C
Immunosuppression in Allotransplantation

This appendix is based on the workshop presentation of Barry Kahan and is included here to provide the reader with background information about the key features considered in developing new immunosupressive drugs or therapies. Many new immunosuppressive medications have been developed in the past two decades for the treatment of graft rejection in allotransplantation. These medications attenuate or abolish the immune reactions responsible for rejection. The new generation of immunosuppressive drugs has significantly prolonged graft survival of kidneys, livers, hearts, and heart–lungs, among others.

The ideal immunosuppressive drug has four features: it is capable of selectivity, synergy, and specificity, and it can overcome sensitization of the recipient to the transplant. These features are described below, and examples of medication in use or under development are given. Although no single immunosuppressive is ideal, and all result in serious side effects, allograft recipients often are treated successfully with combinations of different immunosuppressive drugs.

Selectivity is achieved when the immunosuppressive's effects are restricted to the immune system, as opposed to other systems of the body. For two decades, corticosteroids and azathioprine were the mainstays of treatment for allograft rejection, but they are nonselective. Corticosteroids are anti-inflammatory agents with ubiquitous effects on musculoskeletal, endocrine, gastrointestinal, and other systems. Azathioprine is slightly more selective, but it too has deleterious hematological and gastrointestinal effects. As a nucleoside synthesis inhibitor, azathioprine acts to block cell proliferation. Lymphocytes are more vulnerable than other dividing cells, but azathioprine's



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--> C Immunosuppression in Allotransplantation This appendix is based on the workshop presentation of Barry Kahan and is included here to provide the reader with background information about the key features considered in developing new immunosupressive drugs or therapies. Many new immunosuppressive medications have been developed in the past two decades for the treatment of graft rejection in allotransplantation. These medications attenuate or abolish the immune reactions responsible for rejection. The new generation of immunosuppressive drugs has significantly prolonged graft survival of kidneys, livers, hearts, and heart–lungs, among others. The ideal immunosuppressive drug has four features: it is capable of selectivity, synergy, and specificity, and it can overcome sensitization of the recipient to the transplant. These features are described below, and examples of medication in use or under development are given. Although no single immunosuppressive is ideal, and all result in serious side effects, allograft recipients often are treated successfully with combinations of different immunosuppressive drugs. Selectivity is achieved when the immunosuppressive's effects are restricted to the immune system, as opposed to other systems of the body. For two decades, corticosteroids and azathioprine were the mainstays of treatment for allograft rejection, but they are nonselective. Corticosteroids are anti-inflammatory agents with ubiquitous effects on musculoskeletal, endocrine, gastrointestinal, and other systems. Azathioprine is slightly more selective, but it too has deleterious hematological and gastrointestinal effects. As a nucleoside synthesis inhibitor, azathioprine acts to block cell proliferation. Lymphocytes are more vulnerable than other dividing cells, but azathioprine's

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--> effects do extend beyond the immune system. Corticosteroids and azathioprine have played important roles in nonselective immunosuppression, but they are now rarely used alone because of significant short-term and long-term effects. The ideal immunosuppressive drug should affect not all, but only a distinct subset, of factors in the immune system. Without a high degree of selectivity, an immunosuppressive can destroy much of the recipient's immune system, rendering the patient vulnerable to infection. About 80 percent of transplant recipients suffer from at least one infection, and 40 percent of transplant deaths are attributable to infectious complications of immunosuppression. The risks of immunosuppression can be alleviated by agents that achieve a high degree of selectivity. A new class of highly selective immunosuppressives has revolutionized allotransplantation since the early 1980s. This class of drugs, called anticytokines, interferes with the T-cell response by disrupting cytokine production. The first available anticytokine was cyclosporine, which has twice the effectiveness of azathioprine in extending kidney allograft survival. Cyclosporine inhibits T-cells from producing cytokines, such as interleukin-2, which are the intercellular signals that lead to stimulation of other immune cells to attack the graft. Cyclosporine binds to a protein in the cytoplasm of T-cells to form a complex that eventually blocks a DNA-binding protein necessary for transcription of cytokine-encoding genes. A drug similar to cyclosporine, yet even more potent, is tacrolimus (formerly known as FK506). Tacrolimus disrupts T-cell function by also binding to a cytoplasmic protein and eventually blocking production of cytokines (although the cytoplasmic protein is not the one to which cyclosporine binds). There are major side effects: nephrotoxicity occurs in approximately 30–40 percent of patients; neurological damage can occur; and over the long term, neoplasms also occur in many patients. Tacrolimus has been effective in preventing rejection of liver, kidney, heart, bone marrow, small bowel, pancreas, lung, and skin transplants. It is generally used in conjunction with corticosteroids. Another drug in this class is serolimus (also called rapamycin). Although still in clinical trials, it has proven effective in studies of allografting in animals by prolonging survival of rat heart, kidney, and small bowel transplants, among others. It acts not by inhibiting cytokine synthesis, but rather by interfering with intracellular signal transduction. Cytokine is still produced, but T-cells cannot respond to the cytokine signal by clonal expansion. The reason is that serolimus inhibits the G1 buildup needed for the mitotic phase of the cell cycle (Kahan and Ghobrial, 1994). Not only is serolimus a very selective immunosuppressive, it is also an example of a drug that works synergistically with other drugs. Synergy is the second of the four ideal features of an immunosuppressive. It refers to the combined action of two drugs whose joint effect is greater than the sum of

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--> each. In experiments on rodents and dogs the combination of serolimus and cyclosporine is so synergistic that the individual doses can be reduced at least threefold. Similar results have been achieved in human clinical trials. Reducing the dose of cyclosporine is extremely desirable because it decreases the risk of toxic side effects, including renal dysfunction, hypertension, tremor, and hirsutism. Cyclosporine and other immunosuppressives also carry the long-term risk of lymphoma. Specificity, the third key feature of an immunosuppressive, means that the therapeutic agent is directed at a particular foreign antigen. An immunosuppressive with high specificity is one that diminishes the immune response to the graft antigen but does not diminish the immune response to other antigens such as those on viruses, bacteria, and other foreign invaders. To develop a selective immunosuppressive, the graft epitope must be identified, which represents a major challenge in drug discovery. For example, xenotransplant research has identified the terminal galactose on surface glycoproteins as the determinant of hyperacute rejection and MHC (major histocompatibility complex) Class I and II (and others) as determinants of acute rejection of both allo- and xenografts (described in Chapter 2). Identification of the epitopes of these antigens has led to the development of specific immunosuppressives that modify or abolish the donor antigen. The term ''selective immunosuppression" is somewhat of a misnomer in this context because these strategies do not alter the host immune system; rather, they involve alteration of the graft to prevent an immune response by the host. Strategies that alter the graft are described in more detail in Chapter 2. Overcoming sensitization of the recipient to the transplant is the final feature of an ideal immunosuppressive agent. Immune sensitization either occurs naturally, through preformed antibodies, or is acquired. In acquired sensitization, a second exposure to an antigen results in a more rapid and robust immune response. Either natural or acquired sensitization can lead to graft rejection and generally requires treatment with increased doses of immunosuppressives. However, increasing the dose also increases the risks of side effects. None of the available immunosuppressives effectively treats sensitization. In fact, one of the immunosuppressives in use today, OKT3, is itself subject to sensitization by the host immune system. OKT3 is a mouse monoclonal antibody directed at the CD3 antigen on host T-cells. This drug is designed to deter T-cell activation by blocking T-cell binding to antigen-presenting cells. T-cells have numerous surface markers, such as CD3, that contribute to the formation of a receptor that must bind to antigen-presenting cells before recognition and activation can occur. All antibody medications derived from animal cell lines have the potential to elicit host sensitization because of foreign epitopes. Recent advances in molecular biology have enabled scientists to "humanize" animal antibodies that could result in no, or

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--> at least decreased, sensitization of the host's immune system to antibody medication. In summary, the ideal immunosuppressive medication selectively abolishes host immune response to the graft, without altering host ability to react to other antigens; it is synergistic with combinations of medications allowing reduction in dosage and thereby reducing side effects; it is specific for graft antigens but not for undesirable antigens from infectious agents; and it overcomes the problem of host sensitization. These goals underlie research on the identification of new, less toxic immunosuppressives.