Anti-immunoglobulin E monoclonal antibody administered with immunotherapy
ABSTRACT Despite both efficacy and immunotolerogenic effects, many clinicians still are reluctant to use allergen-specific immunotherapy (SIT) because of the potential for acute allergic reactions. The anti-immunoglobulin E monoclonal antibody, omalizumab, is approved by the U.S. Food and Drug Administration for the treatment of moderate-to-severe allergic asthma and has proven to be a relatively safe agent. Knowledge of the distinct immunologic changes elicited by allergen SIT and omalizumab has established a rationale for investigation into their combined use for the management of allergic diseases. This review summarizes two investigative studies examining the safety and efficacy of the combination of omalizumab + allergen SIT for the treatment of allergic rhinitis. Both studies show that the combination of omalizumab and allergen SIT confer added efficacy to either treatment alone. Pretreatment of patients with omalizumab before rush allergen immunotherapy also showed added safety to rush immunotherapy with the prevention of acute allergic reactions. Results thus far provide the opportunity to develop strategies using omalizumab pretreatment to enhance the safety and efficacy of allergen-immunotherapy to treat a wide variety of allergic diseases.
- SourceAvailable from: Basel al-Ramadi
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- "Based on evidence obtained in both human and animal studies, a link between Pb exposure, Th2 cytokines, increased IgE production, and allergic diseases has been established (Lutz et al., 1999; Snyder et al., 2000; Annesi-Maesano et al., 2003; Heo et al., 2004; Maezawa et al., 2004; Ban and Hettich, 2005; Holgate et al., 2005; Parks and Casale, 2006). In fact, Pbinduced increase in IgE production has become one of the predominant biomarkers of Pb immunotoxicity (Karmaus et al., 2005; Dietert and Piepenbrink, 2006). "
ABSTRACT: Persistent exposure to inorganic lead (Pb) is known to adversely affect the immune system. In the present study, we assessed the effect of chronic Pb exposure on susceptibility to infection by the facultative intracellular pathogen Salmonella enterica serovar Typhimurium. Mice were exposed to 10 mM Pb-acetate in drinking water for approximately 16 weeks, resulting in a significant level of Pb in the blood (106.2+/-8.9 microg/dl). Pb exposure rendered mice susceptible to Salmonella infection, manifested by increased bacterial burden in target organs and heightened mortality. Flow cytometric analysis of the splenic cellular composition in normal and Pb-exposed mice revealed no gross alteration in the ratios of B and T lymphocytes or myeloid cells. Similarly, the capacity of B and T cells to upregulate the expression of activation antigens in response to mitogenic or inflammatory stimuli was not hindered by Pb exposure. Analysis of the ability of ex vivo-cultured splenocytes to secrete cytokines demonstrated a marked reduction in IFN-gamma and IL-12p40 production associated with Pb exposure. In contrast, secretion of IL-4 by splenocytes of Pb-treated mice was 3- to 3.6-fold higher than in normal mice. The increased capacity to produce IL-4 correlated with a shift in the in vivo anti-Salmonella antibody response from the protective IgG2a isotype to the Th2-induced IgG1 isotype. We conclude that chronic exposure to high levels of Pb results in a state of immunodeficiency which is not due to an overt cytotoxic or immunosuppressive mechanism, but rather is largely caused by a shift in immune responsiveness to Th2-type reactions.Toxicology and Applied Pharmacology 03/2007; 218(3):215-26. DOI:10.1016/j.taap.2006.11.018 · 3.63 Impact Factor
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ABSTRACT: The pharmacological purposes of the anti-IgE therapy are to neutralize IgE and to inhibit its production to attenuate type I hypersensitivity reactions. The therapy is based on humanized IgG1 antibodies that bind to free IgE and to membrane-bound IgE on B cells, but not to IgE bound by the high-affinity IgE.Fc receptors on basophils and mast cells or by the low-affinity IgE.Fc receptors on B cells. After nearly 20 years since inception, therapeutic anti-IgE antibodies (anti-IgE) have been studied in about 30 Phase II and III clinical trials in many allergy indications, and a lead antibody, omalizumab, has been approved for treating patients (12 years and older) with moderate-to-severe allergic asthma. Anti-IgE has confirmed the roles of IgE in the pathogenesis of asthma and helped define the concept "allergic asthma" in clinical practice. It has been shown to be safe and efficacious in treating pediatric allergic asthma and treating allergic rhinitis and is being investigated for treating peanut allergy, atopic dermatitis, latex allergy, and others. It has potential for use to combine with specific and rush immunotherapy for increased safety and efficacy. Anti-IgE thus appears to provide a prophylactic and therapeutic option for moderate to severe cases of many allergic diseases and conditions in which IgE plays a significant role. This chapter reviews the evolution of the anti-IgE concept and the clinical studies of anti-IgE on various disease indications, and presents a comprehensive analysis on the multiple intricate immunoregulatory pharmacological effects of anti-IgE. Finally, it reviews other approaches that target IgE or IgE-expressing B cells.Advances in Immunology 02/2007; 93:63-119. DOI:10.1016/S0065-2776(06)93002-8 · 5.53 Impact Factor
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ABSTRACT: Five percent to 10% of patients with asthma have severe disease that is not responsive to mainstream controller medications. Only approximately 13% of this group meet the criteria for treatment with omalizumab, the only available FDA-approved IRM approved for asthma. Clearly, as discussed above, asthma is a complex variable heterogeneous disease. Lotvall et al8 describe their approach in dividing asthma into distinct entities based not only on clinical presentations but also specific mechanisms, such as asthma endotypes. Although the use of IRMs in the treatment of asthma and atopic disorders has not been as successful as anticipated by many or compared with their use in patients with rheumatic diseases, there have been some advances in our understanding of how to use these IRMs in disease endotypes. Although many of the studies with a variety of IRMs have shown little clinical efficacy, subset analysis of patient groups who exhibit certain characteristics, such as sputum eosinophilia, show improved priary end points and clinical efficacy that have led to new studies with a more defined patient population. A good example is the study of anti-IL-5 (mepolizumab). Recent studies of patients with eosinophilic refractory asthma44 and in patients with prednisonedependent asthma with sputum eosinophils41 have been encouraging on the use of anti-IL-5 in certain asthma endotypes. At the same time, we must continue to be vigilant for adverse events and safety while studying these IRMs, as experienced by Wenzel et al131 in a recent study of golimumab, an anti-TNF mAb that had an unfavorable safety profile. Advances in the bioengineering of mAbs, fusion proteins, and small molecules that can be taken orally will be important steps in improving outcomes. For example, mAbs, perhaps bispecific antibodies, fusion proteins, or combination biologics that target more than 1 cytokine receptor or cytokine, such as pitrakinra,26 will be more successful. The biggest issue is identifying asthma endotypes to tailor the correct IRM and to evaluate carefully the best primary outcome for defined patient subpopulations. The development of useful biomarkers is critical to identify patient-specific therapies and achieve these therapeutic goals. A case in point is the study of an anti-IL-13 mAb (lebrikizumab) using blood eosinophil counts and serum periostin levels as biomarkers to identify potential asthma endotypes that would respond to this treatment approach.29 As these clinical trials point out, elucidating the pathobiology and immunology of these patient subpopulations is a critical strategy for success. The development of new biomarkers will be critical in identifying these patient endotypes for more appropriate use of specific IRMs. Novel therapies must be directed at specific asthma endotypes if these new treatment modalities are going to be clinically efficacious and brought from the bench to the bedside.The Journal of allergy and clinical immunology 06/2012; 130(2):311-24. DOI:10.1016/j.jaci.2012.04.046 · 11.25 Impact Factor