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Clinical studies have shown this approach to be effective in humans. LAK cells originally purified from a patient’s own blood, activated in vitro using IL-2 and reintroduced into the patient along with more IL-2, promoted complete tumour regression in 10% of patients suffering from melanoma or renal cancer. Partial regression was observed in a further 10-25% of such patients. Administration of high doses of IL-2 alone could induce similar responses but significant side-effects were noted (discussed later).
IL-2-stimulated cytotoxic T cells appear even more efficacious than LAK cells in promoting tumour regression. The approach adopted here entails removal of a tumour biopsy, followed by isolation of T lymphocytes present within the tumour. These tumour-infiltrating lymphocytes (TILs) are cytotoxic T lymphocytes that apparently display a cell surface receptor that specifically binds the tumour antigen in question. They are thus tumour-specific cells. Further activation of these TILs by in vitro culturing in the presence of IL-2, followed by reintroduction into the patient along with IL-2, promoted partial/full tumour regression in well over 50% of treated patients.
Further studies have shown additional cancer types, most notably ovarian and bladder cancer, non-Hodgkin’s lymphoma and acute myeloid leukaemia, to be at least partially responsive to IL-2 treatment. However, a persistent feature of clinical investigations assessing IL-2 effects on various cancer types, is variability of response. Several trials have yielded conflicting results and no reliable predictor of clinical response is available.
IL-2 and infectious diseases
Although antibiotics have rendered possible medical control of various infectious agents (mainly bacterial), numerous pathogens remain for which no effective treatment exists. Most of these pathogens are non-bacterial (e.g. viral, fungal and parasitic, including protozoan). In addition, the over-use/abuse of antibiotics has hastened the development of antibiotic-resistant ‘super-bacteria’, which have become a serious medical problem.
The most difficult microbial pathogens to treat are often those that replicate within host cells (e.g. viruses and some parasites), e.g. during the complex life cycle of the malaria parasite in man, this protozoan can infect and destroy liver cells and erythrocytes. Over 2 million people die each year from malaria, with at least 200-300 million people being infected at any given time. Some such agents have even evolved to survive and replicate within macrophages subsequent to uptake via phagocytosis. This is often achieved on the basis that the phagocytosed microbe is somehow capable of preventing fusion of the phagocytosed vesicle with lysozomes. Examples of pathogens capable of survival within macrophages include:
• mycobacteria (e.g. M. tuberculosis, the causative agent of tuberculosis, and M. leprae, which causes leprosy);
CYTOKINES: INTERLEUKINS AND TUMOUR NECROSIS FACTOR 231
• Listeria monocytogenes, a bacterium which, when transmitted to man, causes listeriosis, which is characterized by flu-like symptoms but can cause swelling of the brain and induce abortions;
• Legionella pneumophila, the bacterium which causes Legionnaire’s disease.
The immunological response raised against intracellular pathogens is largely a T cell response. IL-2’s ability to stimulate T cells may render it useful in the treatment of a wide range of such conditions. Clinical trials assessing its efficacy in treating a range of infectious diseases, including AIDS, continue.
A related medical application of IL-2 relates to its potential use as adjuvant material, as discussed in Chapter 10.
Like all other cytokines, administration of IL-2 can induce side effects, which can be dose-limiting. Serious side effects, including cardiovascular, hepatic or pulmonary complications, usually necessitate immediate termination of treatment. Such side effects may be induced not only directly by IL-2 but also by a range of additional cytokines whose synthesis is augmented by IL-2 administration. These cytokines, which can include IL-3, -4, -5 and -6, as well as TNF and IFN-g, also likely play a direct role in the overall therapeutic benefits accrued from IL-2 administration.
Inhibition of IL-2 activity
A variety of medical conditions exist which 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: