Modulation of the human IgE response.
Studies on the immunological basis of allergic diseases have indicated that enhanced production of the cytokines interleukin (IL)-4 and IL-13 and the reduced production of interferon-gamma (IFN-gamma) by allergen-specific T-cells contribute to enhanced immunoglobulin E (IgE) synthesis and the development of allergic disease in certain individuals. Therefore, inhibition of IL-4 and IL-13 synthesis or blocking of activities of these cytokines would be one approach to inhibiting IgE production. In the present communication, novel approaches toward this goal are discussed. It is shown that an IL-4 mutant protein, in which the tyrosine residue at position 124 is replaced by aspartic acid (IL-4,Y124D), binds with high affinity to the IL-4 receptor, without receptor activation. IL-4,Y124D acts as a potent antagonist both of IL-4 and IL-13 activity in vitro, and inhibits immunoglobulin G4 (IgG4) and IgE production induced by these cytokines. These data are compatible with the notion that the IL-4 and IL-13 receptors are complex receptors, which share a common component, which is required for signal transduction. In addition, it has been demonstrated that allergen-specific T-cells, belonging to the T-helper 2 (Th2) subset can be rendered anergic after incubation with allergen-derived peptides representing minimal T-cell activation inducing epitopes. These anergic Th2 cells failed to produce IL-4 and IL-13, and failed to proliferate after activation with allergen and antigen-presenting cells (APC). The anergized T cells also failed to give B-cells help in IgE synthesis, although they expressed normal levels of the CD40 ligand (CD40L). Exogenous IL-4 and IL-13 failed to restore IgE synthesis, indicating that in addition to CD40L other co-stimulatory signals are required for productive T-cell/B-cell interactions, resulting in IgE synthesis. IgE production was restored by exogenous IL-2, demonstrating that IL-2 reverses the nonresponsive state and helper function of these nonresponsive T-cells. It is tempting to speculate that induction of T-cell nonresponsiveness by allergen-derived peptides may represent the underlying mechanisms for successful immunotherapy in allergenic patients.
de Vries
J E
JE
Human Immunology Dept, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, CA, USA.
Yssel
H
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance; D016056:Immunodominant Epitopes / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000502:physiology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007167:Immunotherapy; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology
D019013:CD40 Antigens; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D018793:Interleukin-13; D011994:Recombinant Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E