It has recently been reported that interleukin-4 (IL-4) is required for the production of IgE, and anti-IL-4 monoclonal antibody (mAb) inhibits in vivo IgE responses. These suggest that blocking of IL-4 activity may be useful for the prevention or treatment of immediate hypersensitivity disorders. In this study we investigated whether anti-IL-4 has a regulatory role in chicken-gamma globulin (CGG)-induced active systemic anaphylaxis. Multiple injections of anti-IL-4 (up to 40 mg/mouse) failed to protect the mice from fatal anaphylaxis. Anti-IL-4 strongly suppressed CGG-specific IgE response (>90%) without any suppressive effect on CGG-specific IgG (IgG1, IgG2a, IgG2b, and IgG3) responses. Because these data suggest the possibility that fatal anaphylaxis could be induced by IgG antibodies, we examined the possibility using anti-CGG polyclonal and the subclasses of IgG monoclonal antibodies. Passive sensitization of mice with polyclonal antibodies elicited severe and fatal anaphylactic shock; about 50% of the mice died. The activity of antibodies was not diminished by heat treatment (56 degrees C, 2h), suggesting that the anaphylaxis was not mediated by IgE. Shock was also elicited by each subclass of IgG mAb; of these, IgG1 was the most effective. Combination of the IgG subclasses elicited more exaggerated shock; about 30% of mice died. These data indicate that IgG antibodies are themselves sufficient to induce systemic anaphylaxis. Therefore, the failure of anti-IL-4 to prevent active anaphylaxis is probably due to the inability of anti-IL-4 to suppress the production of IgG antibodies.
Anaphylaxis/*immunology/prevention & control ; Animal ; Antibodies, Anti-Idiotypic/immunology ; Antibodies, Monoclonal/*immunology/therapeutic use ; Chickens ; Female ; Gamma-Globulins ; Immunoglobulin E/*immunology ; Immunoglobulin G/*immunology ; Interleukin-4/*immunology/therapeutic use ; Mice ; Mice, Inbred BALB C ; Support, Non-U.S. Gov't

For those with allergy, vaccination with a specific allergen has often been used as a major therapeutic measure. However, the universal application of this technique in clinics have been restricted due to its low success rates and the risk of active systemic anaphylactic shock (ASAS). In this regard, we constructed a fusion protein (OVA-DT), ovalbumin (OVA) fused with diphtheria toxin protein (DT), which may exert a specific cytotoxicity to cells bearing OVA-specific IgE. Its therapeutic effect was evaluated in mice (BALB/c) sensitized with OVA (Os-mice). OVA challenges to the OVA-sensitized mice (Os-mice) caused ASAS to death within 30 min, but OVA-DT treatment afforded mice complete protection. When OVA-DT was treated to the Os-mice, none showed the signs of ASAS when re-challenged 48 h after the treatment. OVA-DT itself was not found to be toxic or allergenic in normal mice. The effect of OVA-DT on the biological functions of mast cells was also studied. Binding of OVA-DT to OVA-specific IgE bearing mast cells and the inhibition of histamine release from these cells were observed. In addition, OVA-DT treatment inhibited the proliferation of OVA-specific B cells in mice. In Os-mice treated with OVA-DT, levels of anti-OVA IgG2a in serum and the production of IFN-gamma by splenic lymphocytes were found to increase, but the production of IL-4 by these cells decreased. Re-direction of cytokine profiles from OVA-specific Th2 to OVA-specific Thl is suggested. These results indicate that OVA-DT can protect Os-mice from ASAS due to OVA challenge, because it inactivates OVA-specific IgE-expressing cells, including mast cells and B cells.
Anaphylaxis/prevention | control* ; Animal ; B-Lymphocytes/immunology ; Female ; Histamine Release/drug effects ; IgE/metabolism ; Interferon Type II/biosynthesis ; Interleukin-4/biosynthesis ; Lymphocyte Transformation/drug effects ; Mast Cells/metabolism ; Mice ; Mice, Inbred BALB C ; Ovalbumin/immunology* ; Recombinant Fusion Proteins/therapeutic use*