PATHOGENESIS OF POST-THYMECTOMY AUTOIMMUNITY - ROLE OF SYNGENEIC MLR-REACTIVE T-CELLS

Thymectomy of 3-day-old mice results in the development of multi-organ -specific autoimmune diseases. The disease process is mediated by CD4( +) T cells and is characterized by an inflammatory infiltrate in the a ffected organ(s) and the presence of autoantibodies. Our analysis of t he phenotype of the CD4(+) T cells that remain in the 3-day thymectomi zed animal revealed that the majority (similar to 80%) of the CD4(+) l ymph node cells express an activated (MEL-14(low)) phenotype and a sma ller percentage expressed the T cell activation Ag CD69 and IL-2R alph a-chain. Thymectomized animals also had an increase in the frequency o f mitogen-induced CD4(+) IL-4 producers and significantly higher level s of total serum IgG. Functional studies demonstrated that lymph node T cells from 3-day thymectomized mice had an enhanced response in the syngeneic MLR and appeared to preferentially respond to syngeneic dend ritic cells. To determine whether the syngeneic MLR-reactive T cells w ere involved in the pathogenesis of the organ-specific disease, we dev eloped a model that mimicked the 3dTx model by grafting neonatal thymi to adult nu/nu recipients followed by removal of the thymus graft on day 3 or 4. When compared with mice transplanted with an untreated thy mus, nu/nu mice transplanted with adult APC-containing thymi demonstra ted a decrease in the incidence and severity of gastritis, a marked de crease in the titer of anti-parietal cell Ab, and a decrease in total serum IgG. Thus, intrathymic tolerization to complexes of self-peptide s and MHC class II on adult APC prevents organ-specific autoimmune dis ease.