immunological reactions by the host that are unique to xenotransplantation. Although immunosuppressive drugs are highly effective in allotransplantation, rejection, especially late after transplantation, still occurs. In contrast, immunosuppressive agents cannot overcome certain aspects of xenograft rejection. It is largely for this reason that investigators worldwide are seeking novel therapies that can supplement the use of immunosuppression to achieve survival of xenografts. New immunosuppressive drugs will also be needed to suppress certain aspects of xenograft rejection. Xenografts of cells and tissues are the first to reach small-scale human trials because means of preventing or blunting the immune response to those transplants are being developed rapidly.

The promise of success of xenografts is derived from research on newer therapies and strategies in animals. Heart transplants from monkeys to baboons (closely related species) have survived for months—some for more than a year. These encouraging results have prompted researchers to propose human trials in which baboon hearts are envisioned as "bridges" for patients awaiting human organs (i.e., as a means of sustaining life until a human donor becomes available). Success has also been achieved with long-term survival of transplanted organs between various rodent combinations (e.g., hamster and rat), but questions remain about the applicability of results of experiments conducted in rodents to human xenografting.

Although the major problem in xenotransplantation is rejection, biochemical and physiological aspects of xenograft function are also unanswered concerns. For example, transplanted bone marrow can react with the heart to cause complications. As new agents are developed and tested, the adverse side effects of those agents will require close monitoring (see Appendix C)

Strategies to counteract human immune rejection of xenografts vary with the tissue or organ being transplanted, the disease being treated (e.g., diabetes, AIDS, or Parkinson's disease), the nature of the transplant (tissues or organs), and the phylogenetic dissimilarity between the patient and the source animal. Both tissues and organs are being modified by either immunological or genetic engineering approaches. Cells or tissues such as pancreatic islets have been encapsulated to deny access to the recipient's immune system. Whole organ xenografts between phylogenetically distant species are the most difficult because a series of new rejection mechanisms, not previously encountered in allograft rejection, must be addressed.

Stages Of The Immune Response

The immunological response to an organ xenograft can be divided into different phases, although the division is to some extent arbitrary, both because the manifestations of one can continue into, or be present in, another and because they can occur as a continuum. The first phase, hyperacute rejection,

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