Inhibition of interleukin2 activity

A variety of medical conditions exist that are caused or exacerbated by the immune system itself. These are usually treated by administering immunosuppressive agents. Examples include:

Autoimmune diseases in which immunological self-tolerance breaks down and the immune system launches an attack on self-antigens.

• Tissue/organ transplantation in which the donor is not genetically identical to the recipient (i.e. in cases other than identical twins). The recipient will mount an immune response against the transplanted tissue, culminating in tissue rejection unless immunosuppressive agents are administered.

Selective immunosuppression in individuals suffering from the above conditions is likely best achieved by preventing the synthesis or functioning of IL-2. Cyclosporin A, one of the foremost immunosuppressive agents currently in use, functions by preventing IL-2 synthesis. A number of alternative approaches are now being considered or tested directly in clinical trials. These include:

• Administration of soluble forms of the IL-2 receptor, which would complete with the native (cell surface) receptor for binding of IL-2.

• Administration of monoclonal antibodies capable of binding the IL-2 receptor. (It must be confirmed that the antibody used is not itself capable of initiating signal transduction upon binding the receptor.) See the products 'Zenapax' and 'Simulect'; Chapter 13.

• Administration of IL-2 variants that retain the ability to bind the receptor, but which fail to initiate signal transduction.

• Administration of IL-2 coupled to bacterial or other toxins. Binding of the cytokine to its receptor brings the associated toxin into intimate contact with the antigen-activated T cells (and other cells, including activated B cells), leading to the destruction of these cells. This would induce selective immunotolerance to whatever specific antigen activated the B/T cells. One product (tradename Ontak; Box 9.1) that is based upon this principle is now in general medical use.

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