To treat organ disease and organ failure, the use of allogeneic, or non-self, transplantation tissue has become increasingly important in medicine. The use of allografts, however, is limited by the frequent rejection of the graft tissue by the recipient host, because of antigenic differences between the donor and recipient.
The antigenic differences between individual members of the same species are referred to as "alloantigens." When alloantigens are involved in rejection of allogeneic tissue grafts, they are referred to as "histocompatibility antigens." The terms "major histocompatibility antigens" and "major histocompatibility complex" (MHC) refer to the products of a single closely linked region of genes.
These MHC gene products are displayed on cell surfaces and are an important barrier to successful allotransplantation. In humans, the MHC is, by international agreement, referred to as "HLA." The individual letters in this abbreviation have a variety of meanings, including "Human Leukocyte (or Lymphocyte) Antigen" and "Histocompatibility Locus Antigen." (Carpenter, C. B., in Harrison's Principles of Internal Medicine, ed. E. Braunwald et al., (McGraw-Hill, New York, 1987, page 337.)
Graft rejection is the consequence of an immune response to the histocompatibility antigens. Allografts generally survive for a period of days to weeks. However, they subsequently become inflamed and infiltrated with lymphocytes and monocytes, and the tissue eventually becomes necrotic. In the case of a skin graft, the grafted tissue is sloughed from the skin. However, in the case of a vital organ such as the heart, the sequelae of tissue rejection can be fatal to the recipient.
Following transplant into a human, a donor heart is closely monitored for signs of graft rejection. Most commonly, rejection is monitored by biopsying the donor heart tissue. A recent study described the performance of endomyocardial biopsies on cardiac transplant recipients weekly for the first 8 weeks after transplant, every other week for the next 8 weeks, monthly for the next year, and every 3-4 months for the remainder of the patient's life. (Ahmed-Ansari, A. et al., Transplantation 45:972-978 (1988)).
The biopsied tissue is then studied histologically for indicia of tissue rejection. A grade of rejection is determined on the basis of the degree of infiltration by leukocytes. (Ahmed-Ansari et al., supra). It is believed that the infiltrating leukocytes become sensitized to MHC antigens expressed by the graft tissue.
Despite the recognition that the MHC plays a major role in the success or failure of graft survival in a host mammal, current attempts to prolong graft survival have not exploited this knowledge. The most common method of prolonging graft survival is the administration of nonspecific immunosuppressive agents such as cyclosporine or cyclosporin AR and steroids. By suppressing the recipient's general immune response, survival of the graft can be enhanced. However, long-term use of immunosuppressive agents is associated with lowered resistance of the recipient to bacterial and viral infections. Furthermore, there is evidence that cancer incidence is increased in individuals such as kidney-transplant recipients, who have been treated long-term with immunosuppressive agents.
Experimental alternatives to non-specific immunosuppression of the transplant recipient have been studied. In mouse model systems, it has been shown that culturing allograft tissue before transplantation can lead to permanent acceptance of the tissue by the recipient. (Lafferty, K. J. et al., Transplantation 22:233-234 (1976); Bowen, K. M. et al., Lancet 2:585-586 (1979)). Although the mechanism by which such culturing leads to graft acceptance is not clear, it has been suggested that such culturing leads to the elimination of dentritic cells and other antigen-presenting cells rich in class 2 antigen expression. (Bach, H. B. and Sachs, D. H., N. E. J. of Medicine, Aug. 20, 1987, 489-492).
In another method of inducing tolerance in an animal model, the recipient is first given total lymphoid radiation, followed by reconstitution of the marrow using mixed donor-recipient marrow. Prior to transplantation, the donor marrow is treated to remove T-cells, thus preventing graft-versus-host disease in the recipient. The recipient is then tolerant to donor grafts. (Ilstadt, S. T., Nature 307:168-170 (1984)). However, this technique is not applicable for clinical use, because of high dosage of whole body irradiation.
Recently, presensitization of recipients with MHC class 1 antigen which present on allograft cells is shown to have antigen-specific immunosuppressive effects against allograft cells.
Despite the significant advances in understanding the MHC, a need exists for an improved method of inducing graft tolerance in mammalian recipients, especially humans.