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BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:1 pages:189-199 ispartof: location:United States status: published

Apple-related allergy is increasing among European population. Avoidance of apple fruit consumption is the only strategy for sensitized people, with a subsequent shortage of healthy nutrients in the diet. Four different protein families, Mal d 1 to 4, determine the allergy to apple causing syndromes known as oral allergy syndrome (OAS) or gastro-intestinal/generalized syndrome (GS) in sensitized patients. With the aim to highlight the dissimilarities in the immunological response inside the Mal d 1 family, recognized as main determinant for OAS, single purified allergens were tested against sera of paediatric and adult patients suffering for both syndromes. Here, we found that Mal d 1 isoallergens showed a remarkable different allergenicity potential, thus indicating an individual pattern in each patient and a diverse sensitization between age groups. Moreover, two different allergens, Mald 2.01 and Mal d 4.01, were analyzed with the above sera. In addition to patients and allergens variability, differences in amount and localization of the allergens, detected by patient’s sera, were revealed among hypo- and hyper allergenic apple varieties, confirming the complexity of this food allergy.

Allergy to freshly consumed apple fruits is often associated to pollinosis and manifested as oral allergy syndrome (OAS). The allergenic properties of apple varieties differ greatly, spanning from low allergenic to high allergenic varieties. The knowledge of the genetic determinants for allergenicity has been of great interest in scientific community for several years, but the molecular mechanisms involved are still little understood. Here, factors putatively involved in allergenicity were investigated at biochemical and molecular level in pollen and in fruits of apple varieties differing in their allergenic potential. Among putative sensitizing factors, transglutaminase (TGase) and phospholipase A2(PLA2) were considered together with reactive oxygen species (ROS) and known apple allergen genes, with particular attention devoted to the Mal d 1 gene family, the most important one in sensitization. We found that the expression of some allergen genes and the activities of TGase, PLA2and ROS producing enzyme are lower in the hypo-allergenic variety ‘Durello di Forlì’ in comparison with the high-allergenic genotypes ‘Gala’ and ‘Florina’. These results highlight correlations among allergen expressions, enzymatic activities and apple cultivars; these data underline the possibility that some of them could be used in the future as markers for allergenicity.

Patients with Oral Allergy Syndrome (OAS) to fresh apple may tolerate low allergenic apple cultivars. We aimed to investigate if the low allergenic properties of Elise and Santana, as previously identified in a Dutch population, could be generalised within North West Europe within the birch pollen region with regard to both the prevalence and degree of sensitization. Prick-to-prick tests (PTP) were performed in eighty-five adult patients with OAS to fresh apple in Great Britain, Switzerland and Northern Italy, before the birch pollen season, using the putatively low allergenic apple cultivars Elise, Santana, Granny Smith, Modi and Mcintosh, as well as the putatively high allergenic apple cultivars Golden Delicious and Kanzi. No significant differences in percentages of negative responses of PTPs were found between the three countries. Negative responses did not differ from negative responses to the different apple cultivars we previously found in 2006/2007 in the Netherlands. The size of the PTPs of all apple cultivars tested were correlated to the size of the skin prick tests with birch pollen. These results add to the indications for the low allergenic properties of the low allergenic apple cultivars Santana and Elise, as the number of negative responses were reproducible in three countries within the birch pollen region and were similar to previous results in the Netherlands. These results justify oral challenge studies with Elise and Santana within the birch pollen region, to establish the low allergenic properties for the benefit for apple allergic consumers for definite conclusions.

Mal d 1 is not equally distributed over the apple. We aimed to examine the influence of the location of pricking in the apple on prick-to-prick skin prick test (PTP) results. PTPs were performed in autumn 2007 and spring 2008, before the birch pollen season, in 32 Dutch adults with symptoms of oral allergy to fresh apple, using apples harvested in autumn 2007. PTPs with fresh intact and unpeeled Pink Lady, Golden Delicious, Elise, Santana and Modi apples were performed using material obtained from approximately 2cm near the stalk (top), and the middle region. All PTP responses were greater when performed with apple material near the stalk than from the middle region. In 2007, these differences were statistically significant for Pink Lady, Golden Delicious and Elise, and in 2008, for Pink Lady and Modi. When performing PTPs, the apple should be pricked near the stalk rather than in the middle.

Background - A considerable number of individuals suffer from oral allergy syndrome (OAS) to apple, resulting in the avoidance of apple consumption. Apple cultivars differ greatly in their allergenic properties, but knowledge of the causes for such differences is incomplete. Mal d 1 is considered the major apple allergen. For Mal d 1, a wide range of isoallergens and variants exist, and they are encoded by a large gene family. To identify the specific proteins/genes that are potentially involved in the allergy, we developed a PCR assay to monitor the expression of each individual Mal d 1 gene. Gene-specific primer pairs were designed for the exploitation of sequence differences among Mal d 1 genes. The specificity of these primers was validated using both in silico and in vitro techniques. Subsequently, this assay was applied to the peel and flesh of fruits from the two cultivars 'Florina' and 'Gala'. Results - We successfully developed gene-specific primer pairs for each of the 31 Mal d 1 genes and incorporated them into a qRT-PCR assay. The results from the application of the assay showed that 11 genes were not expressed in fruit. In addition, differential expression was observed among the Mal d 1 genes that were expressed in the fruit. Moreover, the expression levels were tissue and cultivar dependent. Conclusion - The assay developed in this study facilitated the first characterisation of the expression levels of all known Mal d 1 genes in a gene-specific manner. Using this assay on different fruit tissues and cultivars, we obtained knowledge concerning gene relevance in allergenicity. This study provides new perspectives for research on both plant breeding and immunotherapy.