Organ-specific autoimmunity induced by adult thymectomy and cyclophosphamide-induced lymphopenia.
Autoimmune gastritis, a CD4+ T cell-mediated organ-specific autoimmune disease, can be induced by thymectomy of neonatal, but not of older, BALB/c mice. Here we have shown that autoimmune gastritis can also be induced in 6-8-week-old BALB/c mice by thymectomy combined with a single dose of cyclophosphamide (300 mg/kg). This treatment reduced the numbers of splenic T and B cells approximately 25-fold. However, by 8 days after treatment, the number of splenic lymphocytes had returned to normal adult levels. Approximately 50% of treated mice developed autoimmune gastritis after 10-12 weeks. These mice had mononuclear cellular infiltrates within the gastric mucosa and serum autoantibodies to the alpha and beta subunits of the gastric H+/K+ ATPase. Transgenic mice, expressing the gastric H+/K+ ATPase beta-subunit in the thymus (Alderuccio, F., Toh, B. H., Tan, S. S., Gleeson, P. A. and van Driel, I. R., J. Exp. Med. 1993. 178: 419), did not develop autoimmune gastritis after the adult thymectomy/cyclophosphamide treatment. Thus a T cell response to the H+/K+ ATPase beta-subunit is likely to be required for the onset of gastritis. These observations suggest that pathogenic autoreactive T cells exist in the periphery of normal adult mice and that autoimmunity can be induced by the activation of these autoreactive T cells following transient lymphopenia. Cyclophosphamide-treatment of adult mice without thymectomy did not induce autoimmune gastritis, suggesting thymic regulation of these pathogenic T cells.
Department of Pathology and Immunology, Monash University Medical School, Alfred Hospital, Melbourne, Australia.
S P
SP
Barrett
B H
BH
Toh
F
F
Alderuccio
I R
IR
van Driel
P A
PA
Gleeson
D000375:Aging / Q000276:immunology; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000187:drug effects; D003520:Cyclophosphamide; D005434:Flow Cytometry; D005756:Gastritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000276:immunology; D015151:Immunoblotting; D016219:Immunotherapy, Adoptive; D008231:Lymphopenia / Q000139:chemically induced / Q000150:complications / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects; D013934:Thymectomy; D013950:Thymus Gland / Q000502:physiology*
D003520:Cyclophosphamide; D017506:H(+)-K(+)-Exchanging ATPase