaGal trisaccharide is successful in temporarily depleting baboons of anti-alphaGal antibody, but ii) none of the PI regimens tested suppressed antibody production to levels which would be expected to prevent antibody-mediated rejection of pig xenografts. Additional strategies will therefore be required if xenotransplantation is to become a clinical reality.

although the number of pigs of different genotypes studied was small, on the basis of this limited study, pigs of a low alphaGal expressor genotype that could be selectively bred for use in clinical xenotransplantation were not identified.

Xenotransplantation (XTx) offers a possible solution to the severe shortage of organs for transplantation, but it will raise new legal questions. There are currently no legal impediments to XTx in the United States nor do animals possess common law or constitutional rights that would prevent it. The law remains indefinite regarding what constitutes a human being, allowing the possibility that legal arguments will be raised regarding the legal status of transgenic animals expressing human tissues or cells. As successful XTx will eliminate the organ shortage, Congress or state legislatures will have to reconsider the need for the current centralized system of allocation and distribution of organs, for this could be replaced by a commercial system based on market forces. The most significant legal issue relating to XTx is probably the potential threat to the public health and safety through the transmission of an infectious disease. The Public Health Service has recently issued draft guidelines which make recommendations about how XTx procedures might be performed. These guidelines currently have no legal authority but offer insight into how XTx might be regulated if it becomes a clinical, reality. Existing federal laws, however, empower federal agencies to regulate XTx, in part because of the potential risk to the public health. Additionally, tort liability will impose legal pressure on transplant centers to minimize the level of risk that the general public might face. The most difficult questions facing legislatures and the Public Health Service may well prove to be those raised by the behavior of individual patients or their social contacts who do not comply with the guidelines/regulations relating to long‐term monitoring for infectious complications.