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 affected organ(s) and the presence of autoantibodies. Our analysis of the phenotype of the CD4+ T cells that remain in the 3-day thymectomized animal revealed that the majority (approximately 80%) of the CD4+ lymph node cells express an activated (MEL-14low) phenotype and a smaller percentage expressed the T cell activation Ag CD69 and IL-2R alpha-chain. Thymectomized animals also had an increase in the frequency of mitogen-induced CD4+ IL-4 producers and significantly higher levels 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 dendritic cells. To determine whether the syngeneic MLR-reactive T cells were involved in the pathogenesis of the organ-specific disease, we developed 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 thymus, nu/nu mice transplanted with adult APC-containing thymi demonstrated a decrease in the incidence and severity of gastritis, a marked decrease in the titer of anti-parietal cell Ab, and a decrease in total serum IgG. Thus, intrathymic tolerization to complexes of self-peptides and MHC class II on adult APC prevents organ-specific autoimmune disease.
Bonomo
A
A
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kehn
P J
PJ
Payer
E
E
Rizzo
L
L
Cheever
A W
AW
Shevach
E M
EM
D000818:Animals; D000831:Animals, Newborn; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005756:Gastritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009928:Organ Specificity; D011247:Pregnancy; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology* / Q000637:transplantation; D014185:Transplantation, Isogeneic
D001323:Autoantibodies; D001324:Autoantigens