title: Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype.
abstract: Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF(-/-) mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death.
authors.affiliation: Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. heinrich.koerner@mikrobio.med.unierlangen.de
authors.forename: H
authors.initials: H
authors.lastname: Körner
authors.forename: E
authors.initials: E
authors.lastname: Cretney
authors.forename: P
authors.initials: P
authors.lastname: Wilhelm
authors.forename: J M
authors.initials: JM
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: Röllinghoff
authors.forename: J D
authors.initials: JD
authors.lastname: Sedgwick
authors.forename: M J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D053222:Fas Ligand Protein; D018858:Germinal Center / Q000502:physiology; D008232:Lymphoproliferative Disorders / Q000209:etiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha