PubMed · 7749311
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M Okuhara, T Kino. 1994. Immunomodulators.. https://doi.org/10.1016/b978-0-7506-9003-4.50018-6
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The present study was to ascertain the immunomodulating and anti-tumor effects of Ganoderma (G.) lucidum. Polysaccharides (PS) from fresh fruiting bodies of G. lucidum (PS-G) were isolated and used to potentiate cytokine production by human monocytes-macrophages and T lymphocytes. Our results had shown that the levels of interleukin (IL)-1 beta, tumor necrosis factor (TNF)- alpha, and IL-6 in macrophage cultures treated with PS-G (100 micrograms/ml) were 5.1-, 9.8- and 29-fold higher, respectively, than those of untreated controls. In addition, the release of interferon (IFN)- gamma from T lymphocytes was also greatly promoted in the presence of PS-G (25-100 micrograms/ml). Furthermore, these cytokine-containing mononuclear cell-conditioned media (PSG-MNC-CM) were found to suppress the proliferation and clonogenicity of both the HL-60 and the U937 leukemic cell lines. DNA labeling and gel electrophoresis showed that treatment with PSG-MNC-CM markedly induced leukemic-cell apoptosis. Flow-cytometric analysis revealed that few (2.3 +/- 0.8%) apoptotic cells were seen in the control cultures, while PSG-MNC-CM treatment resulted in a significant increase in the apoptotic population both in the HL-60 (38.3 +/- 4.5%) and in the U937 (44.5 +/- 3.8%) cells. In addition, 40 to 45% of the treated leukemic cells were triggered to differentiate into mature monocytic cells expressing CD14 and CD68 surface antigens. However, PS-G alone had no such effects even at a higher dose of 400 micrograms/ml. Since untreated macrophages and T lymphocytes produced little or no cytokine, and normal MNC-CM did not suppress leukemic cell growth, it was suggestive that the anti-tumor activity of PSG-MNC-CM was derived from the elevated levels of cytokines. Antibody-neutralization studies further revealed that the anti-tumor cytokines in the PSG-MNC-CM were mainly of TNF- alpha and IFN- gamma, and these 2 cytokines acted synergistically on the inhibition of leukemic-cell growth.
Rheumatoid arthritis (RA) is an autoimmune disease that is strongly associated with the expression of several HLA-DR haplotypes, including DR1 (DRB1*0101). Although the antigen that initiates RA remains elusive, it has been shown that many patients have autoimmunity directed to type II collagen (CII). To test the hypothesis that HLA-DR1 is capable of mediating an immune response to CII, we have generated transgenic mice expressing chimeric (human/mouse) HLA-DR1. When the DR1 transgenic mice were immunized with human CII (hCII), they developed a severe autoimmune arthritis, evidenced by severe swelling and erythema of the limbs and marked inflammation and erosion of articular joints. The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII. The T cell response was focused on a dominant determinant contained within CII(259-273) from which an eight amino acid core was defined. The B cell response was characterized by high titers of antibody specific for hCII, and a high degree of cross-reactivity with murine type II collagen. These data demonstrate that HLA-DR1 is capable of presenting peptides derived from hCII, and suggest that this DR1 transgenic model will be useful in the development of DR1-specific therapies for RA.
Since antigen-specific autoaggressive T cells have been found in association with many autoimmune diseases, a treatment to eliminate such antigen-specific T cell clones was developed. The complex of peptide antigen and class II MHC protein is used to target a cytotoxic drug to antigen-specific T cells. The drug is bound covalently to antigen-presenting cells (APC) and protein antigens (Ag) are added to the cells for processing and presentation of peptides. The APC contain class II MHC (Ia) protein to present the peptide Ag to the T cell receptor and adhesion proteins for optimal interaction with the T cell. Either the Ag-bearing intact APC or Ia+ membranes shed or released spontaneously from them were used as drug carriers to target the drug to the T cells. The drugs being used are phototoxic compounds. When irradiated with light of an appropriate wavelength, they give off toxic free radicals and singlet oxygen. These toxic by-products are short-lived and damage cells only in their immediate vicinity, cutting down on nonspecific side effects. APC from thymus cells, or their shed membranes bearing Ia-Ag peptide complexes, were able to target the phototoxic drug specifically to Ag-specific T line cells and ex vivo Ag-specific lymph node cells. Proliferation of the target T cells was inhibited at a three to four times lower drug concentration than required to affect control T cells. The Ag-specific effect was inhibited by anti-Ia antibody and by drug-free membranes carrying the Ag-Ia complex. This indicated that the antigen-specific phototoxic effect was mediated by interaction of the Ag-Ia complex with the T cell receptor.