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.
Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder (gld) Phenotype
Mark Smyth, Laboratory of Cellular Cytoxicity, The Austin Research Institute, Studley Road, Heidelberg, 3084 Victoria, Australia. Phone: 61-39-287-0653; Fax: 61-39-287-0600; E-mail: [email protected]
Abbreviations used in this paper: ABTS, 2.2′-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid); B6, C57BL/6; C3H, C3H/HeJ; DN, double negative; ds, double-stranded; GC, germinal center; gld, generalized lymphoproliferative disorder; HRP, horseradish peroxidase; lpr, lymphoproliferation; mLN, mesenteric LN; pLN, peripheral LN; TPBS, Tween/PBS; WT, wild-type.
Heinrich Körner, Erika Cretney, Patricia Wilhelm, Janice M. Kelly, Martin Röllinghoff, Jonathon D. Sedgwick, Mark J. Smyth; Tumor Necrosis Factor Sustains the Generalized Lymphoproliferative Disorder (gld) Phenotype. J Exp Med 3 January 2000; 191 (1): 89–96. doi: https://doi.org/10.1084/jem.191.1.89
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