A novel in vitro model of thyroid ophthalmopathy

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): Thyroid-associated ophthalmopathy (TAO) is the most commonly encountered orbital disease, affecting vision and producing disfigurement. We are beginning to explore an in vitro model of TAO based upon a new methodology of reverse autologous mixed cell reaction (rAMCR), which studies the effects of autologous T-cells from TAO patients on DNA synthesis in orbital fibroblasts from the same patient. This investigation that should meet the NEI challenge to "yield insight into the initiating events leading to fibroblast activation and tissue remodeling and the cell signaling events that stimulate the trafficking of immunocompetent cells to the orbit". It should also aid in determining the immunologic and hormonal basis for the proliferation and phenotypic alteration of orbital fibroblasts (OF). The purpose of this R03 pilot study application is to further develop this model, including a rigorous evaluation of the immunologic and local environmental mechanisms involved in the enhancement of orbital fibroblast proliferation in the rAMCR. The overall hypothesis to be tested in this proposal is that peripheral blood from TAO patients contains T cells that directly activate OF to enhance fibroproliferation and to drive OF to an activated phenotype and to adipocyte-like cells characteristic of TAO. The two specific aims of the study are to determine 1) which subset(s) of peripheral blood T cells are key for stimulating OF proliferation and activation in vitro and by which means of cell-cell communication is this accomplished? and 2) what are the key functional consequences of activation by peripheral blood T cells? In preliminary studies, we have shown that an enriched T-cell results in a two-to-three fold HLA DRII and CD40/CD 40 ligand dependent increase in fibroproliferation. Understanding which OF subset is the target of the rAMCR will help narrow the avenues for therapeutic exploration and will define the cellular cross-talk between immune cells and OF. The nature of the OFs is of critical importance in TAO as they are the effector cells that cause the tissue pathology, including the accumulation of fatty tissue (especially early in disease) and the muscle fibrosis that occurs later. Exploration of the rAMCR model will help move the TAO field forward and will lead to new insights into the pathophysiology of the disease and identification of target molecules the may serve as a basis for possible therapeutic intervention.