PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

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The aim of our research program is to understand the causes of autoimmune thyroid disease, the mechanism of the immune response and, if possible, to develop preventative or therapeutic immunomodulatory measures. We will identify dominant and pathogenic epitopes of TSH receptor (hTSH-R), determine genetic factors promoting the disease, determine the relationship of epitope recognition to MHG genotypes, and study potential immunotherapeutic measures in vitro and in vivo in a SCID mouse model. Epitopes will be identified using recombinant antigen and synthetic peptides reacting with PBMG, T cell lines and T cell clones derived from patients with GD and controls. We will study populations, families with a high incidence of GD, especially homozygous HLA-DQA1 *0501 patients, and young individuals in such families in the early phase of disease. To establish biologic importance of the epitopes we will consider 1) differential reactivity comparing patients with GD and controls, 2) concordance of reactivity by PBMC, and derived T cell lines and clones, 3) correlation of epitope recognition with disease and MHC genotype within families, 4) recognition of epitopes in young family members genetically at risk for GD, 5) changes in lymphocyte reactivity following antigen deprivation, and 6) relation of specific epitopes to MHG genes. Epitope reactivity will be analyzed following mutation of the peptide. Peptides which may be able to act as antagonists to the natural epitope, or to induce anergy in T cell lines or clones in vitro will be investigated. We will study, in SCID mice, the ability of T cell lines, reacting to specific epitopes, to reconstitute thyroiditis and produce thyroid stimulating antibodies in animals also xeno- transplanted with isologous thyroid tissue. In this model we can also test peptide antagonists, epitope induced T cell anergy, and induction of tolerance by antigen. Class II MHC genotypes will be determined by a PCR/site specific oligonucleotide methodology in Caucasian populations, Black populations, and Caucasian and Black family groups, to determine linkage of HLA with disease. Since it is clear that HLA associations explain only part of the genetic influence, we will proceed to type, in specific highly informative families, a group of at least eight candidate immune-associated genes for linkage to GD.