Table 4 Mechanisms

Intervention

Potential mechanisms

1. Adult TNF therapy (delays type 1 diabetes, prevents β-cell destruction, and delays glomerulonephritis in B/WF1 mice)

1. A decrease in TCR signal transduction and effector T-cell function mediated through TNFR1

2. An increase in T-cell apoptosis mediated by TNFR2

3. Very little effect has been found on CD4⁺CD25⁺ regulatory T cells in adult mice

2. Adult anti-TNF therapy (variably hastens type 1 diabetes, increases B/W F1 nephritis, and increases late EAE)

1. An increase in TCR signal transduction and effector T-cell function through TNFR1

2. A decrease in T-cell apoptosis through TNFR2

3. Very little effect has been found on CD4⁺CD25⁺ regulatory T cell numbers by anti-TNF

3. Neonatal TNF therapy (increases diabetes incidence and hastens onset in NOD mice)

1. Further decreases CD4⁺CD25⁺ regulatory T cells, possibly via TNFR2-mediated T-cell apoptosis

2. Possible activation of macrophages and dendritic cells, increasing insulitis

3. A decrease in TCR signal transduction via TNFR1, permitting potentially autoreactive T cells to escape negative selection, emigrate to the periphery and cause diabetes

4. Neonatal anti-TNF therapy (completely prevents type 1 diabetes in NOD mice)

1. Dramatically increases CD4⁺CD25⁺ regulatory T cells, possibly by blocking TNFR2-mediated T-cell apoptosis

2. Possibly decreases macrophage and dendritic cell activation so that regulatory T cells can function effectively

3. Possibly increases TCR signal transduction so that autoreactive T cells are negatively selected in the thymus and/or in the periphery