Immunomodulatory proteins

Ling Zhi-8 (LZ-8) is an immunomodulatory protein (29,30) isolated from the mycelial extract of Ganoderma lucidium, that has been purified and shown to stimulate mouse spleen and human peripheral blood lymphocytes. LZ-8 is able to inhibit antibody production and prevent the development of autoimmune type I diabetes in NOD mice. 

Rogers, P. D. et al., Differential expression of genes encoding immunomodulatory proteins in response to amphotericin B in human mononuclear cells identified by cDNA microarray analysis, J. Antimicrob. Chemother., 50, 811, 2002. 

The impact of immunomodulatory protein therapeutics on diseases having unmet medical need has already proven remarkable. These new treatments have been credited with a favorable clinical profile from slowing the disease progression to outright cures. Although the cost of these advanced medicines may be offset by the enormous improvement in the quality of life of numerous patients, we must remain vigilant throughout their clinical development. 

Cause for concern based on product class (e.g., growth factor, immunomodulatory protein)... 

Szekenes-Bartho J, Wegmann TG (1996) A progesterone-dependent immunomodulatory protein alters the Thl/Th2 balance. J Reprod Immunol 31 81-95... 

Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 1986 137 3855-3860. 

Ackerman CJ, Harnett MM, Harnett W et al. A solution structure of the filarial nematode immunomodulatory protein, ES-62. Biophys J 2003 84(l) 489-500. 

To enhance tumor toxicity by using the cells own defense system, expression of various cytokines and other immunomodulatory proteins have been investigated as potential strategies for radiosensitization when expressed from various vectors. As with other combined modalities, the combinations of cytokine gene therapy with radiation or chemotherapy have shown some promise in clinical settings. The most advanced studies are those based on tumor necrosis factor-a (TNF-a) in combination with radiation (Kufe and Weichsel-BAUM 2003). TNF-a has potent antitumor and antiangiogenesis activities that synergize with radiation therapy. TNFerade was developed as an ADV that expressed TNF-a under control of a radiation-inducible promoter that limits toxicities to the irradiated area, which is not the case with the direct injection of TNF-a into the tumor. 

Interferon alfacon-1 (Inferax ), interferon alfa-2b (IntronA ), and interferon alfa-2a (Roferon -A) are applied in the treatment of chronic hepatitis B and C and some malignancies, especially hairy cell leukemia. IFN-a proteins induce the expression of antiviral, antiproliferative and immunomodulatory genes. 

Sheng WS, Hu S, Gekker G, Zhu S, Peterson PK, Chao CC (1997) Immunomodulatory role of opioids in the central nervous system. Arch Immunol Ther Exp (Warsz) 45 359-366 Sheng WS, Hu S, Lokensgard JR, Peterson PK (2003) U50, 488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. Biochem Pharmacol 65 9-14... 

Considering the propensity of RPE cells to express a range of anti-inflammatory and pro-inflammatory proteins, the proven role of inflammation in uveitis and AMD, as well as potent immunomodulatory effects of carotenoids, it is of importance to determine the immunomodulatory effects of carotenoids and their degradation products in the RPE. 

This drug has marked immunomodulatory effects and can alter the normal function of T and B lymphocytes, NK cells and macrophages, both in vivo and in vitro, in humans and animals (Table 30.1).910 Although the molecular and cellular mechanisms for these effects are not fully defined, it is believed that both receptor and non-receptor mechanisms are involved. Cannabinoid receptors (CBRs) are G-protein coupled 7-... 

Jean-Marc Sabatier has a Ph.D. and HDR in biochemistry. He is the director of research at the French Centre National de la Recherche Scientifique (CNRS). He heads a research laboratory (ERT 62) entided Engineering of Therapeutic Peptides at the Universite de la Mediterranee, in Marseilles, France. He also holds the position of a senior director (discovery research — peptides) for a public company in Canada. Dr. Sabatier works in the field of animal toxins, and leads the venom peptide group of the International Neuropeptide Society. He also designs immunomodulatory and antiviral drugs, as well as contributes to the field of peptide and protein engineering. He has contributed more than 100 scientific articles, 180 communications, and 43 patents. He is a member of several scientific advisory boards of journals (e.g.. Peptides, Biochemical Journal), and has reviewed articles submitted for publication in more than 30 specialized international journals. 

The enhanced production of the cytokines called interferons is one of the body s earliest responses to a viral infection. These endogenous proteins exert potent antiviral, immunoregulatory, and antiproliferative effects and are classified according to the cell type from which they were initially derived. Interferon-a (type I, leukocyte) and interferon (3-(3 (type I, fibroblast) are synthesized by most types of cells in response to viral infection, certain cytokines, and double-stranded RNA. Interferon-y (type II, immune) is produced by natural killer (NK) cells and T lymphocytes in response to antigens, mitogens, and certain cytokines. Interferon-a and interferon-(3 exert the most potent antiviral effects interferon-y is antiviral and strongly immunomodulatory. 

Haq A, Lobo PI, Al-Tufail M, Rama NR, Al-Sedairy ST. Immunomodulatory effect of Nigella sativa proteins fractionated by ion exchange chromatography. International Journal of Immunopharmacology 1999 21 283-295. 

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