CHALLENGING CYTOKINE REDUNDANCY - INFLAMMATORY CELL-MOVEMENT AND CLINICAL COURSE OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ARE NORMAL INLYMPHOTOXIN-DEFICIENT, BUT NOT TUMOR NECROSIS FACTOR-DEFICIENT, MICE

Lymphotoxin (LT) is widely regarded as a proinflammatory cytokine with activities equivalent to tumor necrosis factor (TNF). The contributio n of LT to experimental autoimmune encephalomyelitis (EAE) was examine d using TNF/LT alpha(-/-) mice, TNF-/- mice, and a new LT alpha(-/-) l ine described here. AU mice were generated directly in the C57BL/b str ain 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, w hen TNF is absent but LT is present, EAE is delayed in onset and infla mmatory leukocytes fail to move normally into the central nervous syst em parenchyma, even at the peak of disease. In the absence of both cyt okines, the clinical and histological picture is identical to that see n when TNF alone is deficient, including demyelination. Furthermore, t he therapeutic inhibition of TNF and LT alpha with soluble TNF recepto r in unmanipulated wild-type or TNF-/- mice exactly reproduces these o utcomes. We conclude from these studies that TNF and LT are functional ly distinct cytokines in vivo, and despite sharing common receptors, s how no redundancy of function nor mutual compensation.