Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model.
Mice that express influenza hemagglutinin under control of the rat insulin promoter (INS-HA) as well as a class II major histocompatibility complex (MHC)-restricted HA-specific transgenic TCR (TCR-HA), develop early insulitis with huge infiltrates, but progress late and irregularly to diabetes. Initially, in these mice, INS-HA modulates the reactivity of antigen-specific lymphocytes, such that outside the pancreas they do not cause lethal shock like their naive counterparts in single transgenic TCR-HA mice, when stimulated with high doses of antigen. Inside the pancreas, the antigen-specific cells do not initially attack the islet cells, and produce some IFN-gamma as well as IL-10 and IL-4. Spontaneous progression to diabetes, which can be accelerated by cyclophosphamide injection, is accompanied by a 10-fold increase in IFN-gamma and a 3-fold decrease in IL-10 and IL-4 production by the locally residing antigen-specific T cells. Also, total islets from non-diabetic mice contain more TNF-alpha, compared with diabetic mice. This scenario is consistent with the view that beta cell destruction depends upon the increased production of certain pro-inflammatory cytokines by infiltrating T cells. Our inability to detect Fas expression on beta cells, but not on lymphoid cells, in diabetic and non-diabetic mice, puts some constraints on the role of Fas in beta cell destruction.
Sarukhan
A
A
Institut Necker, INSERM 373, 156 rue de Vaugirad, 75730 Paris, Cedex 15, France.
Lanoue
A
A
Franzke
A
A
Brousse
N
N
Buer
J
J
von Boehmer
H
H
D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity; D016207:Cytokines / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D007328:Insulin / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
D016207:Cytokines; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007328:Insulin; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D003520:Cyclophosphamide