年間 6 号発行
ISSN 印刷: 1040-8401
ISSN オンライン: 2162-6472
Indexed in
Targeting the Antigen-Binding Site of HLA-Restricting Alleles in Treatment of Autoimmune Disease
要約
In autoimmune disease, production of disease-causing auto-antibodies (Abs) depends on autoreactive T cells that recognize the epitopes of the pathogenic antigen in the context of MHC class II molecules. It is possible that selective inhibition of an antigen-presenting function of disease-associated MHC alleles could lead to suppression of the disease. Myasthenia gravis (MG) is a disabling neuromuscular disease in which autoimmune responses against acetylcholine receptor (AChR), especially against the α chain of AChR, cause a postsynaptic defect. HLA linkage of MG has been thus far best detailed for DQB1. Recently, we have shown that certain DQ haplotypes are associated with presentation of AChR α-chain peptides in MG. In a mouse model for MG, which can be induced in disease-susceptible C57BL/6 (B6, H-2b) mice by injection with Torpedo AChR, region 62-76 of I-Ab β chain is involved in the disease mechanism. Monoclonal Abs (mAbs) against synthetic peptide I-Aβb62-76, which localizes at the rim of the antigen-binding site of I-Ab, inhibited in vitro proliferation of disease-associated T cells. Passive transfer of these mAbs as well as vaccination with this peptide strongly suppressed occurrence of clinical MG in B6 mice. In both cases, Ab and T-cell responses against AChR, especially those related to disease pathogenesis, also decreased. mAbs against peptides from the ridge of the antigen-binding region of the correlate DQB1 sequences inhibited in vitro the proliferation of AChR-specific T cells from MG patients. The results indicated that the function of disease-associated MHC alleles may be blocked by directly and selectively targeting the antigen-presenting region on these MHC molecules. The strategy could provide an effective means for immunointervention in other autoimmune and allergic responses.
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