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Biomedical subjects

A Wesley Burks

Publications and source records attributed to A Wesley Burks.

At least 19 recordsLinked to original sources
PubMed2006

Egg oral immunotherapy in nonanaphylactic children with egg allergy.

BACKGROUND: There is no current active treatment for food allergy. Traditional injection immunotherapy has been proved unsafe, and thus there is a need for other forms of immunotherapy. OBJECTIVE: The purpose was to study the safety and immunologic effects of egg oral immunotherapy (OIT). The short-term goal was to desensitize subjects to protect against accidental ingestion reactions. The eventual goal was to induce lasting clinical and immunologic tolerance. METHODS: Subjects with a history of egg allergy but without a history of anaphylaxis to egg underwent a 24-month egg OIT protocol involving modified rush, build-up, and maintenance phases. Double-blind, placebo-controlled food challenges were performed at study conclusion. Egg-specific IgE and IgG concentrations were followed. RESULTS: Seven subjects completed the protocol. Egg-specific IgG concentrations increased significantly, whereas egg-specific IgE concentrations did not significantly change. Three subjects tolerated known or possible accidental egg ingestions while receiving OIT. During double-blind, placebo-controlled food challenges at study conclusion, all tolerated significantly more egg protein than at study onset and than that found in the typical accidental exposure. Two subjects demonstrated oral tolerance. CONCLUSION: This study provides proof of concept that OIT can be safely used for patients with egg allergy without a history of anaphylaxis to egg. Egg OIT does not heighten sensitivity to egg and might protect against reaction on accidental ingestion. Whether OIT will induce clinical oral tolerance cannot be concluded from this initial cohort. CLINICAL IMPLICATIONS: Use of allergen-specific OIT to protect subjects with food allergy from reaction on accidental ingestion would represent a significant paradigm change in the treatment of food allergy.

Administration, Oral↗
PubMed2006

The major glycoprotein allergen from Arachis hypogaea, Ara h 1, is a ligand of dendritic cell-specific ICAM-grabbing nonintegrin and acts as a Th2 adjuvant in vitro.

Nonmammalian glycan structures from helminths act as Th2 adjuvants. Some of these structures are also common on plant glycoproteins. We hypothesized that glycan structures present on peanut glycoallergens act as Th2 adjuvants. Peanut Ag (PNAg), but not deglycosylated PNAg, activated monocyte-derived dendritic cells (MDDCs) as measured by MHC/costimulatory molecule up-regulation, and by their ability to drive T cell proliferation. Furthermore, PNAg-activated MDDCs induced 2- to 3-fold more IL-4- and IL-13-secreting Th2 cells than immature or TNF/IL-1-activated MDDCs when cultured with naive CD4+ T cells. Human MDDCs rapidly internalized Ag in a calcium- and glycan-dependent manner consistent with recognition by C-type lectin. Dendritic cell (DC)-specific ICAM-grabbing nonintegrin (DC-SIGN) (CD209) was shown to recognize PNAg by enhanced uptake in transfected cell lines. To identify the DC-SIGN ligand from unfractionated PNAg, we expressed the extracellular portion of DC-SIGN as an Fc-fusion protein and used it to immunoprecipitate PNAg. A single glycoprotein was pulled down in a calcium-dependent manner, and its identity as Ara h 1 was proven by immunolabeling and mass spectrometry. Purified Ara h 1 was found to be sufficient for the induction of MDDCs that prime Th2-skewed T cell responses. Both PNAg and purified Ara h 1 induced Erk 1/2 phosphorylation of MDDCs, consistent with previous reports on the effect of Th2 adjuvants on DCs.

Adjuvants, Immunologic↗
PubMed2006

Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy.

BACKGROUND: Current diagnosis of peanut allergy relies on natural extracts that lack standardization. Recombinant DNA technology allows production of pure biochemically characterized proteins. Their usefulness for peanut allergy diagnosis is not established. OBJECTIVE: This study aimed to evaluate the diagnostic value of the 3 major recombinant peanut allergens. METHODS: Recombinant (r) Ara h 1, rAra h 2, and rAra h 3 were produced according to the recommendations of good manufacturing practice for recombinant allergens. Skin prick tests (SPTs) and IgE ELISA assays were performed in 30 patients with peanut allergy and 30 control subjects without food allergy: 15 nonatopic and 15 sensitized to birch pollen. Disease severity was graded by clinical scoring. RESULTS: All patients with peanut allergy showed positive SPT results to rAra h 2; 40% reacted with rAra h 1 and 27% with rAra h 3. No control subjects reacted with any of the recombinant allergens. Monosensitization to rAra h 2 was observed in 53% of patients. Neither SPT size nor levels of specific IgE were correlated with the disease severity. However, patients with monosensitization to rAra h 2 had a significantly lower severity score than polysensitized subjects and a lower level of specific IgE against peanut extract and rAra h 2. CONCLUSION: Skin prick tests to individual recombinant peanut allergens appear to be a safe and effective diagnostic tool. Cosensitization to rAra h 2 and rArah 1 and/or rAra h 3 is predictive of more severe reactions. CLINICAL IMPLICATIONS: Recombinant peanut allergens can be used by SPTs for diagnosis and evaluation of allergy severity.

Adolescent↗
PubMed2006

X-linked agammaglobulinemia: report on a United States registry of 201 patients.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia. Because the disorder is uncommon, no single institution has had sufficient numbers of patients to develop a comprehensive clinical picture of the disorder. Accordingly, a national registry of United States residents with XLA was established in 1999 to provide an updated clinical view of the disorder in a large cohort of patients. A total of 201 patients were registered by 66 physicians. The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000. Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%). Although the average age of diagnosis was younger in patients with a positive family history (mean, 2.59 yr) than in patients with a negative family history (mean, 5.37 yr) (p < 0.001), only 34.5% of patients with a positive family history at the time of their birth were diagnosed before clinical symptoms developed-that is, based on family history alone. Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode of septic arthritis, 6% at least 1 episode of hepatitis, and 3% at least 1 episode of osteomyelitis. Fourteen of 201 (6.9%) patients were dead at the time they were entered in the Registry. However, in a prospective 4 /4-year follow-up of living patients, only 3/80 (3.75%) patients died. Causes of death included disseminated enterovirus infection (n = 6), pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1), acquired immunodeficiency disease syndrome (AIDS) (n = 1), myocarditis (n = 1), hepatitis (n = 2), and stem cell transplantation (n = 1).

Adolescent↗
PubMed2006

Food allergies: prevalence, molecular characterization, and treatment/prevention strategies.

A significant proportion of the population is either affected by or concerned about food allergy. Our knowledge about food allergens and how they stimulate the immune system has increased dramatically over the past decade. However, reasons for the increased prevalence of food allergy are not clear. The diagnosis of food allergy requires that the patient and caregivers examine all foods for the presence of potential allergens in order to prevent inadvertent ingestion and further reactions. Fortunately, many children develop tolerance to allergenic foods after a period of dietary elimination. Various immunotherapy approaches are under investigation to alleviate or prevent food-induced reactions in those who have persistent food allergies.

Diagnosis, Differential↗
PubMed2005

Comparative potency of Ara h 1 and Ara h 2 in immunochemical and functional assays of allergenicity.

To assess the relative potency of the major peanut allergens, Ara h 1 and Ara h 2, we examined the relative ability of purified proteins to bind IgE on immunoblots, to cross-link allergen specific IgE in an in vitro assay of degranulation based on RBL SX-38 cells, and to bind IgE in the ImmunoCap assay. Sera from 12 highly sensitive, peanut allergic patients were studied in all assays. IgE immunoblots with crude peanut extracts showed binding of IgE to multiple bands including the 63 kDa and 17-19 kDa bands that contain Ara h 1 and Ara h 2, respectively. In the functional assay, Ara h 2 was more potent than Ara h 1 in 11 of 12 sera tested with a median potency that was 52.5-fold more than Ara h 1 (P < 0.005). Contrary to findings with the functional assay, IgE immunoblots with purified Ara h 1 and Ara h 2 showed substantially lighter binding of IgE to Ara h 2 compared with Ara h 1 (P = 0.02). The ImmunoCap assay gave intermediate results with slightly more IgE binding to Ara h 2 than to Ara h 1 (P = 0.005). In conclusion, Ara h 2 is a very potent allergen and is much more potent than Ara h 1 for most sera using an in vitro assay of IgE cross-linking and cell activation. This finding is different from what was predicted based on immunoblots or with the ImmunoCap assay.

2S Albumins, Plant↗
PubMed2005

Food allergy in children.

Food allergic reactions have generated increasing concern in the United States, with approximately one fourth of American households altering their dietary habits because a member of the family is perceived to suffer from food allergies. IgE-mediated (type I) hypersensitivity accounts for most well-characterized food allergic reactions, although non-IgE-mediated immune mechanisms are believed to be responsible for a variety of hypersensitivity disorders. This article examines adverse food reactions that are IgE-mediated, non-IgE-mediated, and those entities that have characteristics of both.

Child↗
PubMed2005

Omalizumab : other indications and unanswered questions.

Omalizumab, a recombinant humanized monoclonal antibody against immunoglobulin (Ig)E, represents a unique therapeutic approach for the treatment of allergic diseases. This agent acts as a neutralizing antibody by binding IgE at the same site as the high-affinity receptor. Subsequently, IgE is prevented from sensitizing cells bearing high-affinity receptors. Inhibition of the biological effects of IgE targets an early phase of the allergic cascade before the generation of allergic symptoms. Currently, omalizumab has been approved for the treatment of persistent allergic asthma in patients who are poorly controlled with inhaled corticosteroids. However, other allergic disorders may be amenable to treatment with omalizumab because of its ability to inhibit effector functions of IgE. Studies of omalizumab in the treatment of allergic rhinitis comprise the greater part of the literature pertaining to the use of this agent for clinical indications other than asthma. This article summarizes clinical trials of omalizumab in allergic rhinitis and examines the evidence regarding the effects of omalizumab on the pathophysiological mechanisms underlying allergic rhinitis. Additionally, we consider the role of this novel therapeutic agent in combination with specific allergen immunotherapy and discuss other potential indications for omalizumab in IgE-mediated disorders, including food allergy, latex allergy, atopic dermatitis, and chronic urticaria.

Antibodies, Anti-Idiotypic↗
PubMed2004

Peanut protein allergens: the effect of roasting on solubility and allergenicity.

BACKGROUND: A contributing factor to food allergen stability is heat resistance. Peanut allergens in particular are resistant to heat, which results in their decreased solubility upon routine extraction and may have a profound influence on their continued presence in the digestive tract. Although there have been a number of studies characterizing soluble extracts of raw and roasted proteins, the relative solubility of the insoluble material following routine extraction for residual allergen characterization has not been investigated. The effects of various treatments on the re-solubilization and subsequent allergenicity of this insoluble peanut protein material are presented here. METHODS: Various methods to resolubilize the insoluble protein material were used, including pH, proteases and glycosidases. Protease digestion of nonextractable peanut proteins with pepsin, chymotrypsin and trypsin was performed in appropriate buffers as previously optimized for peanut proteins. Glycosidase activity in the presence of protease inhibitors was performed at pH 2. Digested samples were then subjected to SDS-PAGE/Western blot analysis using serum IgE from peanut-sensitive individuals. RESULTS: Progressive roasting of peanuts resulted in a significant decrease in protein solubility. The acidic proteins were resolubilized moderately at high pH, with solubility decreasing as pH approached the pI of the protein. However, at pH 2 the solubility increased dramatically. More extensive resolubilzation was observed with amylase treatment, presumably due to cleavage of glycoside of glycoproteins. The protein released into solution had a high IgE-binding capacity. While amylase was effective at resolubilizing this material, digestive tract proteases were not. CONCLUSION: The presence of these insolubilized peanut proteins provides a continuous source of major allergens to the gastrointestinal mucosal immune system.

Allergens↗
PubMed2004

Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes.

BACKGROUND: IgE epitope mapping of food allergens is a prerequisite for engineering hypoallergenic immunotherapeutic agents and might reveal basic information regarding a patient's immune response. Mapping of large numbers of epitopes by using individual patient sera has been impractical with current techniques. OBJECTIVE: We sought to develop a peptide microarray-based immunoassay to map peanut epitopes by using microliter quantities of serum. METHODS: A set of 213 overlapping 20-residue peptides was synthesized corresponding to the primary sequences of Ara h 1, Ara h 2, and Ara h 3. These were arrayed in triplicate along with the corresponding recombinant proteins onto glass slides and used for immunolabeling. RESULTS: Seventy-seven patient and 15 control sera were analyzed. The majority of patients (97%) had specific IgE to at least one of the recombinant allergens, and 87% had detectable IgE to sequential epitopes. Microarray mapping correlated well with previous studies. However, the analysis of individual patients revealed remarkable heterogeneity in the number and patterns of epitope recognition. High epitope diversity was found in patients with a history of more severe allergic reactions. Also, sensitization of effector cells with more diverse IgE antibodies conferred greater reactivity to specific allergen. CONCLUSIONS: The protein microarray immunoassay confirmed that Ara h 1, Ara h 2, and Ara h 3 are major peanut allergens and allows for parallel epitope analysis. This has led to the discovery of an additional important epitope of Ara h 1 and the recognition of a high degree of patient heterogeneity. This qualitative difference in epitope diversity might provide prognostic information about the patient.

2S Albumins, Plant↗
PubMed2004

Peanut protein allergens: gastric digestion is carried out exclusively by pepsin.

BACKGROUND: A major characteristic of many food allergens, including Ara h 1, a major peanut allergen, is their resistance to gastric digestion. One estimate of the allergenic potential of a possible protein allergen is its stability under simulated gastric conditions. OBJECTIVE: Because the rate and extent of digestion of allergenic proteins will affect the severity of any subsequent allergic response, it is important to correlate protein allergen digestion in simulated gastric fluid with that in actual gastric fluid. METHODS: A major peanut allergen, Ara h 1, was digested in vitro by using both pepsin and porcine gastric fluid. Several comparisons between the 2 sets of proteolytic conditions were assessed including pH optima and the effect of temperature, denaturants, and specific enzyme inhibitors. RESULTS: In vitro digestion of Ara h 1 with pepsin and porcine gastric fluid resulted in virtually identical hydrolysis patterns as observed on SDS-PAGE. The protease activity of both pepsin and gastric fluid were inhibited at high pH and in the presence of pepstatin. However, both remained active in 4 mol/L urea and at 60 degrees C. CONCLUSIONS: Protein digestion in the porcine stomach is carried out by pepsin. In vivo gastric digestion is modeled accurately by peptic hydrolysis. Digestion conditions in vivo are comparable to experimental conditions in vitro provided that the acidic nature of the stomach contents is optimal for characterization of the allergen under standard pepsin digestion conditions. Additional experimentation using crude food extracts, both in the presence and absence of a complete meal, is needed to elucidate the complete physiologic nature of food allergen digestion.

Allergens↗
PubMed2004

Soy immunotherapy for peanut-allergic mice: modulation of the peanut-allergic response.

BACKGROUND: Allergen-specific immunotherapy (IT) is an effective therapeutic modality to prevent further anaphylactic episodes in patients with insect sting hypersensitivity and is being investigated for peanut allergy. So far, peanut-specific IT has been unsuccessful because of the side effects of therapy. Soybean seed storage proteins share significant homology with the respective peanut allergens. OBJECTIVE: This study was undertaken in mice to investigate whether specific doses of soybean would desensitize peanut-allergic mice. METHODS: C3H/HeJ mice were sensitized to peanut with 3 intraperitoneal (IP) injections of crude peanut extract. The mice were desensitized by IP injections with either crude peanut or soybean extract for 4 weeks, 3 times a week. Controls included placebo desensitization with PBS and naive mice. After 2 weeks of rest, mice were challenged IP with crude peanut extract. Thirty minutes later, symptom scores and body temperatures were recorded. Serum immunoglobulins, peanut-induced splenocyte proliferation, and secreted cytokines were measured before and after desensitization. RESULTS: The clinical symptoms in the soybean- and peanut-desensitized animals were markedly reduced compared with the placebo-treated mice. Specific IgG1 levels to crude peanut were significantly lower in the soy IT group than in the peanut IT group. The cellular response to crude peanut was also downregulated in the soy IT group, as shown by decreased peanut-specific stimulation indices and a cytokine profile skewed toward a T H 1 response. CONCLUSIONS: Soy IT can be used to desensitize/downregulate peanut-specific response in peanut-allergic mice and could provide a new therapeutic intervention for peanut allergy.

Animals↗
PubMed2004

Peanut allergy: recurrence and its management.

BACKGROUND: Although peanut allergy may recur, the frequency with which this occurs is unknown. OBJECTIVE: The goals of this study were to determine the rate of peanut allergy recurrence, identify risk factors for recurrent peanut allergy, and develop specific recommendations for the treatment of patients with resolved peanut allergy. METHODS: Children who outgrew peanut allergy were evaluated with questionnaires, skin tests, and peanut-specific IgE levels. Patients were invited to undergo a double-blind, placebo-controlled food challenge (DBPCFC) unless the history of a possible recurrence reaction was so convincing that a challenge would be potentially dangerous. RESULTS: Sixty-eight patients were evaluated. Forty-seven patients continued to tolerate peanut, of whom 34 ingested concentrated peanut products at least once per month and 13 ate peanut infrequently or in limited amounts but passed a DBPCFC. The status of 18 patients was indeterminate because they ate peanut infrequently or in limited amounts and declined to have a DBPCFC. After excluding 12 patients originally diagnosed with peanut allergy based solely on a positive skin prick test or peanut-specific IgE level, 3 of 15 patients who consumed peanut infrequently or in limited amounts had recurrences, compared with no recurrences in the 23 patients who ate peanut frequently ( P = .025). The recurrence rate was 7.9 (95% CI, 1.7% to 21.4%). CONCLUSION: Children who outgrow peanut allergy are at risk for recurrence, and this risk is significantly higher for patients who continue largely to avoid peanut after resolution of their allergy. On the basis of these findings, we now recommend that patients eat peanut frequently and carry epinephrine indefinitely until they have demonstrated ongoing peanut tolerance.

Arachis↗
PubMed2004

Peanut allergenicity.

OBJECTIVE: To provide the reader with a relevant review of the structure and allergenicity of the major peanut allergens, while also exploring predictors of clinical reactivity to peanuts, the natural history of peanut allergy, and novel therapeutic strategies for peanut hypersensitivity. DATA SOURCES: A PubMed search for the years 1980 to 2004 was performed using the following search terms: peanut allergy, food allergy, anaphylaxis, peanut allergen structure, and peanut immunotherapy. STUDY SELECTION: Articles highlighting major advances in the study of peanut allergy were selected for further review. RESULTS: Peanut allergy is the most serious of the hypersensitivity reactions to foods due to its persistence and high risk of severe anaphylaxis. The major peanut allergens and their associated immunodominant IgE-binding epitopes have been characterized. Definition of these allergens has lead to an increased understanding of the peanut-specific immunologic response and improved predictors of clinical reactivity to peanuts. An understanding of these mechanisms is vital for the eventual development of safe and effective immunotherapy for peanut allergic patients. Novel therapeutic and diagnostic approaches are being developed for patients with peanut hypersensitivity. CONCLUSIONS: Improved understanding of the molecular structure of the major peanut allergens and the peanut-specific immune response has lead to significant diagnostic and therapeutic advances in the study of peanut allergy.

Allergens↗
PubMed2003

Engineered recombinant peanut protein and heat-killed Listeria monocytogenes coadministration protects against peanut-induced anaphylaxis in a murine model.

Peanut allergy (PNA) is the major cause of fatal and near-fatal anaphylactic reactions to foods. Traditional immunotherapy using peanut (PN) protein is not an option for PNA therapy because of the high incidence of adverse reactions. We investigated the effects of s.c. injections of engineered (modified) recombinant PN proteins and heat-killed Listeria monocytogenes (HKLM) as an adjuvant on anaphylactic reactions in a mouse model of PN allergy. PN-allergic C3H/HeJ mice were treated s.c. with a mixture of the three major PN allergens and HKLM (modified (m)Ara h 1-3 plus HKLM). The effects on anaphylactic reactions following PN challenge and the association with Ab levels and cytokine profiles were determined. Although all mice in the sham-treated groups exhibited anaphylactic symptoms with a median symptom score of 3, only 31% of mice in the mAra h 1-3 plus HKLM group developed mild anaphylaxis, with a low median symptom score of 0.5. Alterations in core body temperature, bronchial constriction, plasma histamine, and PN-specific IgE levels were all significantly reduced. This protective effect was markedly more potent than in the mAra h 1-3 protein alone-treated group. HKLM alone did not have any protective effect. Reduced IL-5 and IL-13, and increased IFN-gamma levels were observed only in splenocytes cultures from mAra h 1-3 plus HKLM-treated mice. These results show that immunotherapy with modified PN proteins and HKLM is effective for treating PN allergy in this model, and may be a potential approach for treating PNA.

2S Albumins, Plant↗
PubMed2003

Effect of anti-IgE therapy in patients with peanut allergy.

BACKGROUND: Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc(epsilon) receptor on mast cells and basophils. METHODS: We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a history of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to four weeks after the fourth dose. RESULTS: From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated. CONCLUSIONS: A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanuts.

Adolescent↗