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Patients with progressive multiple sclerosis (MS) and controls were compared with regard to: (a) in vitro pokeweed mitogen (pwm)-induced IgG secretion, as an indirect measure of T8+ cell-mediated suppressor function; (b) alloantigen-directed cytotoxic activity, a predominantly T8+ cell-mediated function. The MS group had increased IgG secretion (4790 +/- 372 ng/ml vs. 1866 +/- 233 ng/ml, P less than 0.001) compared to controls. In contrast, alloantigen-directed cytotoxic activity did not differ between MS and control groups. These results suggest a selective defect of suppressor cell function in MS rather than a generalized dysfunction of T8+ cells. Defective immunoregulatory control coupled with preserved effector functions may contribute to the autoimmune process, suspected to underlie the pathogenesis of MS.

Concanavalin A (Con A)-induced suppressor activity has previously been shown to be reduced in multiple sclerosis (MS) patients with active clinical disease. In this study, we demonstrate that OKT3, as well as Con A induced suppressor activity mediated by unfractionated peripheral blood mononuclear cells is reduced in patients with the progressive form of MS. By performing reconstitution experiments involving E+, T4+, or T8+ cells derived from either MS patients or controls, and normal allogeneic macrophages or E- cells, we sought to define the cellular basis for this suppressor defect. In both MS and control groups, E+ cells were required to obtain measurable levels of suppression. Suppressor levels induced by Con A-activated cultures containing E+ cells from MS patients were lower than those induced by those containing control donor E+ cells. Suppression mediated by T8+ cells from MS patients was also lower than for controls. In the control group, suppression mediated by T8+ cells exceeded that mediated by T4+ cells; such differences were not apparent in the MS group. These results suggest that although Con A-induced suppression can be mediated by a number of T and non-T cell subsets, the functional suppressor defect measured in the MS population does involve the T8+ cell subset.

Patients with progressive multiple sclerosis (MS) demonstrated persistent reductions in levels of concanavalin A (Con A)-induced suppressor activity and heightened levels of in vitro pokeweed mitogen (PWM)-induced IgG secretion. The reduced Con A suppressor activity could not be reversed by addition of interleukin 2 (IL-2). Cyclosporine A (CsA) treatment did not alter the defect in Con A-induced suppressor activity, but did markedly inhibit T8+ cell-mediated alloantigen directed cytolytic activity; this latter defect was reversible by in vitro addition of IL-2. CsA-treated patients did not differ from placebo-treated patients with regard to levels of PWM-induced IgG secretion or proliferative responses of their mononuclear cells to Con A. The results indicate that CsA treatment of MS patients reduces cytolytic function from baseline normal values, but does not alter aberrant suppressor cell function.

In the normal young adult population, in vitro levels of polyclonally-induced IgG secretion by mononuclear cells (MNCs) vary widely amongst individuals. Levels of IgG secretion correlate with functional suppressor activity of T8+ cells but not with their proportion within the MNCs either prior to culture, or as found in this study, at the end of the culture period. The current study also demonstrates a lack of correlation between T8+ cell-mediated suppressor (Ts) function and a second predominantly T8+ cell-mediated function, alloantigen-directed cytolytic (Tc) activity. Whether this dissociation between Ts and Tc functions reflects quantitative differences in subsets contained within the T8+ population or qualitative differences in the mechanisms required for induction or generation of Ts and Tc remains to be established.

The mechanisms accounting for low levels of T-cell-dependent polyclonal IgG secretion in old and young human adults were compared. In elderly donors, in contrast to young donors, low levels of IgG secretion by unfractionated mononuclear cells (MNCs) did not correlate with functional suppressor activity of "panning"-enriched T8+ cells. Levels of IgG secretion by MNCs did not correlate either with proportions of T8+ or T4+ cells in the MNC population or with the functional helper activity of panning-enriched T4+ cells, in either old or young age groups. In young donors suppression mediated by either 2 or 5 X 10(4)T8+ cells of "low" IgG secretors (80.2 +/- 4.8 and 90.2 +/- 1.9%) was significantly greater than that induced by T8+ cells of "high" secretors (41.8 +/- 5.7 and 71.0 +/- 4.0%). Among elderly donors, suppression mediated by either 2 or 5 X 10(4)T8+ cells was reduced in both the low IgG secretion (31.9 +/- 5.3 and 52.3 +/- 7.0%) and high IgG secreting (14.9 +/- 7.2 and 46.8 +/- 5.7%) compared to the corresponding young donor subgroup. Levels of suppression mediated by 2 X 10(4)T8+ cells were suggestively lower in the high IgG secreting elderly subgroup compared to the low secreting subgroup (P less than 0.1). Our data suggest that decreased suppressor activity is a generalized occurrence in aging and that low polyclonal T-dependent MNC IgG secretion in the elderly, in contrast to young adults, cannot be attributed to high T-suppressor activity; nor does it usually reflect defective T-helper activity.

Neuroleukin is a lymphokine product of lectin-stimulated T cells that induces immunoglobulin secretion by cultured human peripheral blood mononuclear cells. Neuroleukin acts early in the in vitro response that leads to formation of antibody-secreting cells, but continued production of immunoglobulin by differentiated antibody-secreting cells is neuroleukin-independent. Although the factor is not directly mitogenic, cellular proliferation is a late component of the response to neuroleukin. Neuroleukin does not have B-cell growth factor (BCGF) or B-cell differentiation factor (BCDF) activity in defined assays. Neuroleukin-evoked induction of immunoglobulin secretion is both monocyte- and T-cell-dependent.