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From the Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert
Einstein College of Medicine, Bronx, New York, 10461
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous
system (CNS), and the most commonly used experimental model for multiple sclerosis. It is
mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to
suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In
this study, we tested the hypothesis that a Th2-type immune response against an exogenous,
nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to
a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's
adjuvant to induce a population of Th2 memory cells that would be expected to release Th2
cytokines when activated by the specific antigen at the time of EAE induction. Four weeks
later, mice received an encephalitogenic challenge containing guinea pig myelin in complete
Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous
antigen at the time of EAE induction developed a severe clinical disease indistinguishable from
control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical
signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the
primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein-specific T cells was shifted
from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4
secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in
which the autoreactive T cells were engaged by the encephalitogenic stimulus were able to bias
their cytokine profile towards a protective Th2 phenotype. This interpretation is supported by
the observation that the protective effect of preimmunization with KLH was overcome by rm-
IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune
response to a predominantly Th1 type. Since IL-4 mRNA could not be detected by reverse
transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells
in the lymphoid system, and not the target organ. We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter
the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide
significant protection against EAE and possibly other T cell-mediated autoimmune diseases.
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