The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/5/1517/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 9, May 4, 1998 1517-1528

Articles

Challenging Cytokine Redundancy: Inflammatory Cell Movement and Clinical Course of Experimental Autoimmune Encephalomyelitis Are Normal in Lymphotoxin-deficient, but Not Tumor Necrosis Factor–deficient, Mice

D. Sean Riminton*, Heinrich Körner*, Deborah H. Strickland*, Frances A. Lemckert*, John D. Pollard{ddagger}, and Jonathon D. Sedgwick*

From the * Centenary Institute of Cancer Medicine and Cell Biology, Sydney, New South Wales 2050, Australia; and {ddagger} Department of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia

Lymphotoxin (LT) is widely regarded as a proinflammatory cytokine with activities equivalent to tumor necrosis factor (TNF). The contribution of LT to experimental autoimmune encephalomyelitis (EAE) was examined using TNF/LT{alpha}–/– mice, TNF–/– mice, and a new LT{alpha}–/– line described here. All mice were generated directly in the C57BL/6 strain and used for the preparation of radiation bone marrow chimeras to reconstitute peripheral lymphoid organs and restore immunocompetence. This approach overcame the problems related to the lack of lymph nodes that results from LT{alpha} gene targeting. We show here that when LT is absent but TNF is present, EAE progresses normally. In contrast, when TNF is absent but LT is present, EAE is delayed in onset and inflammatory leukocytes fail to move normally into the central nervous system parenchyma, even at the peak of disease. In the absence of both cytokines, the clinical and histological picture is identical to that seen when TNF alone is deficient, including demyelination. Furthermore, the therapeutic inhibition of TNF and LT{alpha} with soluble TNF receptor in unmanipulated wild-type or TNF–/– mice exactly reproduces these outcomes. We conclude from these studies that TNF and LT are functionally distinct cytokines in vivo, and despite sharing common receptors, show no redundancy of function nor mutual compensation.

Address correspondence to Jonathon D. Sedgwick, Centenary Institute of Cancer Medicine and Cell Biology, Bldg. 93, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia. Phone: 61-2-9565-6116; Fax: 61-2-9565-6103; E-mail: j.sedgwick{at}centenary.usyd.edu.au

Ms. Lisa Galli's role in the generation of the LT{alpha}–/– mice is acknowledged. We thank Dr. Robert Hoek for advice on the RT-PCR analysis, and Dr. Bernie Scallon (Centocor, Inc., Malvern, PA) for providing the TNFR–IgG fusion protein. We appreciate the contributions of Mr. Jim Bonner for technical assistance and Ms. Karen Knight and Mr. James Crozer for expert animal husbandry.

Abbreviations used: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; ES, embryonic stem; iNOS, inducible nitric oxide synthase; LT, lymphotoxin; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; RAG, recombinase activation gene; RT-PCR, reverse transcriptase PCR; TNFR–IgG, TNFR–human IgG fusion protein; WT, wild type.Radiation bone marrow chimeras: WT-> WT, WT bone marrow transplanted into WT recipients; WT-> RAG, WT bone marrow transplanted into RAG-1–/– recipients; LT-> RAG, LT{alpha}–/– bone marrow transplanted into RAG-1–/– recipients; TNF-> RAG, TNF–/– bone marrow transplanted into RAG-1–/– recipients; TNF-> TNF, TNF–/– bone marrow transplanted into TNF–/– recipients; TNF/LT-> TNF, TNF/LT{alpha}–/– bone marrow transplanted into TNF–/– recipients.


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