Lymphokines Cytokines

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). 

TABLE 27.5 Lymphokines/cytokines with antitumor activity whose inhibition may mediate atypical tumor promotion... 

Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker EB, Daynes RA, WeindmchR (1993) Inter-leukin-6 and aging Blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12 225-230. 

Lote et al., High-Dose Recombinant Interleukin-2. The critical review was published in the same issue Moertel, On Lymphokines, Cytokines, and Breakthroughs. ... 

Brahn E, Peacock D J, Banquerigo M L, et al. (1992). Effects of tumor necrosis factor alpha (TNF-alpha) on collagen arthritis. Lymphokine Cytokine Res. 11 253-256. 

Jenkins JK, Malyak M, Arend WP Xhe effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res 1994 13 47-54. 

Ruby J, Ramshaw I. The antiviral activity of immune CD8+ T cells is dependent on interferon-gamma. Lymphokine Cytokine Res 1991 10 353-358. 

Endo H, Akahoshi T, Takagishi K et al. Elevation of interleukin-8 (IL-8) levels in joint fluids of patients with rheumatoid arthritis and the induction by IL-8 of leukocyte infiltration and synovitis in rabbit joints. Lymphokine Cytokine Res 1991 10 245-252. 

Akahoshi, Y., Endo, H., Kondo, H., Kashiwazaki.S., Kasahara, T., Mukaida, N., Harada, A., and Matsushima, K. (1993) Essential involvement of interleukin 8 in neutrophil recruitment in rabbit with acute experimental arthritis induced by lipopolysaccharide and interleukin 1. Lymphokine Cytokine Res. 13,113-116. 

Warren S, Torti SV, Torti FM. The role ofiron in the cytotoxicity of tumor necrosis factor. Lymphokine Cytokine Res 1993 12 75-80. 

Kato M, Liu MC, Stealey BA, Friedman B, Lichtenstein LM, Permutt S, Schleimer RP. Production of granulocyte/macrophage colony-stimulating factor in human airways during allergen-induced late-phase reactions in atopic subjects. Lymphokine Cytokine Res 1992 11 287-292. 

These are supplied by the secretion of peptide molecules (termed cytokines or lymphokines) fiom a subset of the T-cell family (the helper T cells, TH cells). These peptide molecules (interleukins (IL) 2,4,5 and 6) stimulate the B cells to proliferate, undergo clonal expansion and mature into plasma cells which secrete antibody and also into the longer-hving, non-dividing memory cells. 

These are the eentral eells of the immune system as they are essential for activation of the other eells assoeiated with an effeetive immune response hy the secretion of peptide mediators termed eytokines. Cytokines produeed hy macrophages and monocytes are termed monokines whilst those produeed hy lymphocytes are termed lymphokines. TH eells express CD4 on their surfaee. 

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. 

Stimulation for 24 hours with LPS leads to the release of interleukin-1 [3, IL-6, IL-8, TNF-a and by prolonging the incubation period from 48 to 72 hours, the whole blood model can detect the release of other lymphokines [45], including IL-2, IL-4, IL-13 and IFN-y. Skewing of the T-helper cell response to antigens can likewise be detected by evaluating the pattern of cytokine release, corresponding to a predominance of Th 1 or Th2 cytokine production. The predictive value of these approaches is currently under investigation. 

Wood, D.D. et al., Role of Interleukin-1 in the Adjuvanticity of Muramyl Dipeptide in Vivo, in Interleukins, Lymphokines and Cytokines, Oppenheim, J J. and Cohen, S., Eds., Raven Press, New York, 1983... 

Includes lymphokines, monokines, and cytokines produced by T cells, macrophages, and other cells, respectively. Source Extracted and modified from Golub and Green, 1991. 

Cytokines are produced mainly by the leukocytes (white blood cells). They are potent polypeptide molecules that regulate the immune and inflammation functions, as well as hematopoiesis (production of blood cells) and wound healing. There are two major classes of cytokines (1) lymphokines and monokines and (2) growth factors. 

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). 

Almost 20 years ago the ammonium tellnrolate AS 101 was demonstrated to possess immnnomodnlating properties and to mediate anti-tumour effects in rats. The same com-ponnd stimnlates hnman lymphoid cells to proliferate and produce lymphokines, tumour necrosis factor (TNF) and other cytokines in vitro ... 

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. 

Muromonab is a mouse monoclonal antibody against the CD3 receptor of T-lymphocytes. Its activity is based on inhibition of interactions between antigen-presenting cells and T-cells. By preventing antigen presentation it suppresses T-cell activation and proliferation. The indication for muromonab is the treatment of acute graft rejection after kidney, liver and hart transplantations. Its adverse effects consist of those symptoms that are initiated by the release of cytokines and lymphokines as a result of the reaction of muromonab with CD3 positive T-lymphocytes. These symptoms may vary from a mild flu-like syndrome to serious cardiac, pulmonale and neurological reactions. 

An exciting application of immunomodulating therapy is in the use of cytokines lymphokines, monokines). As mentioned earlier in this chapter, immune cell function is regulated by cytokines produced by leukocytes or other supporting cells. With the advent of genetic engineering, cytokines can be produced in pure form and in large quantities. 

---