PATTERNS OF CYTOKINE SECRETION BY AUTOREACTIVE PROTEOLIPID PROTEIN-SPECIFIC T-CELL CLONES DURING THE COURSE OF MULTIPLE-SCLEROSIS

To determine whether cytokine secretion patterns change with disease s tatus in patients with multiple sclerosis (MS), we measured IFN-gamma, TNF-gamma beta, IL-4, IL-6, IL-10 and TGF-beta secretion in a panel o f T cell clones (TCCs) specific for proteolipid protein (PLP) after st imulation with PLP peptides or polyclonal activators. During acute att ack, the predominant pattern of cytokine secretion resembled that of m urine Th1 cells; i.e, IFN-gamma and TNF-alpha beta, and appeared to be restricted to PLP-reactive TCCs. None of the TCCs isolated during acu te attack produced TGF-beta in response to PLP, Con A, or anti-CD3 Ab. Half of these TCCs were, however, capable of TGF-beta secretion and m RNA expression upon stimulation with PMA and the calcium ionophore A23 187, suggesting a possible defect in activation through the TCR/CD3 pa thway. During remission in the same patients all but two PLP-TCCs show ed patterns of cytokine secretion resembling that of murine Th0, Th1, and Th2 subsets. The levels of IL-10 secreted by these TCCs were signi ficantly higher than those of TCCs isolated during acute attacks and t hose derived from normal subjects and patients with other noninflammat ory neurologic diseases. Furthermore, 50% of these TCCs were capable o f producing TGF-beta after Ag-specific or polyclonal stimulation. All TCCs isolated from control subjects exhibited a Th0 like secretion pro file. These data indicate that different stages of disease in MS are c haracterized by different patterns of cytokine secretion by PLP-specif ic TCCs, suggesting a role for cytokines in clinical events during the course of MS.