Immunosuppressive agents monoclonal antibodies

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Contraindications Concurrent use of immunosuppressive agents, hypersensitivity to any murine or humanized monoclonal antibody preparation... 

The major classes of immunosuppressive drugs employed in clinical practice to avoid tissue rejection include calcineurin inhibitors, target of rapamycin (TOR) inhibitors, sphingosine-1 -phosphate receptor (S1P-R) modulators, cytotoxic agents, glucocorticoids and monoclonal antibodies. These drugs need to be used on a lifelong basis and have major undesirable side effects. 

The monoclonal antibodies used as immunosuppressive agents in tissue transplantation include muromonoab-CD3, daclizumab and basiliximab. Muromonoab-CD3 binds to a specific site on CD3 receptors and interferes with the ability of the TCR to bind the antigen and also inhibits CD3 receptor-dependent signal transduction mechanisms, all of which result in immune suppression. Both daclizumab and basiliximab are monoclonal antibodies directed against IL-2 receptors and consequently inhibit IL-2-dependent responses after tissue transplantation, resulting in immune suppression. The monoclonal antibodies used as immunosuppressive agents are described in detail in Chapter 5. 

Alemtuzumab (campath-lH) is a humanized monoclonal antibody specific for the CDw52 antigen, present on cell membranes of lymphocytes and monocytes. It has been used for treatment of patients with rheumatoid arthritis and vasculitis, is being investigated for the treatment of chronic lymphocytic leukemia, and has been used to deplete circulating lymphocytes in patients with multiple sclerosis (1). In 2001, alemtuzumab was approved in Europe for the treatment of chronic B cell lymphocytic leukemia that had been treated previously with alkylating agents and was refractory to fludarabine (2). It has also been used for induction of immunosuppression/tolerance in liver transplant recipients (3,4) and kidney/pancreas transplant recipients (5). 

The interaction of indometacin with the immunosuppressive agent muromonab, a monoclonal antibody to CDS, is characterized by an increased risk of encephalopathic or psychotic features (71). 

In the two decades since they were first described by Kohler and Milstein monoclonal antibodies have proved to be invaluable tools for research, not only in immunology, but also in many aspects of biomedical research. Monoclonal antibodies revolutionized lymphocyte biology by permitting the precise characterization of cell surface molecules which until that time were ill-defined by polyclonal sera. To date numerous mAbs have been used in animal models as either immunosuppressants or agents to induce tolerance. It may therefore come as some surprise to the reader that since their inception onty two mAbs have been licensed fiar this purpose in humans. 

Later we shall review the extensive literature that exists for monoclonal antibody therapy in animal models both as immunosuppressants and agents to induce antigen-spedfic immunological tolerance and yet, as already stated, only mAbs to CDS and CD25 (IL-2 receptor) are licensed for transplantation in humans. These two targets for therapy may not even be the best choices based on experimental data, so why have they had such relative success ... 

Disease unresponsive to conventional therapy can be treated with cytolytic agents or monoclonal antibodies (discussed later), but data are limited to small series and anecdotal case reports. Before discussing these novel approaches, we will briefly discuss the salient aspects of the conventional immunosuppressive and cytotoxic agents used to treat WG and AAV. 

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