PubMed · 8100390
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W R Benjamin, B Jaffee. 1993. Immunoregulation workshop.. https://pubmed.ncbi.nlm.nih.gov/8100390/
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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.
Because of the massive cytokine response elicited by superantigen exposure, it has been suggested that superantigens may act as adjuvants to boost conventional antigen responses. However, most previous studies have shown that in vivo exposure to superantigen suppressed subsequent T cell responses. Here we analyzed the effect of the superantigen Staphylococcal enterotoxin B (SEB) on a concurrent CD4(+) immune response to a conventional antigen, an I-Ab-restricted epitope derived from the same protein (SEB127-142). Heat-inactivated SEB, which had lost all superantigenic activity, was capable of eliciting a strong CD4(+) proliferative T cell response to SEB127-142. In contrast, native SEB was relatively nonimmunogenic, even when administered in association with complete Freund's adjuvant. High doses of native SEB coadministered with heat-inactivated SEB had no effect on the peptide response. However, low doses of native SEB were able to strongly enhance the ability of inactive SEB to prime CD4(+) T cells to SEB127-142. Thus, SEB is not always immunosuppressive, and low doses may actually enhance a concurrent immune response. Also, the contribution of Vbeta8(+)/CD4(+) T cells to peptide reactivity was not affected by the presence of low doses of native SEB, suggesting that the enhanced reactivity was not a Vbeta-specific effect of SEB, but was cytokine-mediated.