An individual mammal's immune system functions through recognition of certain cell surface proteins, some of which are termed major histocompatibility complex proteins, or MHC proteins. Additional minor histocompatibility proteins exist which can also contribute to immunological recognition events. The individual mammal's immune system recognizes its own MHC proteins, or those of its identical twin, as self and thus does not destroy its own cells or those of its identical twin. Members of the same species may share major and/or minor histocompatibility antigens, and thus an individual may not recognize the cells of another member of its species as non-self, depending on the degree of the differences between the MHC proteins of the two individuals. When an individual's immune system recognizes the cells of other members of the same species as non-self, the first individual's immune system may proceed to destroy the cells of the second individual. In humans, the major histocompatibility proteins are known as “HLA” antigens.
When tissues such as bone marrow, blood cells, or solid organs are transplanted from one individual to another, normally the recipient will recognize the donor's cells as non-self and the recipient's immune system will destroy the donor's cells as described above. For this reason, in a tissue transplantation, the recipient is normally subjected to immunosuppressive drugs and/or irradiation. However, transplantation patients are also subject to immunologic recognition in the opposite direction, that is, the donor tissue may contain immunologically competent cells which proceed to destroy the recipient's cells, a condition termed “graft-versus-host disease” or “GVHD”.
Graft-versus-host disease can develop when bone marrow, blood products, or solid organs containing immunocompetent cells are transferred from a donor to a recipient. Thus, when MHC antigenic differences exist between the donor and recipient, the recipient is at risk for the development of graft-versus-host disease. Graft-versus-host disease may also develop when there are antigenic differences between donor and recipient for the minor histocompatibility antigens. Thus, graft-versus-host disease can also develop between MHC-matched persons. Moreover, surgery patents who receive directed blood transfusion, for example, transfusion of blood from an HLA homozygous child to a heterozygous parent, may also develop graft-versus-host disease.
Current approaches to preventing graft-versus-host disease include attempts to eliminate immunocompetent donor cells, for example, by in vitro manipulation of the donor tissue. For example, immunocompetent T cells may be removed from donor bone marrow through physical separation such as by lectin agglutination, or by treatment of the bone marrow with monoclonal antibodies directed to T cells. However, use of bone marrow depleted of T cells is associated with a higher rate of graft failure, which is frequently fatal. Use of T cell depleted bone marrow grafts is also associated with an increased incidence of relapse among the recipients, particularly recipients having chronic myelocytic leukemia.
Another approach to preventing immune-mediated injury is to interrupt the complement cascade (e.g., by depleting C3 with cobra venom factor or by inhibiting the C3 convertase with recombinant soluble CR1). However, antibody depletion has unacceptable risks of over-immunosuppression (i.e., infection), and experimental studies of inhibition of the complement cascade with cobra venom factor or sCR1 show incomplete inhibition. An additional drawback to the use of cobra venom is the prospect of systemic effects due to the large amounts of vasoactive and chemotactic C3a and C5a produced.
Another common practice for inhibiting immune-mediated disorders is to subject the recipient to immunosuppressive therapy after transplantation. Such immunosuppression may occur by use of glucocorticoids, cyclosporin, methotrexate, or combinations of such drugs. However, immunosuppression also results in increased incidence of infection, and even when immunosuppressant drugs are used, immune-mediated cytotoxicity may still occur.
Although many approaches to controlling immune-mediated disorders have been attempted, none of these approaches have been particularly successful. Thus there remains a need for an effective, clinically applicable means of preventing or treating GVHD and CTL- and/or complement-dependent rejection of organ or tissue transplants.