Omalizumab for refractory chronic spontaneous urticaria during concurrent immunomodulatory therapy for multiple sclerosis.

SUMMARY: Data derived from previous clinical trials and real-life studies have shown that omalizumab may represent an effective third-line treatment option for patients with chronic spontaneous urticaria (CSU) refractory to standard antihistamine treatment. Nevertheless, the safety and efficacy of omalizumab treatment for CSU, when administered concurrently with other immunomodulatory agents remains largely unknown. We herein present the case of a female patient with relapsing-remitting multiple sclerosis (RRMS), under treatment with interferon beta-1a, azathioprine and gabapentin, who was successfully treated with omalizumab for refractory CSU. To the best of our knowledge, this is the first reported case attesting to the safety and efficacy of omalizumab for CSU when administered concurrently with other immunomodulatory agents.

Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Allergic rhinitis is a common problem involving activation of nasal mast cells and irritability. The hypothalamic-pituitary-adrenal (HPA) axis is stimulated in cases of emotional or environmental stress, and mast cells have been implicated in stress-induced immune responses. OBJECTIVE: To investigate whether intranasal challenge of patients allergic to a single antigen would stimulate the HPA axis. METHODS: Plasma corticotropin and cortisol levels were measured 20, 40, 60, 80, 100, and 120 minutes after intranasal antigen administration in healthy volunteers (n=3) and in patients with rhinitis who are allergic to Parietaria (n=10). RESULTS: Mean +/- SD corticotropin levels were 24.43 +/- 14.38 pg/mL in patients compared with 8.83 + 5.02 pg/mL in controls, and this increase was statistically significant (P = .049). Patient cortisol levels also increased to a mean +/- SD of 8.87 +/- 4.90 pg/mL (at 40 minutes) compared with 4.36 +/- 1.72 pg/mL in controls (P = .11 due to 1 outlier). Compared with individual patient prechallenge levels, corticotropin levels increased in 7 patients and cortisol levels increased in 5 at 40 minutes. CONCLUSION: These results suggest that allergic rhinitis may activate the HPA axis. A larger study with additional controls is required for definitive conclusions.

Proliferation and release of IL-5 and IFN-gamma by peripheral blood mononuclear cells from cat-allergic asthmatics and rhinitics, non-cat-allergic asthmatics, and normal controls to peptides derived from Fel d 1 chain 1.

BACKGROUND: In general, T cells from normal, nonatopic individuals respond to aeroallergens with synthesis and release of IFN-gamma. In contrast, release of T(H)2-type cytokines by activated lymphocytes is a feature of allergic rhinitis and atopic asthma. OBJECTIVE: The purpose of this study was to determine differences in T-cell recognition of epitopes within allergenic sequences, in terms of proliferation and cytokine production, in subjects with atopic asthma compared with subjects with allergic rhinitis and normal controls. METHODS: Proliferative responses and IL-5/IFN-gamma release patterns from PBMCs from cat-allergic asthmatic, cat-allergic rhinitic, and non-cat-allergic asthmatic subjects and nonatopic normal controls were determined in primary cultures. Cells were challenged with 7 overlapping peptides spanning chain 1 of the major cat allergen, Fel d 1. RESULTS: The 4 groups did not differ with respect to the ability to mount proliferative responses to Fel d 1 peptides. In all groups, the IFN-gamma responses were predominantly to the amino terminus peptides. Cat-allergic and non-cat-allergic asthmatic subjects (and not cat-allergic rhinitic subjects and normal controls) made IL-5 responses to most of the Fel d 1 peptides, the result being a mixed (T(H)0) cytokine response at the N-terminus and a restricted (T(H)2) response at the C-terminus. CONCLUSION: Proliferative and IL-5/IFN-gamma responses of T cells from asthmatic and atopic rhinitic subjects and normal controls to allergen peptides can be dissociated. Furthermore, differing cytokine responses to peptides derived from a single antigen suggest that certain domains of the molecule might preferentially induce IL-5 rather than IFN-gamma and as a result could be more important in disease pathogenesis.

Correlation of lymphocyte proliferating cell nuclear antigen expression with dietary cow's milk antigen load in infants with allergy to cow's milk.

BACKGROUND: Controversial results have been reported on the participation and diagnostic value of lymphocyte reactivity in cow's milk (CM) allergy. In this study, we used a specific nuclear marker to evaluate lymphocyte proliferation in IgE-mediated CM allergy in infants, and examine its relation with diets containing different CM antigen loads. METHODS: Infants with IgE-mediated CM allergy, as assessed by open provocation and RAST, were grouped according to their exclusive diet, either CM formulae, breast feeding, or hydrolysed whey formulae. A group of non-atopic infants receiving CM was also examined. Lymphocyte proliferation to beta-lactoglobulin was evaluated by quantitation of the proliferating cell nuclear antigen (PCNA) expression in peripheral blood mononuclear cells, by flow cytometry. Immunophenotypic surface markers were also examined. RESULTS: A marked difference of PCNA expression between CM-fed allergic infants and healthy controls was observed (p<0.001). In this setting, PCNA expression >/=10% was highly specific and sensitive as a marker of CM allergy in CM-fed infants. Moreover, a significant correlation (p<0.001) between antigen load and PCNA was established in CM-allergic infants under different diets, higher values obtained with increasing antigen loads. In addition, within the group fed hydrolyzed formulae, low-molecular-weight products resulted in marginally lower PCNA expression than higher-molecular-weight formulae. No differences in immunophenotype were found, with the exception of a higher CD23 expression in the breast-fed group. CONCLUSIONS: PCNA could be a useful marker in the assessment of lymphocyte proliferation to CM antigens. Low CM antigen diets are related with reduced lymphocyte reactivity, which may partly explain the clinical benefit observed with such diets.

Prognostic significance of autoantibodies against tropomyosin in patients with colorectal adenocarcinoma.

We examined, with an enzyme-linked immunoadsorbent assay (ELISA) method, the serum of 55 patients with Colon Adenocarcinoma (CA) for the presence of autoantibodies against tropomyosin (TMS), of IgM and IgG isotypes, before and 1 month after surgery. Twenty-six (26) patients with benign surgical diseases (BSD) (hernia or cholelithiasis) and 40 healthy volunteers were used as controls. Preoperatively, 20/55 (36.3%) of CA patients and 2/26 (7.7%) of BSD patients were positive for anti-TMS antibodies, while postoperatively, the positive samples were 22/55 (40%) and 2/26 (7.7%), respectively. The difference between the group of CA patients and the two control groups was statistically significant (p < 0.001). The presence of anti-TMS antibodies has been associated with better outcome of CA patients: 30 CA patients (30/55, 54.5%) had detectable anti-TMS antibodies either preoperatively or postoperatively and 25 CA patients (25/55, 45%) were completely negative in both occasions. In the first group of patients, four (4) recurrences were detected (4/30, 13.3%) while in the second group nine (9) recurrences were found (9/25, 36%). The difference between the two groups was statistically significant (p < 0.01). Anti-tropomyosin antibodies could be used as biological markers of prognosis in colon cancer patients.

Interferon-gamma pretreatment of peripheral blood mononuclear cells partially restores defective cytokine production in children with atopic dermatitis.

Interferon-gamma (IFN-gamma) is considered an important determinant of the balance between T-helper type 1 and 2 cytokines and has been used experimentally for the treatment of atopic dermatitis. However, contrasting results have been reported relative to the Th-1/Th-2 cytokine profile in atopic patients. In this study, we examined cytokine production by polyclonally activated peripheral blood mononuclear cells (PBMC) from children with atopic dermatitis, and assessed the influence of in vitro IFN-gamma pretreatment on these cells. A fraction of PBMC isolated from children with severe atopic dermatitis, as well as from age-matched controls, was initially exposed to IFN-gamma. After washing, both treated and untreated cells were then put into culture either alone or with the addition of phytohemagglutinin (PHA) or phorbol myristate acetate (PMA) plus ionomycin. IL-4, IL-5, IL-10 and IFN-gamma production were measured in the supernatants using commercially available ELISAs. PBMC from atopic patients produced more IL-4 (P = 0.04) and IL-10 (P = 0.03) and less IFN-gamma (P = 0.01) than controls, when stimulated with PHA. Interestingly, in PMA + ionomycin stimulated cultures, the atopic cytokine profile was different with more IL-5 (P = 0.0068) and less IFN-gamma production (P = 0.00046) than the control group. When cells were pretreated with IFN-gamma, there were no significant differences between patients and controls. PBMC from children with atopic dermatitis show alterations in cytokine production, compatible in general terms with the Th-1/Th-2 model. Exposure of PBMC to IFN-gamma before activation results in a reduction of these differences, so that cytokine production becomes similar in the atopic and normal groups.

Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization.

For evaluation of the efficacy and the safety of specific sublingual immunotherapy with high allergen dose, 66 children with seasonal asthma, rhinitis, and conjunctivitis due to sensitization to olive pollen were enrolled in a double-blind, randomized, placebo-controlled study between October 1994 and October 1996 in Greece. Thirty-four patients were randomly allocated to the active group, and 32 received placebo. Immunotherapy consisted of olive-allergen extracts (Stallergènes SA) administered sublingually pre- and coseasonally from January to July for 2 consecutive years. Serial concentrations from 1 to 300 IR. were used up to the maintenance dose of 20 drops of 300 IR daily. The cumulative dose for each patient was 300 times higher than in parenteral immunotherapy, and the cumulative dose of the major allergen Ole e 1 was 8.1 mg/2 years. The patients were assessed by clinical parameters (symptom and medication scores from patients' daily diaries) and immunologic measurements (specific IgE, IgG4, eosinophil cationic protein [ECP]) were performed. The actively treated patients had a significantly lower score for dyspnea (P<0.04 during the first season; P<0.03 during the second season). At the pollinic peak during the second year, a lower score of conjunctivitis was recorded (P<0.05) in the actively treated patients. The analysis of intragroup evolution showed that the total score of rhinitis increased significantly during the pollinic peak in the group under placebo, whereas there was no symptomatic peak for the same period in the group under active treatment. However, the difference between the groups was not significant. The medication score did not differ significantly between the groups. Oral steroids were the only variables with a P value near the significance level (P=0.06) in favor of the actively treated group. A significant decrease in skin reactivity was recorded in the active group after 2 years of treatment. No significant variation in specific IgE and IgG4 was detected. A significantly lower level of serum ECP was observed at the pollinic peak in the actively treated patients during the first pollen season (P=0.01), but this was not confirmed the second year when the ECP levels doubled in both groups without correlation to the clinical findings. Tolerance was excellent with only a few minor side-effects reported. In conclusion, high-dose specific sublingual immunotherapy appears to be safe and effective in improving mild seasonal asthma and conjunctivitis linked to olive-pollen sensitization.

Abnormal expression of p120 correlates with poor survival in patients with bladder cancer.

p120 is a cytoplasmic molecule closely associated with the Ca(2+)-dependent cell-cell adhesion molecule E-cadherin, by forming complexes between the cytoplasmic domain of E-cadherin and the cytoskeleton. Although it has been shown that loss or downregulation of E-cadherin is associated with an invasive and poorly differentiated phenotype in several tumours, there is very little information available concerning p120 expression in malignant disease. We used an avidin-biotin immunoperoxidase technique to examine the immunoreactivity and cellular localisation of p120 and E-cadherin in 68 transitional cell carcinomas (TCC) and 14 normal bladder biopsies and correlated these results with pathological and clinical parameters. E-cadherin and p120 were expressed in a normal membranous pattern in all normal bladder epithelium specimens. Loss of normal surface E-cadherin and p120 expression was found in 52/68 (76%) and 57/68 (84%) tumours, respectively. There was a significant correlation between the loss of normal membranous expression of p120 and increased grade (P < 0.001) and T stage (P < 0.001). The abnormal expression of p120 was correlated with poor survival (P < 0.05). Our data indicate that the E-cadherin-p120 complex may be a useful prognostic marker in bladder cancer.

Determinants of age at menarche as early life predictors of breast cancer risk.

Age at menarche is one of the few established risk factors for breast cancer; identification of its exogenous determinants could throw light on the origins of breast cancer. We have undertaken an epidemiologic study in Greece to ascertain whether: 1) energy intake, an indicator of physical activity, is associated with later age at menarche; 2) energy-adjusted fat intake is related to earlier age at menarche; and 3) other macronutrients and anthropometric variables are predictors of age at menarche. Anthropometric, socio-economic, familiar, nutritional and lifestyle predictors of age at menarche were studied by interviewing in person 345 female students 9 to 16 years old attending 8 schools of Greater Athens. Menarche was the outcome variable in a proportional hazards model assessing the mutually adjusted incidence rate ratio by a series of predictor variables. In a complementary analysis, age at menarche was the dependent variable among menstruating girls. Consistent results were derived from the main and the complementary analysis. Increased height and body mass index accelerate the occurrence of menarche. Maternal and daughter's ages at menarche are correlated, but there is no evidence of an association with paternal education. Various measures of moderate physical activity as well as increased total energy intake were associated with a delay in age at menarche. Energy-adjusted macronutrients were not associated with age at menarche. It appears that an alteration of energy balance in early life through increased physical activity could delay age at menarche and reduce the risk for breast cancer in later life.

Effect of testosterone administration, pre- and postnatally, on the immune system of rats.

This study was undertaken to investigate and compare in vitro and in vivo immune parameters between female and male rats. We analysed the T-cell proliferative responses to syngeneic and allogeneic cellular antigens (syngeneic and allogeneic mixed lymphocyte reaction), as well as the IgG levels in the sera of our study groups. It has also been studied the influence of gonadectomy and the effect of testosterone administration pre- and postnatally on the above parameters. Our findings showed that hormonal manipulations, can alter the differences observed in immune response between female and male rats. In addition, it is demonstrated that pre- and postnatal sexual steroid manipulations could provoke long lasting immunological effects.

Non-specific autoantibodies in cardiomyopathies and myocardial infarction.

In the present study we evaluated the importance of autoimmune mechanisms in cardiomyopathies. Sera from 22 patients with dilated cardiomyopathy, 23 patients with hypertrophic cardiomyopathy, 24 patients with myocardial infarction and 40 apparently healthy blood donors were tested with an immunoassay method for the presence of autoantibodies against dsDNA, ssDNA and cardiolipin. Elevated values of autoantibodies, mainly of the IgG subtype, were obtained in a high percentage of patients with cardiomyopathy (30-50%), as compared to the control group (5%). The incidence of these autoantibodies has been found significantly high in both groups of dilated and hypertrophic cardiomyopathies. Although further investigation is needed, it is concluded that the detection of these autoantibodies may contribute in the better understanding of the pathogenesis of cardiomyopathies and could be a useful tool for the diagnosis, follow up and prognosis of these patients.