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Year 2007, Volume 27 / Issue 3

Pages: 77

Article price - $35.00

Targeting the Antigen-Binding Site of HLA-Restricting Alleles in Treatment of Autoimmune Disease

Minako Oshima
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA

Philip Deitiker
Departments of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas

M. Zouhair Atassi
Department of Biochemistry and Molecular Biology, Department of Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

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-2^b) mice by injection with Torpedo AChR, region 62-76 of I-A^b β chain is involved in the disease mechanism. Monoclonal Abs (mAbs) against synthetic peptide I-Aβ^b62-76, which localizes at the rim of the antigen-binding site of I-A^b, 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.

pages 271-288

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