Immune suppression in the treatment of disease

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Immune function may be suppressed to prevent organ transplant rejection which is mediated by T-cell activity. This involves the use of multiple drugs, each directed at different points in the T-cell activation cascade. They prevent T-cell activation, T-cell proliferation, and/or cytokine production. The use of combinations of agents allows the dosage of individual drugs to be reduced, thus minimizing side-effects. The targeted action of these drugs is becoming progressively more refined and specific, which also reduces side-effects.

Prevention of organ transplant rejection can be divided into three phases ( Kahan a.n..d G.hpbri.a.l 1994).

1. Induction of prophylaxis, which often involves the use of cyclosporine (cyclosporin), steroids, an antimitotic such as azathioprine, and an antilymphocyte antibody.

2. Maintenance of prophylaxis, which involves the use of cyclosporine, steroids, and an antimitotic (at lower dose).

3. Treatment of acute rejection, which involves high-dose steroids and an antilymphocyte antibody.

Immunosuppression is now a common component of management of a number of other conditions including the following.

1. Asthma: steroids and methotrexate.

2. Inflammatory bowel disease: steroids, 5-aminosalicylic acid, 6-mercaptopurine, and cyclosporine.

3. Autoimmune connective tissue diseases: methotrexate is widely used for rheumatoid arthritis.

4. Certain skin disorders: pemphigus, pemphigoid, and pyoderma gangrenosa may all be treated with steroids in combination with other drugs such as azathioprine, cyclophosphamide, methotrexate, or cyclosporine.

5. Neurological diseases: multiple sclerosis may be treated with steroids and cyclophosphamide. Immune side-effects of cytotoxic drugs

Combinations of immunomodulating drugs are used for their cytotoxic activity against malignant cells. Frequently used cytotoxic agents are listed in Table 1. As the effect is not specific against the malignant cells, immunosuppression is frequent.

Table 1 Commonly used cytotoxic agents

Drugs used for immune suppression or chemotherapy

Steroids

Steroids lyse lymphocytes and thus decrease their total number. This is a dose-dependent response; a high steroid dose will reduce the total number of lymphocytes by a maximum of 50 to 75 per cent. Steroids also block the production and release of a number of inflammatory cytokines including prostaglandins and leukotrienes. They inhibit the non-specific immune response, modulate (downregulate) expression of human MHC class II (HLA-DR), and increase the number of neutrophils.

Lymphokine synthesis inhibitors (cyclosporine, tacrolimus)

The introduction of cyclosporine dramatically changed the management of organ transplant because its specific activity results in reduced immunosuppression. However, its use is limited by nephrotoxocity. Cyclosporine and its more recent derivative tacrolimus bind to separate but related proteins in the plasma, which are known as immunophilins. These complexes interact with receptors in the T-cell cytoplasm. The T cells fail to respond to stimulation because they fail to produce interleukin 2 (IL-2) which is necessary for proliferation to occur. Cyclosporine also suppresses the development of cytotoxic T cells and interferes with the functions of antigen-presenting cells and B cells. Both cyclosporine and tacrolimus act primarily on resting T cells. Other drugs have been developed that block lymphocyte signal transduction and inhibit nucleoside synthesis.

Cytokine signal transduction inhibitors (rapamycin, leflunomide)

Rapamycin is a macrolide antibiotic similar to cyclosporine and tacrolimus in that it binds to immunophilin (although on a different site) and blocks intracellular signal transduction at a different point. It inhibits activated T and B cells and does not block IL-2 production. Tacrolimus and rapamycin can be used synergistically because they act at separate sites.

Antilymphocyte antibodies (polyclonal antithymocyte globulin, antilymphocyte globulin, or monoclonal antilymphocyte antibody)

Antilymphocyte (thymocyte) globulin (ALG/ATG) is produced by injecting human lymphocytes into animals and raising antibodies against them. T lymphocytes from the thymus are often used as these are responsible for graft rejection. The active immunoglobulin is the IgG fraction and ALG/ATG is a complex biological product that has inherent composition variability between batches. After injection the ALG/ATG attaches to circulating lymphocytes. Owing to its molecular size it is confined to the vascular space so that only circulating lymphocytes are exposed. Lymphocytes are lysed by a complement-dependent process. The antibodies may also bind to the antigen receptor sites, thus inhibiting the effect of the lymphocytes.

Monoclonal antilymphocyte antibody (OKT3) is a monoclonal mouse antibody directed against the CD3 protein complex, a cell marker found only on the cell membrane of human T cells. It binds to CD3 and probably causes complement lysis of the cell or opsonizes the cell leading to its destruction.

Antimetabolites

Purine analogs (azathioprine, 6-mercaptopurine) block synthesis of DNA/RNA and other essential cell products by interfering with purine metabolism. They prevent proliferation of lymphocytes in response to an antigenic challenge and are only active as an immunosuppressant when given after the antigen. Azathioprine is converted to 6-mercaptopurine.

When used to treat inflammatory bowel disease, 6-mercaptopurine causes bone marrow depression in 3 per cent of patients and infection in 7 per cent. Azathioprine causes profound lymphopenia in 5 per cent which can occur at any time between 2 weeks and 11 years. A marked decrease in CD4 cells may persist for several years.

Antifolate medications include methotrexate, sulfasalazine, and aminopterin. Methotrexate decreases DNA/RNA and protein synthesis (thus inhibiting cell replication), inhibits production of leukotriene B 4 (a potent chemotactic agent), decreases neutrophil and monocyte chemotactic response to leukotriene B 4, decreases production of IL-1 and C5a, inhibits neutrophil adherence (by increasing adenosine production), and lowers the production of rheumatoid factor in patients with rheumatoid arthritis

When high doses are used, drug levels may be monitored and folinic acid may be given to allow bone marrow recovery. The toxicity (but not the efficacy) of methotrexate is mediated via the dihydrofolate reductase pathways.

5-Aminosalicylic acid

5-Aminosalicylic acid inhibits the production of arachidonic acid pathway inflammatory mediators, inhibits oxygen radical production, and scavenges oxygen radicals. Gold

Gold usually lowers serum IgM and IgG levels, and occasionally causes severe IgA deficiency or hypogammaglobulinemia. Management of patients with immune suppression

Overuse of antibiotics should be avoided as these predispose to infections with fungi and resistant organisms. Appropriate use of antibiotics is important, and protocols for prophylactic antibiotics should be followed. Prophylaxis against fungal infection with oral and nasogastric nystatin or low-dose intravenous amphotericin

B (10 mg/day) may be used. Prophylaxis against Pneumocystis carinii and cytomegalovirus may also be used.

Infective complications can be difficult to diagnose in the immunocompromised patient. The temperature may not rise in the patient on steroids or the neutropenic patient, or the leukocytes may already be elevated by steroid use. Infection must be suspected if the patient's condition deteriorates, although there are often many possible causes for this in the postoperative organ recipient. Any deterioration suspected to be due to bacterial infection should be rapidly treated with broad-spectrum antibiotics after appropriate cultures have been taken, as infection can be rapidly progressive. Opportunistic organisms must be sought, including cytomegalovirus, P. carinii, Legionella pneumophila, and Epstein-Barr virus when clinically relevant.

More than 80 per cent of transplant recipients develop at least one infection after transplantation, and 40 per cent of deaths are due to infectious complications. About 55 per cent of post-transplant infections are caused by bacteria, 30 per cent are viral, and 15 per cent are fungal. Certain infections tend to occur at particular times after transplantation. The most common viral infection is cytomegalovirus, but the other herpes viruses (Epstein-Barr, herpes simplex, and varicella zoster) also occur. Symptomatic cytomegalovirus infection is associated with intense immune suppression, and particularly with the use of antithymocyte globulin. Candida albicans is the most common fungal infection. P. carinii pneumonia has become less of a problem since the routine use of prophylaxis with trimethoprim-sulfamethoxasole.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic factor that plays a central role in precursor cell proliferation and differentiation into neutrophils

(D§m.e.t.ri 1995). As well as increasing neutrophil numbers, it increases activity including chemotaxis, superoxide generation, bactericidal function, and phagocytic activity. The most extensively studied clinical application of G-CSF has been in chemotherapy-induced myelosuppression during the treatment of non-myeloid tumors. Its prophylactic use has been shown to reduce the duration of severe neutropenia, the incidence of febrile neutropenic episodes, the overall duration of intravenous antibiotic therapy, and the length of hospital stay. G-CSF is well tolerated; the most frequently reported adverse side-effect is mild to moderate bone pain.

Immunoglobulin administration may be of use for acquired hypogammaglobulinemia. Human cytomegalovirus immunoglobulin reduces the rate of severe cytomegalovirus-associated disease in patients undergoing orthotopic liver transplantation. However, it is not effective when the donor is cytomegalovirus positive and the recipient is cytomegalovirus negative, which suggests a need for additional prophylaxis in this high-risk group.

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