CONTROL OF IMMUNE-MEDIATED DISEASE OF THE CENTRAL-NERVOUS-SYSTEM WITHMONOCLONAL (CD4-SPECIFIC) ANTIBODIES

Chronic relapsing experimental allergic encephalomyelitis (CREAE) was induced in Biozzi AB/H (H-2dq1) mice by active sensitization with spin al cord antigens. A single i.p. injection of CD8-depleting (YTS169.4) monoclonal antibody (mAb) failed to affect the clinical course of CREA E when administered prior to and during the onset of both the initial clinical and subsequent relapse phase of the disease. By contrast simi lar treatment with both CD4-depleting (YTS191.1) or CD4-blocking/non-d epleting (YTS177.9) mAb significantly inhibited disease progression. T reatment shortly before the anticipated onset of clinical EAE prevente d the subsequent development of disease, although disease could be pro voked following antigen-rechallenge. In contrast, treatment with these antibodies during post-acute remission phase mainly served to delay t he incidence of relapse. This suggests that, unless tolerance can be r e-induced, treatment of ongoing neuroimmunological disease will requir e 'pulse' therapy and thus potentiate the problems of long-term immuno suppresion. Despite the findings that CD4-specific antibodies can rapi dly reverse overt clinical disease shortly after the onset of disease exacerbation, once neurological dysfunction becomes established anti-C D4 treatment fails to improve the animals clinically, possibly due to the inability to rapidly reverse established demyelination. Although t his study does not exclude the potential central action of the injecte d mAb, the failure to significantly dissociate therapeutic benefit bet ween mAb administered directly into the CNS and that given systemicall y suggests that a major action of these agents is probably by selectiv ely removing T cells in the peripheral T cell pool.