Interferon exogenous

High temperatures can break native S-S bonds and form new S-S bonds which can lock the protein into a denatured eonfiguration [89]. Low pH, sodium dodecyl sulfate. Tween 80, chaotropie salts, and exogenous proteins have been used to protect proteins from thermal inaetivation [90]. Ethylene glycol at 30-50% was used to protect the antiviral activity of P-interferon preparations [91]. Human serum albumin was used in recombinant human interferon-Psei-n which resulted in increased thermal stability [62]. Water-soluble polysaeeharides sueh as dextrans and amylose [92], as well as point-specific (site-directed) mutagenesis [93] have also been used to increase thermal stability of therapeutie proteins and peptides. 

The possibility that interferons can be used as pharmacologic agents has aroused a great deal of interest. Recombinant DNA techniques and cell tissue cultures have been used to produce sufficient quantities of interferons for clinical drug trials. The rationale is that exogenously administered interferons will produce antiviral and other beneficial effects in healthy cells in a manner similar to their endogenously produced counterparts. Some of the pertinent aspects of interferon action and clinical applications are presented below. 

Interferon (IFN) is a cytokine that is used as a drug for a variety of purposes, including the treatment of kidney cancer and tuberculosis. Following challenge or infection by viruses, IFNs are rapidly induced in cells. Conversely, viral replication can be inhibited by the addition of exogenous natural and recombinant IFNs in cell culture. 

Consistent with this suggestion, administration of exogenous pro-inflammatory cytokines, particularly interferon (IFNy), markedly upregulates baseline la expression (Kradin et ol., 1991 Nelson et ol., 1994). Similar conclusions follow from the results of comparative studies on lung DCs from smokers versus non-smokers (Soler et ol., 1989), and from observations on changes in the phenotype of nasal mucosal DCs in rhinitis patients during the pollen season (Fokkens et ol., 1989). 

Benzo[a]pyrene has also been shown to affect immune responses to viral infection. Benzo[a]pyrene can reversibly inhibit the induction of viral interferon in 32 different mammalian cell lines but only in the presence of S9 metabolic activation (Hahon and Booth 1988). This inhibition must occur at an early level and not affect viral interferon interactions because the activity of exogenous interferon was unaffected. In addition, influenza virus multiplication was also inhibited by activated benzo[a]pyrene. Benzo[e]pyrene had no effect on interferon induction. The authors suggest that benzo[a]pyrene s inhibition of interferon induction may be an early step in compromising the host s immune function, thereby allowing the induction of carcinogenesis. 

The second group of tests comprises cell culture-based bioassays, which are more favorable in terms of standardization, costs and time consumption, but stiU exhibit variabihty of living cells. Permanent cell hnes are used to test (e.g., on microtiter plates) survival rates against exogenous stimuli as a function of the protective effect of the analyte in case of antiviral activity. In a similar analytical setting, viral activity can be tested. For interferon (IFN)... 

Heremans H, Billiau A, DeSorner P (1980). Interferon in experimental viral interferon in mice tissue interferon levels resulting from virus infection and from exogenous interferon therapy. Infect. Immun. 30 513-522. 

Interferon alpha has no role in therapy, with the possible exception of Rift Valley fever,34 where fatal hemorrhagic fever has been associated with low interferon responses in experimental animals. However, as an adjunct to ribavirin, exogenous interferon gamma holds promise in treatment of arenaviral infections. 

The interactions between the exogenous chitosan used in a wound and the human cells have been widely investigated (Muzzarelli 1997). Lysozyme, normally produced by macrophages, hydrolyzes the susceptible modified chitosan into oligomers, which activate the macrophages to produce nitric oxide, activated oxygen species, tumor necrotic factor-a, interferon, and interleukin (IL) 1. The activated macrophages increase their production of lysozyme, chitinase, and... 

Analysis of the cell-free translation system by sucrose gradient centrifugation, shows that PK-i causes a marked decrease in the amount of (55S-met-tRNA 4OS ribosome) complexes (12). Exogenous eIF-2 overcomes part of the dsRNA-dependent translational inhibition of mengo or globin mRNA in extracts from interferon treated cells (13) ... 

Extracts from cells treated with interferon show in many cases a reduced ability to translate exogenous mRNAs (25), even in the absence of dsRNA. Analysis of the products shows that incomplete polypeptide chains are formed (24) and the defect can be corrected by addition of tRNA (25-26). 

Administration of exogenous interferon is reported to exert a protective effect in tissue culture against adeno-2 virus and in mice has prolonged life or prevented death caused by Rauscher virus , vesicular stomatitis virus and encephalonyocarditis virus. There are reports that some interferons could cross species lines and be effective unlike earlier evidence of greater specificity. 

In spite of the efficacy of exogenous interferon, the major search has been for Interferon inducers. Synthetic polymers have been effective inducers and some of the characteristics apparently necessary for activity are as follows a large molecule with a high density of free anionic groups, not readily degradable and not readily eliminated. Agents with these characteristics include polymers of maleic anhydrides, polyacrylates and carboxylates. Polyacrylic acid (PAA) and polymethacrylic acid (PMAA) have induced Interferon in tissue culture and protected mice infected with Mengo virus and vaccinia and vesicular stomatitis viruses,76. Salts of polyvinyl sulfate appear to have dual activity since they induce interferon activity in mice but not in tissue culture, and the antiviral activity exerted is not correlated with virus interferon sensitivity. ... 

In confirmation of earlier studies by Yamazaki and Wagner (1970), Marcus and Sekellick (1976) next extended their studies by testing the effect of exogenous interferon or endogenous interferon induced by poly(I) poly(C) on the cell-killing activity of VSV. They... 

One of the rationales for the use of cytokine gene therapy in mesothelioma is that exogenous cytokines are known to have direct antiproliferative effects upon mesothelioma cells, as well as the ability to activate intrapleural and intratumoral immune effector cells in vivo. Several published Phase I and Phase II clinical trials have decumenfed mesothelioma tumor responses to intrapleural infusion of interleukin-2 (IL-2), interferon-P (IFN-P), and inteiferon-y (IFN-y) (70-76). In particular,... 

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