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Table 4 Mechanisms

From: Multiple roles for tumor necrosis factor-α and lymphotoxin α/β in immunity and autoimmunity

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
  1. EAE, experimental allergic encephalomyelitis; NOD, nonobese diabetic; TCR, T-cell receptor; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor 1 (55 kb); TNFR2, tumor necrosis factor receptor 2 (75 kb).