Immunization protocols that induce high levels of delayed-type hypersensitivity are often associated with low levels of antibody production, whereas alternative immunization strategies can produce the opposite effect. This reciprocal relationship appears to depend, at least in part, on the fact that T cell-derived lymphokines that are predominantly involved in one type of response inhibit the development of those T cells that promote the alternative one. Such a regulatory mechanism is likely to be bistable in that whenever one form of response is established, spontaneous development of the alternative one will be inhibited. We have applied this concept to the control of a cell-mediated autoimmune disease in rats. By covalently linking the autoantigen to anti-IgD antibody, we have targeted it to B cells for presentation to antigen-specific T cells. This form of presentation favors antibody production and may be expected to antagonize the cell-mediated disease-inducing response to the same antigen. To test this hypothesis, use was made of the fact that experimental allergic encephalomyelitis (EAE), when induced with the encephalitogenic peptide of guinea pig myelin basic protein, is purely a cell-mediated disease. The experiments show that Lewis rats, immunized with the peptide in its encephalitogenic form, were protected from disease when simultaneously injected with the peptide coupled to anti-IgD monoclonal antibodies. Control experiments showed that neither peptide nor anti-IgD alone were protective, and the peptide covalently coupled to irrelevant antibodies also failed to protect. Spleen cells from animals protected from disease by the anti-IgD-peptide conjugate, when activated in vitro with the encephalitogen, were able to transfer EAE to naive recipients. The results demonstrate that a cell-mediated immune response can be controlled by appropriate targeting of the specific antigen without inducing T cell anergy and suggest a potential strategy for preventing autoimmune diseases that are essentially cell-mediated in type.

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