Background: Antenatal and postnatal treatment with dexamethasone (DEX) may negatively affect the neuropsychological development in children. Maternal anti-Ro/Sjögren’s syndrome A (SSA) antibodies may ...also be associated with learning disabilities in offspring. Objective: To assess neuropsychological development in babies exposed to very high dosages of DEX in utero, whose mothers were anti-Ro/SSA positive. Methods: 13 children with congenital complete heart block (CHB) (11 exposed and 2 not exposed to DEX) and 3 healthy siblings, all of anti-Ro/SSA-positive women, were evaluated. 11 preschool-aged children (5 boys) were assessed using Griffiths Mental Development Scales. 5 school-aged children (2 boys) were examined using Wechsler Intelligence Scale for Children—Revised to check IQ and reading tests to explore the existence of learning disabilities or dyslexia. None of the children had had major neonatal complications, although those with CHB had to be paced at different intervals from birth. Results: The children had been exposed in utero to a mean total dose of 186.6 mg DEX. IQ levels were always normal (mean IQ 105.1, standard deviation (SD) 9.5). Only one child had a learning disability, of borderline clinical significance, but this child had never been exposed to DEX. Conclusion: No negative effects were found on the neuropsychological development in this cohort of children, even if they had been exposed to maternal anti-Ro/SSA antibodies and to very high dosages of DEX (much higher than those used to improve fetal lung maturity). These findings might be of interest in view of the large number of infants exposed in the past to repeated antenatal courses of steroids.
To assess the capacity of a peptide-based immunotherapy to induce systemic tolerance via the nasal route, we designed three long overlapping peptides of 44-60 aa covering the entire sequence of ...phospholipase A2 (PLA2), a major bee venom allergen. Both prophylactic and therapeutic intranasal administrations of long peptides to PLA2-hypersensitive CBA/J mice induced specific T cell tolerance to the native allergen. In prophylactic conditions, this tolerance was marked by a suppression of subsequent specific IgE response, whereas the therapeutic approach in presensitized mice induced a more than 60% decrease in PLA2-specific IgE. This decline was associated with a shift in the cytokine response toward a Th1 profile, as demonstrated by decreased PLA2-specific IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN-gamma ratios. T cell transfer from long peptide-tolerized mice to naive animals abrogated the expected anti-PLA2 IgE and IgG1 Ab response, as well as specific T cell proliferation, but enhanced specific IgG2a response upon sensitization with PLA2. These events were strongly suggestive of a clonal anergy affecting more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate that allergen-derived long peptides delivered via the nasal mucosa may offer an alternative to immunotherapy with native allergens without the inherent risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast to immunotherapy strategies based on short peptides, have the advantage of covering all potential T cell epitopes, and may represent novel and safe tools for the therapy of allergic diseases.
Background Murine models of hypersensitivity to allergens are useful tools for the evaluation of preclinical strategies to down‐regulate the IgE response.
Objective To monitor the long‐term kinetics ...of T and B cell responses to allergen as a function of allergen dosage and to investigate the effect of parallel immunization with a second antigen; to correlate B cell response with anaphylaxis.
Methods CBA/J mice were sensitized every other week by subcutaneous injections of phospholipase A2 (PLA2) and/or ovalbumin (OVA) adsorbed to alum. Specific antibody isotype responses, T cell proliferation, T cell cytokine production and anaphylaxis were assessed throughout the sensitization phase.
Results Low‐dose immunization with PLA2 (0.1 µg) favoured a long‐term, specific T helper (Th)2 response with high IgE and IL‐4 production in contrast to high‐dose PLA2 (10 µg) immunization, which biased the immune response towards a Th1 response with high IgG2a and low IL‐4 production. Parallel immunization with an unrelated antigen (ovalbumin) had a significant bystander effect on the immunization with PLA2, which was also dose‐dependent. Finally, although anaphylaxis as measured by rectal temperature drop was allergen‐specific, it could be induced in the high‐ and low‐dose immunization groups, and was not solely dependent on IgE levels.
Conclusion Though low‐dose allergen immunization appears to induce an efficient IgE response, the intensity and quality of this response may be modulated by bystander effects of parallel immunization and does not correlate strictly with anaphylaxis. This observation has relevance to the design of clinical immunotherapy protocols using murine model‐based data.
Api m 6: A new bee venom allergen Kettner, Alexander; Hughes, Graham J.; Frutiger, Séverine ...
Journal of allergy and clinical immunology,
05/2001, Letnik:
107, Številka:
5
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Background: Characterization of the primary structure of allergens is a prerequisite for the design of new diagnostic and therapeutic tools for allergic diseases. Objective: The purpose of this study ...was the identification and characterization of a low-molecular-weight, IgE-binding, bee venom (BV) allergen. Methods: BV proteins were separated by using size exclusion chromatography and HPLC. IgE antibody binding to purified proteins was analyzed by means of immunoblotting, and T-cell response was analyzed by means of proliferation assay. Amino acid sequence was determined with 2 approaches, namely Edman degradation and carboxy terminal analysis with mass spectrometry. Results: Api m 6, which migrated as an 8-kd band in SDS-PAGE, was frequently (42%) recognized by IgE from BV-hypersensitive patients. In addition, PBMCs from BV-hypersensitive patients, as well as from a normal control subject, proliferated in response to this allergen. Api m 6 exists as 4 isoforms of 7190, 7400, 7598, and 7808 d, respectively. Amino acid sequences obtained from HPLC-purified preparations revealed that the isoforms were constituted of a common central core of 67 residues, only differing in the amino- and carboxy-terminal ends. Api m 6 showed no significant sequence homology with known proteins. Conclusions: We have identified and sequenced a new BV allergen that elicits a strong IgE and T-cell response in a large number of BV-hypersensitive patients. Api m 6 should be considered in the diagnostic and therapeutic approach of BV immunotherapy on the basis of peptides or recombinant proteins. (J Allergy Clin Immunol 2001;107:914-20.)
To evaluate a long peptide‐based allergy vaccine in a murine model, CBA/J mice were sensitized with low dose alum‐adsorbed phospholipase A2 (PLA2), a major bee venom allergen. Presensitized mice were ...treated by daily i.p. injections of a mixture of three long overlapping peptides (44‐ to 60‐mer) spanning the entire PLA2 molecule (100 μ g/peptide) for 6 consecutive days. This therapeutic approach induced a sharp drop in PLA2‐specific IgE, an increase in specific IgG2a, and a marked T cell hyporesponsiveness. T cell cytokine secretion was characterized by a shift from a Th2 to a Th1 profile. Prophylactic treatment of naive mice with long peptides prior to sensitization with PLA2 induced a comparable modulation of B and T cell responses. Upon i.p. challenge with native PLA2, presensitized mice treated with the long peptide mixture were fully protected from anaphylaxis. This indicated that allergen‐derived long overlapping peptides were safe and able to modulate an established Th2 response or to prevent its development. Furthermore, long peptide‐based immunotherapy provided clinical protection against anaphylaxis, thus appearing as a promising approach of the therapy of allergic diseases.
Sedation by the enteral route is unusual in intensive medicine. We analysed the feasibility/efficacy of long-term enteral sedation in ventilated critically ill patients.
Prospective interventional ...cohort study.
General ICU.
Forty-two patients needing ventilation and sedation for at least 4 days.
At admission, sedation was induced with propofol or midazolam. Enteral hydroxyzine (+/- enteral lorazepam) was added in all patients within the second day. Intravenous drugs were gradually withdrawn, trying to maintain only enteral sedation after the initial 48 h. Analgesia was provided with continuous IV fentanyl.
Sedation level was assessed evaluating, on a daily basis, patients' compliance to the invasive care and comparing observed vs planned Ramsay scores three times a day. Excluding the first 2 days of patient-stabilisation and fast titration of sedation level, 577 days with ventilatory support were analysed. In 460 days (79.7%) total enteral sedation was given. This percentage rose to 94.2% when the requested Ramsay was 2 (347 days). Daily sedation was judged as adequate in 82.8% of days of total enteral sedation. Thirty-one patients had total enteral as the exclusive route of sedation.
After 24-48 h, enteral sedation may replace, totally/in part, IV sedation in ventilated patients. Total enteral sedation easily fits the target when a Ramsay score 2 is planned. When a deeper sedation is needed, a mixed regimen is effective and lowers IV drug dosages. No side effects were reported.
The neonatal immune response is impaired during the first weeks after birth. To obtain a better understanding of this immaturity, we investigated the development of T cell interactions with B cells ...in mice. For this purpose, we analyzed the immune response to three T-dependent antigens in vivo: (i) the polyclonal antibody response induced by vaccinia virus; (ii) the production of polyclonal and specific antibodies following immunization with hapten–carrier conjugates; (iii) the mouse mammary tumor virus superantigen (sAg) response involving an increase in sAg-reactive T cells and induction of polyclonal antibody production. After vaccinia virus injection into neonates, the polyclonal antibody response was similar to that observed in adult mice. The antibody response to hapten–carrier conjugates, however, was delayed and reduced. Injection with sAg-expressing B cells from neonatal or adult mice allowed us to determine whether B cells, T cells or both were implicated in the reduced immune response. In these sAg responses, neonatal T cells were stimulated by both neonatal and adult sAg-presenting B cells but only B cells from adult mice differentiated into IgM- and IgG-secreting plasma cells in the neonatal environment in vivo. Injecting neonatal B cells into adult mice did not induce antibody production. These results demonstrate that the environment of the neonatal lymph node is able to support a T and B cell response, and that immaturity of B cells plays a key role in the reduced immune response observed in the neonate.
Summary Splenic marginal zone B-cell lymphoma is characterized by high genetic heterogeneity, and hepatitis C virus infection seems to be involved in a subset of patients. The aims of the analysis ...were to identify potential genetic alterations related to hepatitis C virus status, IgVH gene mutational status, and prognostic categories identified in a multicenter study ( Blood 2006;107:4643). Genome-wide array comparative genomic hybridization at a 100-kilobase (kb) resolution was performed in 34 patients with splenic marginal zone B-cell lymphoma, 12 of whom were hepatitis C virus positive. Array-comparative genomic hybridization experiments revealed no copy number alterations in 10 patients (4 were hepatitis C virus positive). A median of 5.6 and 3.8 copy number alterations were detected in hepatitis C virus–positive and in hepatitis C virus–negative patients, respectively. The most frequent copy number alterations involved chromosomes 7 and 17 (21% and 24%, respectively). Except for Xp gain ( P = .01), no differences in common alterations were found between hepatitis C virus–positive and hepatitis C virus–negative cases. Unmutated status of the IgVH gene was related to del(7q) ( P = .04) and dup(12q) ( P = .03). The high-risk group identified according to the new splenic marginal zone B-cell lymphoma prognostic score was associated with del(7q) ( P = .01) and del(17p) ( P = .02). Hepatitis C virus–positive splenic marginal zone B-cell lymphoma patients have no specific chromosome alterations. Patients with poor prognosis are characterized by distinctive imbalances.
BALB/c mice were immunized with the EP3 surface epitope of the mouse mammary tumour virus (MMTV) gp52 envelope protein before systemic infection with MMTV(C3H) or MMTV(SW). Analysis of the successive ...stages of the virus infection showed that although these mice were protected against mammary tumour formation, earlier stages of the infection were not inhibited, as reflected by the persisting superantigen-induced activation and deletion of Vbeta-specific T cells. Transplacental transfer of maternal anti-EP3 immunoglobulins to newborns did not protect them from infection through the Peyer's patches. Preincubation of the MMTVs with an anti-EP3 serum before injection, however, successfully inhibited the early stages of the infection. Results from this study show that to inhibit infection by MMTV efficiently, the virus must be neutralized before its interaction with the cell membrane, and that the affinity of the virus-membrane interaction is higher than that of the virus-antibody interaction.
The effects of a gluten-free diet on catch-up growth and predicted height were evaluated in 12 children with coeliac disease diagnosed after the age of 5 years and followed for 2-5.5 years. In the ...majority of the patients, height and bone age were retarded at the time of diagnosis. Under a gluten-free diet growth velocity, age-related height, predicted height and relative bone age increased, height for bone age slightly decreased. In four patients the predicted height remained below the target height, indicating incomplete catch-up growth.
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