Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes.

The onset of type 1 diabetes in NOD mice is delayed by oral administration of a bacterial extract (OM-85) and can be completely prevented by its intraperitoneal administration. Optimal prevention is observed when starting treatment at 3 or 6 weeks of age, and some effect is still observed with treatment at 10 weeks of age. Using genetically deficient mice and cytokine-neutralizing monoclonal antibodies, we demonstrate here that the therapeutic effect does not involve T-helper type 2 cytokines (interleukin [IL]-4 and -10) but is tightly dependent on transforming growth factor (TGF)-beta. Natural killer T-cells also participate in the therapeutic effect because CD1d(-/-) NOD mice are partially resistant to the protective effect of OM-85. The question remains of the specificity of the protective effect of OM-85, which may include proinflammatory components. It will thus be important to further characterize the molecular components that afford protection from type 1 diabetes. Lipopolysaccharide is excluded, but other Toll-like receptor (TLR) agonists could be involved because OM-85 stimulated dendritic cells and induced TGF-beta production by splenocytes in a TLR-2-, TLR-4-, and MyD88-dependent fashion.

Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells.

Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+ CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-beta-dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-beta-dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell's escape from TGF-beta-dependent T-cell-mediated regulation.

Diversity of regulatory CD4+T cells controlling distinct organ-specific autoimmune diseases.

Depletion of selected regulatory CD4+ T cell subsets induces the spontaneous onset of various immune or autoimmune disorders. It is not clear, however, whether a given subset, notably CD4+CD25+ regulatory T cells, protects from a wide spectrum of immune disorders, or whether specialized subsets of regulatory T cells control each given disease or group of diseases. We report here, using diabetes prone nonobese diabetic (NOD) mice, that depending on the regulatory T cells that are depleted, i.e., CD25+, CD62L+, or CD45RB(low), distinct immune diseases appear after transfer into NOD severe combined immunodeficiency (SCID) recipients. Thus, reconstitution of NOD SCID mice with CD25- T cells induces major gastritis and late-onset diabetes, but no or mild colitis. Reconstitution with CD62L- T cells induces fulminant diabetes with no colitis or gastritis. Reconstitution with CD45RB(high) T cells induces major colitis with wasting disease and no or very moderate gastritis and diabetes. Major differences among the three regulatory T cell subsets are also seen in vitro. The bulk of suppressor cells inhibiting the proliferation of CD4+CD25- T cells in coculture is concentrated within the CD25+ but not the CD62L+ or CD45RB(low) T cell subsets. Similarly, cytokine production patterns are significantly different for each regulatory T cell subset. Collectively, these data point to the diversity and organ selectivity of regulatory T cells controlling distinct autoimmune diseases whatever the underlying mechanisms.