Immunosuppressive antibodies

Immunosuppressant antibodies continue to gain acceptance as a method for preventing rejection of transplanted tissues and for treating various autoimmune diseases.17,47 For more information on the use of specific antibodies in specific disorders, please refer to other sources on this topic.17,41,47,56... 

The potential for tumour formation in patients after treatment with immunosuppressive antibodies must be evaluated. However, the issue is not carcinogenesis per se such antibodies do not cause tumours, they allow nascent tumours to become expressed. Hence, this is a host defence issue which may be addressed using models of tumour rejection. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

Inhibition of immunomodulatory cytokines (Fig. 1) Anti-T-cell receptor antibodies Muromonab (OKT3, Orthoclone ) binds to the CD3 complex of the T-cell receptor and induces depletion of T-lymphocytes. It is applied to prevent acute rejection of kidney, liver, and heart allografts. Rapid side effects (within 30-60 min) include a cytokine release syndrome with fever, flu-like symptoms, and shock. Late side effects include an increased risk of viral and bacterial infections and an increased incidence of lymphproliferative diseases due to immunosuppression. 

Humanized recombinant anti-IL-2 receptor antibodies (Basiliximab, Simulect , and Daclizumab Zenapax ). These antibodies bind with high affinity to the IL-2 receptor on T-lymphocytes and prevent activation and clonal expansion of anti-allograft T-lymphocytes by endogenous IL-2. They are used to prevent kidney allograft rejection. The main side effect is immunosuppression. 

Murine monoclonal antibodies reacting with CD4, which is solely located on T-helper lymphocytes and monocytes/macrophages, may also be suited for immunosuppression. 

Thyroid-associated ophthalmopathy (TAO) is present in 90% of patients with the classical triad of Graves disease (goiter, ophthalmopathy, dermopathy) but these features may follow independent courses and successful control of the hyperthyroidism improves TAO in less than 5% cases. Immunosuppression has been used since theories of the etiology of TAO include the presence of circulating antibodies to both thyroid and ocular muscle fibers, and of thyroglobulin-antithy-roglobulin complexes with high affinity for extraocular muscles. 

The improved short-term outcomes gained from induction therapy come with a degree of risk. By using these highly immunosuppressive agents, particularly the antilymphocyte antibodies (ALAs), muronomab-CD3 (OKT-3), and the antithymocyte antibodies, the body loses much of its innate ability to mount a cell-mediated immune response, which increases the risk of opportunistic infections and cancer.7,10... 

Treatment for PTLD is still controversial however, the most common treatment options include reduction of immunosuppression, chemotherapy,11,82 and anti-B cell monoclonal antibodies.79... 

Alemtuzumab is the antibody to the CD52 receptor present on B and T lymphocytes. The pharmacokinetics of alemtuzumab demonstrate a terminal half-life of 7 days. Alemtuzumab has shown clinical activity in the treatment of chronic lymphocytic leukemia. Severe and prolonged (6 months) immunosuppression may result, which necessitates prophylaxis with cotrimox-azole and antivirals to prevent opportunistic infections. 

Fig. 10 Multifunctional solid biodegradable PLGA nanoparticles attached to several moieties such as T-cell antibodies, magnetic resonance contrast agent (biotin-BSA-Gd-DTPA) and encapsulated immunosuppressive drug (doxorubicin). (Adapted from [48])...

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

This antibody is raised against the protein-based CD3 antigen, present on the cell surface of most T-lymphocytes. I.v. administration of (unconjugated) antibody appears to block normal functioning of such T-cells and promote their clearance from the blood. However, upon cessation of antibody administration, CD3 positive cell numbers rapidly revert to normal values. Therefore, maintenance immunosuppressives (e.g. with cyclosporine) must subsequently be restored. 

The major types of drug therapy used in IBD include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopu-rine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor-a (TNF-a) (anti-TNF-a antibodies). 

The vaccine should not be given to immunosuppressed patients (except those infected with HIV) or pregnant women. HIV-infected persons who have never had measles or have never been vaccinated should be given measles-containing vaccine unless there is evidence of severe immunosuppression. The vaccine should not be given within 1 month of any other live vaccine unless the vaccine is given on the same day (as with the MMR vaccine). Measles vaccine is indicated in all persons born after 1956 or in those who lack documentation of wild virus infection either by history or antibody titers. 

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