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CLINICAL USES OF IMMUNOSUPPRESSIVE DRUGS
Immunosuppressive agents are commonly used in two clinical cir-cumstances: transplantation and autoimmune disorders. The agents used differ somewhat for the specific disorders treated (see specific agents and Table 55–1), as do administration schedules. Because autoimmune disorders are very complex, optimal treatment sched-ules have yet to be established in many clinical situations.
In organ transplantation, tissue typing—based on donor and recipient histocompatibility matching with the human leukocyte antigen (HLA) haplotype system—is required. Close histocompat-ibility matching reduces the likelihood of graft rejection and may also reduce the requirements for intensive immunosuppressive therapy. Prior to transplant, patients may receive an immunosup-pressive regimen, including antithymocyte globulin, muromonab-CD3, daclizumab, or basiliximab. Four types of rejection can occur in a solid organ transplant recipient: hyperacute, accelerated,acute, and chronic. Hyperacute rejection is due to preformedantibodies against the donor organ, such as anti-blood group anti-bodies. Hyperacute rejection occurs within hours of the transplant and cannot be stopped with immunosuppressive drugs. It results in rapid necrosis and failure of the transplanted organ. Accelerated rejection is mediated by both antibodies and T cells, and it also cannot be stopped by immunosuppressive drugs. Acute rejection of an organ occurs within days to months and involves mainly cellular immunity. Reversal of acute rejection is usually possible with general immunosuppressive drugs such as azathioprine, myco-phenolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclo-phosphamide, methotrexate, and sirolimus. Recently, biologic agents such as anti-CD3 monoclonal antibodies have been used to stem acute rejection. Chronic rejection usually occurs months or even years after transplantation. It is characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving both cellular and humoral immunity. Chronic rejection is treated with the same drugs as those used for acute rejection.
Allogeneic hematopoietic stem cell transplantation is a well-established treatment for many malignant and nonmalignant dis-eases. An HLA-matched donor, usually a family member, is located, patients are conditioned with high-dose chemotherapy or radiation therapy, and then donor stem cells are infused. The con-ditioning regimen is used not only to kill cancer cells in the case of malignant disease, but also to totally suppress the immune system so that the patient does not reject the donor stem cells. As patients’ blood counts recover (after reduction by the conditioning regimen) they develop a new immune system that is created from the donor stem cells. Rejection of donor stem cells is uncommon, and can only be treated by infusion of more stem cells from the donor.
Graft-versus-host disease, however, is very common, occurring in the majority of patients who receive an allogeneic transplant. Graft-versus-host disease occurs as donor T cells fail to recognize the patient’s skin, liver, and gut (usually) as self and attack those tissues. Although patients are given immunosuppressive therapy (cyclosporine, methotrexate, and others) early in the transplant course to help prevent this development, it usually occurs despite these medications. Acute graft-versus-host disease occurs within the first 100 days, and is usually manifested as a skin rash, severe diar-rhea, or hepatotoxicity. Additional medications are added, invari-ably starting with high-dose corticosteroids, and adding drugs such as mycophenolate mofetil, sirolimus, tacrolimus, daclizumab, and others, with variable success rates. Patients generally progress to chronic graft-versus-host disease (after 100 days) and require ther-apy for variable periods thereafter. Unlike solid organ transplant patients, however, most stem cell transplant patients are able to eventually discontinue immunosuppressive drugs as graft-versus-host disease resolves (usually 1–2 years after their transplant).
The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoim-mune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto’s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myo-pathy, scleroderma, and certain other autoimmune states.
Immunosuppressive therapy is utilized in chronic severe asthma, where cyclosporine is often effective and sirolimus is another alternative. Omalizumab (anti-IgE antibody) has been approved for the treatment of severe asthma (see previous section). Tacrolimus is currently under clinical investigation for the man-agement of autoimmune chronic active hepatitis and of multiple sclerosis, where IFN-β has a definitive role.
The development of agents that modulate the immune response rather than suppress it has become an important area of pharma-cology. The rationale underlying this approach is that such drugs may increase the immune responsiveness of patients who have either selective or generalized immunodeficiency. The major poten-tial uses are in immunodeficiency disorders, chronic infectious diseases, and cancer. The AIDS epidemic has greatly increased interest in developing more effective immunomodulating drugs.
The cytokines are a large and heterogeneous group of proteins with diverse functions. Some are immunoregulatory proteins syn-thesized within lymphoreticular cells and play numerous interact-ing roles in the function of the immune system and in the control of hematopoiesis. The cytokines that have been clearly identified are summarized in Table 55–2. In most instances, cytokines medi-ate their effects through receptors on relevant target cells and appear to act in a manner similar to the mechanism of action of hormones. In other instances, cytokines may have antiprolifera-tive, antimicrobial, and antitumor effects.
The first group of cytokines discovered, the interferons (IFNs), were followed by the colony-stimulating factors. The latter regulate the proliferation and differen-tiation of bone marrow progenitor cells. Most of the more recently discovered cytokines have been classified as interleukins (ILs) and numbered in the order of their discovery. Cytokines are produced using gene cloning techniques.
cytokines (including TNF-α, IFN-γ, IL-2, granulocyte
colony-stimulating factor [G-CSF], and granulocyte-macrophage
colony-stimulating factor [GM-CSF]) have very short serum half-lives (minutes).
The usual subcutaneous route of administration provides slower release into the
circulation and a longer duration of action. Each cytokine has its own unique
toxicity, but some toxicities are shared. For example, IFN-α, IFN-β, IFN-γ, IL-2, and
all induce fever, flu-like symptoms, anorexia, fatigue, and malaise.
Interferons are proteins that are currently grouped into three families: IFN-`, IFN-a, and IFN-f. The IFN-α and IFN-β fami-lies comprise type I IFNs, ie, acid-stable proteins that act on the same receptor on target cells. IFN-γ, a type II IFN, is acid-labile and acts on a separate receptor on target cells. Type I IFNs are usually induced by virus infections, with leukocytes producing IFN-α. Fibroblasts and epithelial cells produce IFN-β. IFN-γ is usually the product of activated T lymphocytes.
IFNs interact with cell receptors to produce a wide variety of effects that depend on the cell and IFN types. IFNs, particularly IFN-γ, display immune-enhancing properties, which include increased antigen presentation and macrophage, NK cell, and cytotoxic T-lymphocyte activation. IFNs also inhibit cell prolifera-tion. In this respect, IFN-α and IFN-β are more potent than IFN-γ. Another striking IFN action is increased expression of MHC molecules on cell surfaces. While all three types of IFN induce MHC class I molecules, only IFN-γ induces class II expres-sion. In glial cells, IFN-β antagonizes this effect and may, in fact, decrease antigen presentation within the nervous system.
IFN-α is approved for the treatment of several neoplasms, including hairy cell leukemia, chronic myelogenous leukemia,malignant melanoma, and Kaposi’s sarcoma, and for use in hepati-tis B and C infections. It has also shown activity as an anticancer agent in renal cell carcinoma, carcinoid syndrome, and T-cell leu-kemia. IFN-β is approved for use in relapsing-type multiple sclero-sis. IFN-γ is approved for the treatment of chronic granulomatous disease and IL-2, for metastatic renal cell carcinoma and malignant melanoma. Clinical investigations of other cytokines, including IL-1, -3, -4, -6, -10, -11, and -12, are ongoing. Toxicities of IFNs, which include fever, chills, malaise, myalgias, myelosuppression, headache, and depression, can severely restrict their clinical use.
TNF-α has been extensively tested in the therapy of various malignancies, but results have been disappointing due to dose-limiting toxicities. One exception is the use of intra-arterial high-dose TNF-α for malignant melanoma and soft tissue sarcoma of the extremities. In these settings, response rates greater than 80% have been noted.
Cytokines have been under clinical investigation as adjuvants to vaccines, and IFNs and IL-2 have shown some positive effects in the response of human subjects to hepatitis B vaccine. Denileukin diftitox is IL-2 fused to diphtheria toxin, used for the treatment of patients with CD25+ cutaneous T-cell lymphomas. IL-12 and GM-CSF have also shown adjuvant effects with vac-cines. GM-CSF is of particular interest because it promotes recruitment of professional antigen-presenting cells such as the dendritic cells required for priming naive antigen-specific T-lymphocyte responses. There are some claims that GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer.
It is important to emphasize that cytokine interactions with target cells often result in the release of a cascade of different endogenous cytokines, which exert their effects sequentially or simultaneously. For example, IFN-γ exposure increases the num-ber of cell-surface receptors on target cells for TNF-α. Therapy with IL-2 induces the production of TNF-α, while therapy with IL-12 induces the production of IFN-γ.
A more recent application of immunomodulation therapy involves the use of cytokine inhibitors for inflammatory diseases and septic shock, conditions in which cytokines such as IL-1 and TNF-α (see above) are involved in the pathogenesis. Drugs now in use or under investigation include anticytokine antibodies and soluble cytokine receptors. Anakinra is a recombinant form of the naturally occur-ring IL-1 receptor antagonist that prevents IL-1 from binding to its receptor, stemming the cascade of cytokines that would otherwise be released. Anakinra is approved for use in adult rheumatoid arthri-tis patients who have failed treatment with one or more disease-modifying antirheumatic drugs. Canakinumab is a recombinant human anti-IL-1β monoclonal antibody. It binds to human IL-1β and prevents it from binding to IL-1 receptors. Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor com-ponent (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) fused to the Fc portion of human IgG1. These molecules are indi-cated for treatment of cryopyrin-associated periodic syndromes.
Patients must be carefully monitored for serious infections or malignancies if they are also taking an anti-TNF-α drug, have chronic infections, or are otherwise immunosuppressed.
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