Cytokines recombinant

Several of these IFNs of mouse and human lymphocytes and fibroblasts are available commercially and have been best prepared in quantity by recombinant DNA procedures because they are produced in very small amounts by the cells. The commercial materials do not generally require further purification for their intended purposes. [Pestkas, Interferons and Interferon standards and general abbreviations. Methods Enzymol, Wiley Sons, 119 1986, ISBN 012182019X Lengyel, Biochemistry of interferons and their actions, Ann Bev Biochem 51 251-282 7982 De Maeyer and De Maeyer-Guignard, Interferons in The Cytokine Handbook, 3rd Edn, Thomson et al. Eds, pp. 491-516 7998 Academic Press, San Diego, ISBN 0126896623.]... 

Cellular cytokines (interferons, G-CSF) and immune response modifiers originally produced from human cells, most often leukocytes, have now been replaced with recombinant products with well-defined structure/function. Futuristic advances in experimental hematology portend development of human blood cells produced from the hemopoetic stem cells. Yet for the foreseeable future, homologous blood donated by healthy, altruistic voluntary blood donors remains the principal source of safe and adequate supply of blood and blood products for transfusion therapy. 

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

PI. polymorpha [80] is generally referred to as safe and was widely used for pharma-protein production (cytokines, vaccines, coagulation factors) [80]. The genome sequence is known and DNA chip technologies have been established. Hansenula was developed to an expression platform which was implemented for the production of recombinant vaccines. 

Based on the above principles, it might be assumed that a therapeutic protein obtained by direct extraction from human sources (e.g. some antibody preparations) or produced via recombinant expression of a human gene/cDNA sequence (e.g. recombinant human hormones or cytokines) would be non-immunogenic in humans whereas foreign therapeutic proteins (e.g. non-engineered monoclonal antibodies) would stimulate a human immune response. This general principle holds in many cases, but not all. So why do therapeutic proteins of human amino acid sequences have the potential to trigger an immune response Potential reasons can include ... 

During the 1980s, rapid developments in the areas of recombinant DNA technology and monoclonal antibody technology contributed to a greater depth of understanding of cytokine biology ... 

Recombinant DNA technology has also facilitated detailed study of cytokine receptors. Based upon amino acid sequence homology, receptors are usually classified as belonging to one of six known superfamilies (Table 8.3). Individual members of any one superfamily characteristically display 20-50 per cent homology. Conserved amino acids normally occur in discrete bands or clusters, which usually correspond to a discrete domain in the receptor. Most receptors exhibit multiple domains. In some cases a single receptor may contain domains characteristic of two or more superfamilies. For example, the IL-6 receptor contains domains characteristic of both the haematopoietic and immunoglobulin superfamilies, making it a member of both. 

Piscitelli, S.C., Reiss, W.G., Figg, W.D., and Petros, W.P. 1997. Pharmacokinetic studies with recombinant cytokines scientific issues and practical considerations. Clinical Pharmacokinetics 32(5), 368-381. 

As was the case for most other cytokines, medical appraisal/use of IL-2 was initially impractical due to the minute quantities in which it is normally produced. Some transformed cell lines, most notably the Jurkat leukaemia cell line, produces IL-2 in increased quantities, and much of the IL-2 used for initial characterization studies was obtained from this source. Large-scale IL-2 production was made possible by recombinant DNA technologies. Although the IL-2 gene/cDNA has now been expressed in a wide variety of host systems, it was initially expressed in E. coli, and most products being clinically evaluated are obtained from that source. As mentioned previously, the absence of glycosylation on the recombinant product does not alter its biological activity. 

The availability of large quantities of recombinant TNF-a facilitates rigorous investigation of the effects of this cytokine on cells in vitro, as well as its systemic in vivo effects. Like most cytokines, TNF-a exhibits pleiotropic effects on various cell types. The major biological responses induced by this cytokine include ... 

EPO is present in serum and (at very low concentrations) in urine, particularly of anaemic individuals. This cytokine/hormone was first purified in 1971 from the plasma of anaemic sheep, and small quantities of human EPO were later purified (in 1977) from over 2500 1 of urine collected from anaemic patients. Large-scale purification from native sources was thus impractical. The isolation (in 1985) of the human EPO gene from a genomic DNA library facilitated its transfection into CHO cells. This now facilitates large-scale commercial production of the recombinant human product (rhEPO), which has found widespread medical application. 

Scallon, BJ. et al., Chimericanti- TNF-a monoclonal antibody cA2 binds recombinant transmembrane TNF-a and activates immune effector functions, Cytokine, 7, 251,1995. 

Therapeutics Recombinant Cytokines and Biological Response Modifiers... 

---