Targeted at learning about inflammatory eye diseases, this project continued to focus on ocular antigens capable of initiating pathogenic autoimmune processes in the eye, the disease processes, and mechanisms that modulate such diseases. The major achievements from the project in fiscal year (FY) 1996 include the following: (1) Using the sensitive RT-PCR method, we detected the mRNA of three retinal-specific binding proteins and rhodopsin. This finding suggests that small amounts of retinal antigens are expressed in mouse thymus and are responsible for the partial resistance of mice to autoimmune eye diseases by rendering these animals unresponsive to ocular antigens. (2) Mice deficient of alpha-A-crystallin due to genetic manipulation (""""""""knockout"""""""" mice) were tested for their response to mouse alpha-A-crystallin; lack of autologous antigen was assumed to abolish the natural tolerance to this antigen. Unexpectedly, however, the knockout mice resembled their wild-type controls in being tolerant to mouse alpha-A-crystallin. Although no alpha-A-crystallin was detected in their lens, the knockout mice contained alpha-A-crystallin mRNA in their thymus, thus providing a putative mechanism for the tolerance in these animals. (3) We have previously shown (FY 1994 and 1995) that transgenic (Tg) mice expressing a foreign antigen in their lens, hen egg lysozyme (HEL), are totally tolerant to HEL. Double Tg mice, that express both HEL and a proinflammatory cytokine, interleukin 1 or interferon-gamma, were found to exhibit partial breakdown of their tolerance state: following immunization with HEL, the double Tg mice developed antibodies to HEL while their cellular response to this antigen remained negative. These data thus indicate that the tolerance process can be modulated by certain cytokines. (4) Antigen presentation by B-cells preferentially stimulates """"""""type 2"""""""" helper T-cells, a subset of lymphocytes that inhibit rather than initiate immune-mediated inflammatory processes. To achieve selective presentation of a uveitogenic peptide by B-cells, we conjugated the peptide to a monoclonal antibody specific to a B-cell. Treatment of rats with the conjugate prior to a challenge with the same peptide in a disease-inducing form completely inhibited or dramatically reduced the development of uveitic changes in the eyes of the treated animals. This experimental procedure thus provides a new type of immunosuppression of immune-mediated ocular inflammation.
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