Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.

Anti-IgE therapy with omalizumab, a recombinant humanized monoclonal antibody, has anti-inflammatory effects in allergic asthma and rhinitis. Although omalizumab has been exceptionally safe, reactions after its administration have been reported. The goal of this study was to assess two patients who experienced apparent anaphylaxis after omalizumab administration. Two cases of apparent anaphylaxis after omalizumab administration are reported with diagnostic evaluation using skin testing and unique IgE and IgG anti-omalizumab serological assays. At the time of evaluation, both atopic asthmatic patients had total (free and bound) serum IgE levels of 199 kIU/L (100% free) and 200 kIU/L (80% free and 20% bound), respectively. Epicutaneous skin tests to omalizumab were negative at 150 mg/mL of omalizumab in both subjects and the nonexposed negative control subject. Intradermal skin tests were positive at 0.15 mg/mL in subject 1 and negative at 1.5 mg/mL of omalizumab in subject 2 and the control subject. Intradermal testing to polysorbate produced significant wheal/flare reaction in subject 2 but not in the negative control subject. Serological assays for IgE or IgG antibodies reactive with omalizumab were negative. The in vitro and in vivo immunologic data support the conclusion that the adverse reactions experienced by two patients after omalizumab administration after more than a year of successful omalizumab therapy for asthma were likely anaphylactoid in nature. Polysorbate, an excipient in omalizumab, is known to cause similar reactivity to other medicines and is the most likely cause of these reactions.

Taxol reactions.

Paclitaxel (Taxol) a taxane antineoplastic agent causing irreversible microtubule aggregation with activity against breast, ovarian, lung, head and neck, bladder, testicular, esophageal, endometrial and other less common tumors was derived from the bark of the Pacific yew (Taxus brevifolia). Phase I trials conducted in the late 1980s were almost halted because of the high frequency of hypersensitivity-like reactions. Respiratory distress (dyspnea and/or bronchospasm), hypotension, and angioedema were the major manifestations, but flushing, urticaria, chest, abdomen, and extremity pains were described also. Reactions occurred on first exposure in the majority of cases raising etiologic questions. The vehicle for paclitaxel Cremophor EL (polyoxyethylated castor oil in 50% ethanol) was strongly suspect as a direct (non-immunoglobulin E dependent) histamine releaser. Premedication regimens and longer infusion times lowered the incidence of reactivity allowing phase II and III trials to progress through the early 1990s. The mechanism(s) underlying paclitaxel hypersensitivity-like reactions is still unknown, and clinical data on probable complement and mast cell activation are lacking. The original clinical trial protocols for paclitaxel required discontinuation of therapy for patients who experienced hypersensitivity-like reactions. Here, we review the current etiologic knowledge of these reactions and describe our clinical approach to allow completion of chemotherapy with this powerful plant-derived agent.

Lysophosphatidic acid accelerates the development of human mast cells.

Mast cells (MCs) initiate immune responses from mucosal surfaces and perivascular spaces. Stem cell factor (SCF) regulates MC development and viability, but the role of innate serum factors in MC development is unexplored. Cultured cord blood-derived human MCs (hMCs) express mRNA transcripts for all 4 known receptors for lysophosphatidic acid (LPA), an abundant serum-associated lipid growth factor. In an SCF-dependent serum-free culture system, LPA (2.5-10 microM) increased the total number of hMCs by approximately 10-fold compared with cultures maintained in the absence of LPA under otherwise identical conditions. LPA was comitogenic with SCF but did not prolong MC survival. LPA-mediated proliferation was blocked by VPC-32179, a competitive antagonist of LPA(1) and LPA(3) receptors, and by pertussis toxin, and it was also attenuated by GW9662, a selective antagonist of peroxisome proliferator-activated receptor (PPAR)-gamma. LPA accelerated the acquisition of hMC granules and increased Kit expression. hMCs derived in the presence of LPA were functional, as evidenced by their immunoglobulin E (IgE)-dependent histamine release and by their characteristic proliferative responses to interleukin-3 (IL-3), IL-4, and IL-9 in combination with SCF. Thus, LPA acts through LPA receptor and PPAR-gamma-dependent pathways to accelerate hMC proliferation and differentiation, and it modulates their phenotype without providing cytoprotection. LPA could facilitate MC hyperplasia in inflammation associated with either innate or adaptive immunity.

CC chemokine receptor 3 mobilizes to the surface of human mast cells and potentiates immunoglobulin E-dependent generation of interleukin 13.

Eotaxins-1, -2, and -3 mediate the recruitment of blood-borne eosinophils to allergically inflamed tissues by binding CC chemokine receptor (CCR) 3. Mast cells (MCs) are resident tissue cells that also express CCR3. In the present study, we demonstrate that human (h) MCs in nasal polyps and cultured cord blood-derived hMCs express CCR3 not only on their surfaces but also in their secretory granules. Activation of hMCs mediated by the high-affinity Fc receptor for immunoglobulin (Ig)E (Fc epsilon RI) increased the surface presentation of CCR3 within 1 h, with a parallel decrease in intracellular CCR3 as determined by flow cytometry on saponin-permeabilized hMCs. Recombinant eotaxin-1 alone did not induce histamine release or cytokine generation, and did not significantly augment IgE-dependent histamine release by interleukin (IL)-4-primed hMCs. Nevertheless, stimulation of hMCs with eotaxin-1 2 h after Fc epsilon RI cross-linkage (concomitantly with maximal surface CCR3 expression) increased Fc epsilon RI-dependent IL-13 generation by hMCs, compared with their replicates stimulated simultaneously with both agonists. Thus, hMCs may store CCR3 and rapidly mobilize it to their surface with IgE-dependent activation, providing a novel potential mechanism for enhanced hMC effector function, including IL-13 production.

FcepsilonRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines.

BACKGROUND: Mast cells (MCs) proliferate in response to T(H)2 cytokines and express genes de novo after activation. Limited information is available concerning the interplay between these events. OBJECTIVE: We explored the potential for T(H)2 cytokines to alter activation-dependent gene expression by MCs. METHODS: Cord blood-derived human (h)MCs maintained in stem cell factor (SCF) alone were compared with replicates treated with IL-4, IL-5, or IL-9, respectively, for their patterns of FcepsilonRI-dependent gene induction using microarray technology. RESULTS: Activation of SCF-treated hMCs upregulated their expression of roughly 140 transcripts at 2 hours, including genes involved in cell cycle progression and arrest. Each cytokine substantially modified this profile; approximately 800 inducible genes apiece were controlled by IL-5 or IL-9, whereas 169 inducible genes were controlled by IL-4. IL-4 favored the induction of cytokines and of genes associated with cell growth arrest (GADD34, GAS-1, CIDE-A, INK4D, and BAX) and completely abolished the enhanced proliferation observed in the other 3 groups after activation. Conversely, IL-5 priming induced preferential upregulation of genes involved in cell proliferation and did not abolish thymidine incorporation. CONCLUSIONS: T(H)2 cytokines differentially modulate gene induction in hMCs after FcepsilonRI cross-linkage. IL-4 uniquely controls cytokine gene expression by hMCs and might also limit their activation-driven proliferation.