Immunostimulatory Activity

Chitosan owes its immxmostimulatory activity to the enhancement of humoral and cell-mediated immune response [40]. Glycated chitosan, a water-soluble derivative of chitosan, in which galactose molecules are attached to the chitosan molecules, serves as an efficient immunoadjuvant for the treatment of cancer, especially when combined with laser phototherapies [41]. Chitosan nanoparticles, when administered intravenously. 

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Fig. 8 Immunostimulatory activity of MGX from beech wood (BwGX), Rudbeckia fulgida (RudGX), Altheae officinalis (AltGX), and Mahonia aquifolium (MahGX) [146] a Mitogenic activity, SImit and b comitogenic activity, Skomit...

The scientific interest in cereal /1-glucans arose partly from the problems they cause in brewing and animal-feed industries in the case of barley [318] and partly from the health benefits, such as cholesterol reduction [319-321], regulation of postgrandial seriun glucose levels in humans and animals [319,322], and immunostimulatory activity [323,324]. Some of these activities have been observed with both oat and barley )6-glucans [325]. 

The immunostimulatory activity of IL-2 has proven beneficial in the treatment of some cancer types. An effective anti-cancer agent would prove not only medically valuable, but also commercially very successful. In the developed world, an average of one-in-six deaths is caused by cancer. In the USA alone, the annual death toll from cancer stands in the region of half a million people. 

Freund s incomplete adjuvant (FIA) is a similar product. It differs from FCA in that it lacks the mycobacterial component and, consequently, displays somewhat lesser adjuvanticity. The mode of action of FIA is largely attributed to depot formation. The mycobacterial components in FCA have additional direct immunostimulatory activities. Although it is one of the most potent adjuvant substances known, FCA is too toxic for human use. 

Guillot, L., et al., Cutting edge The immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4, J. Immunol. 168, 12, 5989, 2002. 

DPDPE has been found to have marked in vitro immunostimulant activity in patients suffering from leprosy and tuberculosis, enhancing antigen-stimulated proliferation of peripheral blood mononuclear cells and T-cell rosetting. DPDPE has been found to enhance cytokine production by T-helper cells, IL-6 production by macrophages and NK cell activity in murine splenocytes, suggesting immunostimulatory activity at low in vitro... 

It has been reported that some simple, synthetic glycollpids, such as II-fatty acylated 2-amino-2-deoxy-D-glucose derivatives, exhibit potent immunostimulatory activities (5). We first examined a facile preparation of N-fatty acylated 2-amino-2-deoxy-D-glucopyranosides, which would be key intermediates for the synthesis of lipid A and its analogs (Figure 2). For this purpose, the one-step glycosylation catalyzed by ferric chloride (6, 7) was employed. 

Nonbacterial milk components and components produced from milk fermentation may also contribute to the immunostimulatory activity of yogurt. Peptides and free fatty acids generated by fermentation have been shown to enhance the immune response. Milk components such as whey protein, calcium, and certain vitamin and trace elements also can influence the immune system. 

Hie first preparation of an LPS derivative which retained immunostimulatory activity yet had significantly reduced toxicity was made in 1979 by Ribi et al. (1979) who found that mild acid hydrolysis of LPS reduced the pyrogenicity without affecting tumor inhibition activity. Uiis reduced-toxicity product was shown to be the 4/-monophosphoryl derivative of lipid-A (MPL ) (Qureshi et al., 1982). Ribi s group later demonstrated that further alkaline hydrolysis of MPL resulted in de-acylation at the 3 position, producing a molecule with even lower toxicity... 

A 1,2-dihydroxy moiety is a structural feature of molecules susceptible to the enzymatic degradation by polyphenol oxidase (PPO). Cichoric acid contains this structural feature and is thus susceptible to enzymatic degradation (Bauer, 1997). The immunostimulatory activity of Echinacea is partly due to the cichoric acid, and hence protection against enzymatic degradation is critical for retaining the potency of Echinacea preparations. 

Thermal cyclization was also the route employed to prepare 9-hydroxy-7-methyl-l/f-pyrazolo[3,4-/]quinoline (74) from the 6-aminoindazole/ethyl acetoacetate condensation adduct shown in Equation (41) <92JMC4595>. The hydroxyl substituent of compound (74) was then converted (POCl3, DMF) to a chloro, which in turn was displaced by treatment with aryl amines to give tricyclics with potent in vivo immunostimulatory activity like that noted for regioisomeric l//-imidazo[4,5-/]quinolines but unlike the inactive pyrazolo[4,3-/]quinolines. Although it was noted with some interest that none of the linear tricyclic isomer had been isolated, this finding actually parallels that reported earlier for the similar condensation of 1- and (V(6)-alkyl and unsubstituted 6-amino-indazoles with diethyl ethoxymethylenemalonate <83JHC1351>. 

Tetrahydro-6-phenylimidazo[2,l-6]thiazoIe hydrochloride (tetramisole) is a broad-spectrum anthelmintic the D-form is an antidepressant the L-form (levamisole) is known to possess immunoregulatory or immunostimulatory activity. Some phenacylthio-imidazolines which are tautomeric to cyclic carbinolamines are very potent antagonists of reserpine-induced hypothermia in mice. The corresponding 3-aryl-5,6-dihydroimidazo[2,l-6]thiazoles are also potent antidepressants. 5,6-Bis(4-methylsulfinylphenyl)-2,3-dihy-droimidazo[2,1 -b Jthiazole is used especially in the treatment of rheumatic arthritis. 

Among the most highly selective cytokine biopharmaceuticals are the interferons. Interferons are members of a large family of related proteins that may be divided into two categories type I and type II interferons. Type I interferons (i.e., a- and P-interferon) possess antiviral and anti-proliferative properties, whereas type II interferons (i.e., y-interferon) have immunostimulatory activity. Several animal species were examined for their responsiveness to interferons, and with the exception of nonhuman primates, all tested animal species were found to be unresponsive [15]. 

Chimeric peptides are unnatural constructs consisting of bioactive compounds from at least two different peptide(s) and/or protein(s) or two sequences from different parts of the same protein. Such multifunctional peptide combinations are prepared to enhance the biological activity or selectivity of their components. New biological effects can also be achieved with the chimera. In this chapter the synthesis of three different types of chimeric peptides will be described. In a linear chimera, two peptide epitopes from different parts of glycoprotein D (gD) of herpes simplex virus (HSV) are combined. A branched chimera, built from linear peptides, consists of tuftsin oligomers with immunostimulatory activity and an epitope peptide of HSV gD. The third compound is a cyclic chimeric molecule, where a-cono-toxin GI as a host peptide is modified by the incorporation of a core epitope from HSV gD as a guest sequence. 

In this chimeric peptide construct the aim was to combine the carrier function and immunstimulatory activity of tuftsin derivatives with an epitope derived from HSV gD to achieve an increased antibody response. Tuftsin is a well-known natural tetrapeptide (TKPR) that has a pronounced effect on the immune system (28,29). Polymerized tuftsin (polytuftsin) is also considered as a carrier molecule that increased antibody levels against attached epitopes in mice (30,31). New, sequential oligopeptides based on repeated tuftsin derivatives (H-[Thr-Lys-Pro-Lys-Gly]n-NH2, where n = 2,4,6,8) were developed in our laboratory to eliminate the drawbacks of tuftsin derivatives produced by polymerization. These new, nontoxic, nonimmunogenic compounds have immunostimulatory activity and a minor chemoattractant effect on monocytes (32). An oligotuftsin derivative was used in this study for the synthesis of a peptide chimera containing an HSV peptide epitope. 

Over the years, our laboratory has generated a library of analogues of C5a 5 in which backbone flexibility was restricted by certain amino acid substitutions. This was done with the goal of biasing certain conformational features that might be helpful in the search for biologically relevant conformations responsible for the induction of C5a-like immunostimulatory activities versus those responsible for C5a-like inflammation. 

Vollmer J, Weeratna R, Payette P, et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol. 2004 34 251-262. 

Echinacea is one of the best-selling herbal products in the United States (Brevoort, 1998) and is promoted as an immunostimulatory agent (Bauer, 1999a, 2000). The alkamides, caffeic acid derivatives (e.g., cichoric acid), glycoproteins, and polysaccharides are believed to be responsible for Echinacea s observed immunostimulatory activity. Bauer (1997) reported that the variation in alkamide concentrations of Echinacea products was due to a number of factors such as growing season, which part of the plant was utilized in the preparation of the commercial product,... 

Cichoric acid is believed to contribute to the immunostimulatory activity, but the compound tends to decompose through enzymatic degradation during extractions (Bauer, 1997) thus, the variability in cichoric acid levels found by many researchers may be due to the extraction methodology and not to the plant species or origin. Bauer (1999b) evaluated the cichoric acid content of six commercially available expressed juice preparations of E. purpurea. The thermally treated preparations had higher cichoric acid than ethanol-preserved preparations. The inactivation of polyphenol oxidase by heat may account for the difference found between heated and nonheated preparations. 

Recent studies have suggested that compounds acting as delta opioid receptor agonists may exhibit immunostimulatory activity. For example, both IL-2 and IL-4 production were markedly enhanced by DPDPE at concentrations between 0.00001 and 0.1 M. Exposure to H-Tyr-D-Thr-Gly-Phe-Leu-Thr-OH (DTEET) and DPDPE was associated with a significant enhancement in NK cell activity. More extensive mechanistic studies are in progress to define the nature of this immunomodulatory activity. 

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