Lymphokines interferons

The term cytokine was first introduced in the mid 1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. The interferons and interleukins represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including lymphokines (cytokines such as IL-2 and IFN-y, produced by lymphocytes) and monokines (cytokines such as TNF-a, produced by monocytes). However, classification on the basis of producing cell types also proved inappropriate, as most cytokines are produced by a range of cell types (e.g. both lymphocytes and monocytes produce IFN-a). 

A third biological activity of IL-2 pertinent to immunostimulation is its ability to promote the growth of NK cells. It also promotes further differentiation of NK cells, forming lymphokine-activated killer (LAK) cells, which exhibit an enhanced ability to kill tumour cells or virally infected cells directly. NK cells express the P and y IL-2 receptor subunits only thus, their stimulation by IL-2 requires elevated concentrations of this cytokine. NK cells are also activated by a variety of additional cytokines, including all interferons and TNF. 

It is necessary to work in a species capable of responding to the principal activity. Interferons are notorious for their species specificity, but most other lymphokines at least are more generally active. Work in a primate may be required, but it depends on the substance to be tested. There may be no point in using more than one species in pivotal studies. 

Since cellular immunity results in the release of chemotactic lymphocytes that in turn enhance phagocytosis, a deficiency in cellular immunity may also result in chronic infections. Cellular immunity is mediated by T cells, macrophages, and NK cells involved in complex compensatory networks and secondary changes. Immunosuppressive agents may act directly by lethality to T cells, or indirectly by blocking mitosis, lymphokine synthesis, lymphokine release, or membrane receptors to lymphokines. In addition, cellular immunity is involved in the production and release of interferon, a lymphokine that ultimately results in blockage of viral replication (Table 15.4). Viruses are particularly susceptible to cytolysis by T cells since they often attach to the surface of infected cells. Thus, immunosuppression of any of the components of cellular immunity may result in an increase in protozoan, fungal, and viral infections as well as opportunistic bacterial infections. 

Interferon-7 was the first secretory product of T cells to be discovered when it was found that supernatants derived from suspensions of T cells that had been treated with mitogenic agents could activate macrophages. This macrophage activating factor , subsequently found to interfere with the replication of viruses, was thus named interferon. The production of this compound, associated with delayed-type hypersensitivity and cell-mediated immunity, was termed immune interferon or type II interferon. With the discovery of other lymphokines with interferon-like activity (interferon-a and -j3), the compound was finally designated interferon-7. 

Cytokines produced by lymphocytes are called lymphokines, and those produced by monocytes are termed monokines. Lymphocytes and monocytes are different types of white blood cells. The major lymphokines are interferons (IFNs) and some interleukins (ILs). Monokines include other interleukins and tumor necrosis factor (TNF). 

There is an extremely large number of cytokines only the most important representatives are listed opposite. The cytokines include interleukins (IL), lymphokines, monokines, chemokines, interferons (IFN), and colony-stimulating factors (CSF). Via interleukins, immune cells stimulate the proliferation and activity of other immune cells (see p. 294). Interferons are used medically in the treatment of viral infections and other diseases. 

Stuehr, D. J., and Marietta (1987). Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, t>r interferon-gamma. J. Immunol. 139, 518-525. 

Lymphokines Chemicals released from activated lymphocytes that help mediate various aspects of the immune response. Common lymphokines include the interleukins and gamma interferon. 

Human recombinant interferon gamma-lb multiple targets within the lymphokine regulatory network... 

Betaseron (interferon beta-lb) (US) Approval 2003 Human recombinant interferon beta-lb multiple targets within the lymphokine regulatory network Multiple sclerosis... 

IL-2 is a lymphokine produced by activated helper T-lympho-cytes. It induces the proliferation of T cells and promotes the differentiation of lymphocytes into cytotoxic cells. IL-2 also induces interferon gamma production (Lewko and Oldham, 2003). Activation of peripheral leukocytes with the drug produces lymphokine-activated killer cells (LAK) that lyse a variety of tumor cells in vitro. IL-2 has been cloned in bacteria through recombinant DNA technology, thus allowing the production of large amounts. IL-2 alone or with LAK cells can cause regression of several established metastatic tumors in animals (Lewko and Oldham, 2003 Dorr, 1993). 

Potential drugs, such as interferons, interleukins (as well as other lymphokines), growth factors, and plasminogen activators are also being used as diagnostics. They are very sensitive to many diseases, such as hepatitis, herpes, and AIDS. ... 

In early trials, aldesleukin was given with lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes. However, later data showed that the addition of LAK cells does not improve the therapeutic response in renal cell carcinoma and can produce more pulmonary toxicity and hypotension (1). Compared with aldesleukin or interferon alfa alone, the combination of aldesleukin plus interferon alfa produces a significantly longer event-free survival without effect on the overall survival, but induces substantial toxicity with severe and resistant hypotension (3). The optimal safe and effective dose and schedule of administration of aldesleukin is not yet well defined, and a variety of regimens have been tested, with doses of 600 000 units/kg by intermittent bolus intravenous infusion or 18 106 units/m by continuous subcutaneous or intravenous infusion. 

Risk factors for renal dysfunction have been analysed in 72 patients with metastatic renal cell cancer treated with high-dose aldesleukin (18 MU/m /day), interferon alfa (5 MU/m /day), and lymphokine-activated killer lymphocytes (94). There was some tjrpe of renal dysfunction in 97%, of whom 69% developed renal toxicity of grade 2 (creatinine 260-525 pmol/l) or grade 3 (creatinine 525-1050 pmol/l). Although renal function commonly resolved between successive treatment courses, six patients had a persistently raised creatinine concentration (more than 20% above baseline). Among the various potential risk factors, a multivariate analysis showed that the significant risk factors for severe renal dysfunction were male sex, pre-treatment hjrpertension, and sepsis during treatment. 

Schomburg A, Kirchner H, Atzpodien J Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha evidence of a risk/benefit advantage of subcutaneous therapy, J Cancer Res Clin Oncol 1993,119 745-755 Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher Rl, Weiss GR, Doroshow JH, Jaffe HS, Roper M, et al. Inter-leukin-2 and lymphokine-activated killer cell therapy of solid tumors analysis of toxicity and management guidelines, J Clin Oncol 1989,7 486-498... 

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