Tryptophan catabolism in nonobese diabetic mice.
Autoimmune diseases including insulin-dependent diabetes mellitus (IDDM) are characterized by the loss of tolerance to self determinants, activation of autoreactive lymphocytes, and subsequent damage to target organs. Recent evidence suggests that the development of autoimmune diabetes in the nonobese diabetic mouse (NOD), an animal model of IDDM, is under the control of dendritic cells. The potent antigen-presenting capacity of dendritic cells can be strongly influenced by the cell maturation state and by the cytokine milieu, and in fact these cells may acquire disparate functional abilities, from immunity to tolerance. We have previously demonstrated that, in the DBA/2 mouse, IFN-gamma potentiates the tolerogenic potential of a subset of splenic dendritic cells via activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and production of tryptophan catabolites capable of inducing apoptosis in T cells. In the present study, we wanted to examine whether dendritic cells from NOD mice could be subjected to regulation by proinflammatory cytokines in the same fashion as in conventional mice. We found that IFN-gamma does not potentiate the tolerogenic effects of dendritic cells from NOD mice at four weeks of age. This finding correlates with a low expression of IDO activity, thus suggesting that poor expression of IDO by dendritic cells may play a role in the development of diabetes.
Grohmann
Ursula
U
Department of Experimental Medicine, University of Perugia, Italy. ugrohmann@tin.it
Fallarino
Francesca
F
Bianchi
Roberta
R
Vacca
Carmine
C
Orabona
Ciriana
C
Belladonna
Maria Laura
ML
Fioretti
Maria Cristina
MC
Puccetti
Paolo
P
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D009842:Oligopeptides / Q000276:immunology; D011994:Recombinant Proteins; D017634:Self Tolerance / Q000187:drug effects; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009842:Oligopeptides; D011994:Recombinant Proteins; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase