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Original Article

^a From the Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
^b Institut für Klinische Mikrobiologie, Immunologie und Hygiene, D-91054 Erlangen, Germany
^c DNAX Research Institute, Palo Alto, California 94304
^d Laboratory of Cellular Cytoxicity, The Austin Research Institute, Heidelberg, 3084 Victoria, Australia
IZKF Nachwuchsgruppe, Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Wasserturmstrasse 3-5, D-91054 Erlangen, Germany.91-31-852- 257391-31-852-2665

heinrich.koerner{at}mikrobio.med.uni-erlangen.de

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.

Key Words: lymphoproliferation • apoptosis • lymphadenopathy • Fas ligand • gene targeting

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.

© 2000 The Rockefeller University Press

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