Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model.

BACKGROUND: The prebiotic nature of human milk oligosaccharides (HMOs) and increasing evidence of direct immunomodulatory effects of these sugars suggest that they may have some therapeutic potential in allergy. Here, we assess the effect of two HMOs, 2'-fucosyllactose and 6'-sialyllactose, on symptomatology and immune responses in an ovalbumin-sensitized mouse model of food allergy. METHODS: The effects of oral treatment with 2'-fucosyllactose and 6'-sialyllactose on anaphylactic symptoms induced by oral ovalbumin (OVA) challenge in sensitized mice were investigated. Mast cell functions in response to oral HMO treatment were also measured in the passive cutaneous anaphylaxis model, and direct effects on IgE-mediated degranulation of mast cells were assessed. RESULTS: Daily oral treatment with 2'-fucosyllactose or 6'-sialyllactose attenuated food allergy symptoms including diarrhea and hypothermia. Treatment with HMOs also suppressed antigen-induced increases in mouse mast cell protease-1 in serum and mast cell numbers in the intestine. These effects were associated with increases in the CD4(+) CD25(+) IL-10(+) cell populations in the Peyer's patches and mesenteric lymph nodes, while 6'-sialyllactose also induced increased IL-10 and decreased TNF production in antigen-stimulated splenocytes. Both 2'-fucosyllactose and 6'-sialyllactose reduced the passive cutaneous anaphylaxis response, but only 6'-sialyllactose directly inhibited mast cell degranulation in vitro, at high concentrations. CONCLUSIONS: Our results suggest that 2'-fucosyllactose and 6'-sialyllactose reduce the symptoms of food allergy through induction of IL-10(+) T regulatory cells and indirect stabilization of mast cells. Thus, human milk oligosaccharides may have therapeutic potential in allergic disease.

Environmental and lunar cues are predictive of the timing of river entry and spawning-site arrival in lake sturgeon Acipenser fulvescens.

The associations were quantified between daily and interannual variation in the timing of a closed population of lake sturgeon Acipenser fulvescens migration and arrival at spawning sites with stream environmental and lunar covariates. Spawning data were gathered from 1262 fish in Black Lake, Michigan 2001 to 2008 and by video monitoring 2000 to 2002. Sex-specific variation in responses to external cues was also tested. Results showed that a greater number of individuals initiated migration from lake to riverine habitats at dawn and dusk relative to other times of the day. Current and lagged effects of water temperature and river discharge, and periods in the lunar cycle were important variables in models quantifying movements into the river and timing of adult arrival at spawning sites. Different suites of covariates were predictive of A. fulverscens responses during different periods of the spawning season. The timing of initiation of migration and spawning, and the importance of covariates to the timing of these events, did not differ between sexes. Stream flow and temperature covaried with other variables including day length and the lunar cycle. Anthropogenic disruption of relationships among variables may mean that environmental cues may no longer reliably convey information for Acipenseriformes and other migratory fishes.

Transforming growth factor beta abrogates the effects of hematopoietins on eosinophils and induces their apoptosis.

Hematopoietins, interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) have previously been shown to prolong eosinophil survival and abrogate apoptosis. The objective of this study was to investigate the effect of transforming growth factor beta (TGF-beta) on eosinophil survival and apoptosis. Eosinophils from peripheral blood of mildly eosinophilic donors were isolated to > 97% purity using discontinuous Percoll density gradient. Eosinophils were cultured with hematopoietins with or without TGF-beta for 4 d and their viability was assessed. We confirmed previous observations that hematopoietins prolonged eosinophil survival and inhibited apoptosis. TGF-beta at concentrations > or = 10(-12) M abrogated the survival-prolonging effects of hematopoietins in a dose-dependent manner and induced apoptosis as determined by DNA fragmentation in agarose gels. The effect of TGF-beta was blocked by an anti-TGF-beta antibody. The anti-TGF-beta antibody also prolonged eosinophil survival on its own. The culture of eosinophils with IL-3 and GM-CSF stimulated the synthesis of GM-CSF and IL-5, respectively, suggesting an autocrine mechanism of growth factor production. TGF-beta inhibited the synthesis of GM-CSF and IL-5 by eosinophils. TGF-beta did not have any effect on the expression of GM-CSF receptors on eosinophils. We also studied the effect of TGF-beta on eosinophil function and found that TGF-beta inhibited the release of eosinophil peroxidase. Thus, TGF-beta seems to inhibit eosinophil survival and function. The inhibition of endogenous synthesis of hematopoietins may be one mechanism by which TGF-beta blocks eosinophil survival and induces apoptosis.

The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the Ras-Raf-1-MEK-microtubule-associated protein kinase pathway.

Interleukin 5 (IL-5) regulates the growth and function of eosinophils. The objective of this study was to investigate the intracellular signal transduction mechanism of IL-5 in eosinophils. Purified eosinophils were stimulated with IL-5, and the involvement of various kinases was investigated by immunoblotting, immune complex kinase assay, and in situ denatured/renatured kinase assay. We found that IL-5 induced tyrosine phosphorylation and activation of a number of kinases. Two species of lyn kinases (53 and 56 kD) were present in eosinophils. Both forms were Tyr-phosphorylated and activated rapidly within 1 min. Further, lyn kinase was physically associated with the IL-5 beta receptor in eosinophils. Ras was studied by immunoprecipitation followed by thin-layer chromatography. Ras bound higher quantities of [alpha-32P]guanosine 5'triphosphate upon stimulation with IL-5. Raf-1 kinase showed increased Tyr phosphorylation on immunoblotting and increased activity in the immune complex kinase assay. Two species of MEK (MAP or Erk kinase) (41 and 45 kD) were identified in eosinophils, which underwent autophosphorylation upon stimulation. Microtubule-associated protein (MAP) kinase (p44) was Tyr-phosphorylated on immunoblotting and had increased activity in the immune-complex kinase assay. MAP kinases were also studied after metabolic radiolabeling of the cells with [32P]orthophosphates. IL-5 stimulated phosphorylation of MAP kinases in situ. Thus, we have delineated major components of an important signaling pathway in eosinophils. We believe that one of the signals generated by IL-5 receptor activation is propagated through the lyn-Ras-Raf-1-MEK-MAP kinase pathway.

Macrophage inflammatory protein-1 alpha activates basophils and mast cells.

Macrophage inflammatory protein-1 (MIP) is a recently cloned cytokine that causes neutrophilic infiltration and induces an inflammatory response. We studied the effect of MIP-1 alpha on histamine secretion from basophils and mast cells. Leukocytes from allergic and normal subjects were studied. MIP-1 alpha caused dose-dependent release of histamine from basophils of 14 of 20 allergic donors at concentrations of 10(-9)-10(-7) M, and the mean release was 13.50 +/- 2.9% at the highest concentration. In the same experiments, the mean histamine release by anti-immunoglobulin E and monocyte chemotactic and activating factor (MCAF) (10(-7) M) was 32 +/- 7% and 31 +/- 3%, respectively. The cells from only 2 of 10 normal subjects released histamine in response to MIP-1 alpha. Histamine release by MIP-1 alpha was rapid, and almost complete within the first 3 min. MIP-1 alpha-induced degranulation was a calcium-dependent noncytotoxic process. MIP-1 alpha showed chemotactic activity for purified basophils that was comparable to MCAF. Both MIP-1 alpha and MCAF at 10(-7) M concentration elicited a chemotactic response that was 40% of the maximal response to C5a (1 microgram/ml). Murine MIP-1 alpha induced histamine release from mouse peritoneal mast cells in a dose-dependent manner. Thus, we have established that MIP-1 alpha is a novel activator of basophils and mast cells.

Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models.

BACKGROUND: The incidence of atopic disease has increased dramatically during recent decades and the potential immunoregulatory influence of the microbiota in these individuals is under investigation. OBJECTIVE: The aim of our study was to identify a bacterial strain that is protective in murine allergy models and to determine if microbial induction of T regulatory cells was associated with protection from allergic inflammation. METHODS: Three microbes (Bifidobacterium breve AH1205, B. longum AH1206 and Lactobacillus salivarius AH102) of human origin were fed to newborn, adult and germ-free animals. Induction of Foxp3(+) T regulatory cells was assessed by flow cytometry. Gene array analysis was performed on Peyer's patches. Strains were also examined for their protective effects in the ovalbumin (OVA) respiratory allergy model and the OVA-cholera toxin dietary allergy model. RESULTS: Bifidobacterium longum AH1206 consumption resulted in increased numbers of Foxp3(+) T regulatory cells in infant, adult and germ-free animals. B. breve AH1205 induced Foxp3(+) T regulatory cell expansion only in infant mice while L. salivarius AH102 did not alter T regulatory cell numbers in any animal model tested. B. longum AH1206 reduced the Peyer's patch gene expression associated with antigen presentation, TLR signalling and cytokine production while increasing the expression of genes associated with retinoic acid metabolism. B. longum AH1206 protected against airway inflammation in OVA-sensitized animals and B. longum AH1206 blocked the induction of IgE to orally administered OVA. Neither B. breve AH1205 nor L. salivarius AH102 had a protective effect in either model. CONCLUSION: Bacterial strain-specific induction of Foxp3(+) T regulatory cells in vivo is associated with protection from respiratory and oral allergy.

Differences in cecal microbiome of selected high and low feather-pecking laying hens.

In mammals, it has become increasingly clear that the gut microbiota influences not only gastrointestinal physiology but also modulates behavior. In domestic birds, ceca have the greatest gastrointestinal microbial population. Feather-pecking (FP) behavior in laying hens is one of the most important unsolved behavioral issues in modern agriculture. The aim of the present study was to assess the cecal microbial community of divergently selected high (HFP; n = 20) and low (LFP; n = 20) feather-pecking birds at 60 wk of age. The cecal samples were subjected to community profiling of 16S rRNA and in silico metagenomics using a modified bar-coded Illumina sequencing method on a MiSeq Illumina sequencer. Our results revealed that compared to HFP birds, LFP birds are characterized by an increased overall microbial diversity (beta diversity) shown by a difference in the Bray-Curtis index (R2 = 0.171, P < 0.05). Furthermore, operational taxonomic unit comparisons showed an increased presence of Clostridiae and decreased presence of Lactobaccillacae in HFP birds when compared to LFP birds (False Discovery Rate < 0.05, Mann-Whitney comparisons). Our data indicate that there may be differences in the cecal profile between these 2 lines of laying hens. More research, building on this first study using sequencing technology for profiling the chicken cecal microbiome, will be needed in order to reveal if and how there exists a functional link between the performance of FP and the cecal microbial community.

Monocyte chemotactic and activating factor is a potent histamine-releasing factor for basophils.

Monocyte chemotactic and activating factor (MCAF) is a recently cloned cytokine that causes chemotaxis of basophils. In our pursuit of cytokines affecting basophil function, we studied the effect of MCAF on histamine secretion from basophils. Leukocytes from 20 donors, 10 allergic and 10 normal subjects, were studied. MCAF caused dose-dependent release of histamine at concentrations of 10(-8) and 10(-7) M, and the mean release was 31.25 +/- 2.9% at the highest concentration. In the same experiments the mean histamine release by anti-IgE and histamine releasing factor (HRF) was 27.05 +/- 4% and 32.70 +/- 2.7%, respectively. All 20 subjects responded to MCAF with significant histamine release. Allergic subjects released significantly more histamine than normals in response to anti-IgE (P less than 0.01) but not to MCAF (P = 0.2) and HRF (P = 0.1). The histamine release was significantly correlated between MCAF and HRF (P less than 0.01), but not between MCAF and anti-IgE (P greater than 0.05). The histamine release by MCAF was complete within the first 3 min. MCAF-induced degranulation was a calcium-dependent process. Leukocytes depleted of monocytes responded equally well to MCAF. Using an anti-MCAF affinity column we determined that greater than 50% of HRF activity of crude PBMC supernatant could be attributed to MCAF. Thus, we established that MCAF is a potent secretagogue for basophils.

Lactobacillus rhamnosus strain JB-1 reverses restraint stress-induced gut dysmotility.

BACKGROUND: Environmental stress affects the gut with dysmotility being a common consequence. Although a variety of microbes or molecules may prevent the dysmotility, none reverse the dysmotility. METHODS: We have used a 1 hour restraint stress mouse model to test for treatment effects of the neuroactive microbe, L. rhamnosus JB-1™ . Motility of fluid-filled ex vivo gut segments in a perfusion organ bath was recorded by video and migrating motor complexes measured using spatiotemporal maps of diameter changes. KEY RESULTS: Stress reduced jejunal and increased colonic propagating contractile cluster velocities and frequencies, while increasing contraction amplitudes for both. Luminal application of 10E8 cfu/mL JB-1 restored motor complex variables to unstressed levels within minutes of application. L. salivarius or Na.acetate had no treatment effects, while Na.butyrate partially reversed stress effects on colonic frequency and amplitude. Na.propionate reversed the stress effects for jejunum and colon except on jejunal amplitude. CONCLUSIONS & INFERENCES: Our findings demonstrate, for the first time, a potential for certain beneficial microbes as treatment of stress-induced intestinal dysmotility and that the mechanism for restoration of function occurs within the intestine via a rapid drug-like action on the enteric nervous system.

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

PURPOSE: Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS: Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION: Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

Past trauma and present functioning of patients attending a women's psychiatric clinic.

A women's psychiatric clinic, incorporated within a university teaching general hospital and staffed entirely by women, was opened in March of 1980. The authors studied a sample of 100 women who came to the clinic and characterized them by demographic variables, psychiatric diagnoses, health problems, chronic illness, death in the family, and traumatic incidents. Death in the family before she was 18 was found to predict a woman's subsequent request for or completion of sterilization. Physical or sexual abuse was significantly related to abortion, and abortion and trauma were significantly correlated.

PIP: Data were collected from the intake forms completed by 100 patients of a women's psychiatric clinic in order to characterize them by demographic variables, psychiatric diagnoses, health problems, chronic illness, death in the family, and traumatic incidents. Having postulated that the sample could be divided into specific groups according to the history of trauma, history of deaths in the family, and chronic illness in the patient and her family, an attempt was made to discover any relationship between such histories and the patient's current health problems. The existence of specific and different health issues and implications for the trauma group, the death group, and the chronic illness group was postulated. The only demographic characteristic that was significantly correlated with other variables was education. Women having no more than high school education were more likely to have experienced physical or sexual abuse than were those having postsecondary education. Members of the former group also were significantly more likely to have had an abortion. There was no statistically significant relationship between education level and other health or trauma variables. 49% of the sample had experienced the death of a family member. Of these, 25% had experienced at least 1 of these deaths before age 18. There was a small but significant correlation between death in the family and a personal history of chronic illness and 3 or more gynecological problems. There was a small statistical correlation between death in the family and a diagnosis of neurotic or adjustment disorder and finding of a high stress level. There was no statistical correlation between death in the family and abortion, there was a highly significant correlation between death in the family and request for or completion of sterilization. When the factor of physical and/or sexual abuse was examined separately, there was a significant correlation with abortion and a somewhat weaker correlation with sterilization. Abortion correlated very significant with 3 or more trauma factors; sterilization correlated also but at a less significant level than abortion.

Mast cells and nitric oxide: control of production, mechanisms of response.

Mast cells are involved in numerous activities ranging from control of the vasculature, to tissue injury and repair, allergic inflammation and host defences. They synthesize and secrete a variety of mediators, activating and modulating the functions of nearby cells and initiating complex physiological changes. Interestingly, NO produced by mast cells and/or other cells in the microenvironment appears to regulate these diverse roles. This review outlines some of the pathways central to the production of NO by mast cells and identifies many of the tightly controlled regulatory mechanisms involved. Several cofactors and regulatory elements are involved in NO production, and these act at transcriptional and post-translational sites. Their involvement in NO production will be outlined and the possibility that these pathways are critically important in mast cell functions will be discussed. The effects of NO on mast cell functions such as adhesion, activation and mediator secretion will be examined with a focus on molecular mechanisms by which NO modifies intracellular signalling pathways dependent or independent of cGMP and soluble guanylate cyclase. The possibility that NO regulates mast cell function through effects on selected ion channels will be discussed. Metabolic products of NO including peroxynitrite and other reactive species may be the critical elements that affect the actions of NO on mast cell functions. Further understanding of the actions of NO on mast cell activities may uncover novel strategies to modulate inflammatory conditions.

Sarcomatous transformation in cranial chordoma.

In a study of 52 patients with cranial chordoma treated at the Mayo Clinic over a 19-year period (1966-1984), two tumors showed anaplastic features, both de novo, i.e., unassociated with prior irradiation. The incidence of anaplastic transformation was thus 4%. Immunohistochemistry showed the mixed mesenchymal-epithelial phenotype typical of chordoma in portions of both tumors, but loss of reactivity for keratin and epithelial membrane antigen was noted in anaplastic components. The study indicates that sarcomatous change in chordoma is a rare event that may occur de novo and is associated with the loss of immunophenotypic features of epithelial differentiation.

New practices in the transitional care center improve outcomes for babies and their families.

Assuming sole responsibility of parenting a high-risk infant after a prolonged hospital stay can be a complex and traumatic event, especially when the infant is discharged with residual health care problems requiring medical management and treatment at home. A parent's ability to successfully transition the management of their infant's care from hospital to home depends on a collaborative discharge process where parents are ongoing, full participants. The Transitional Care Center environment makes learning comfortable for parents, allows parental care-giver mastery to occur, and fosters family integration. Favorable clinical outcomes concurrent with decreased lengths of hospital stays and readmission rates have been demonstrated.

Research utilization and the consumers of care: the parent's perspective.

Parents and professionals enter into research relationships with differing expectations and purposes. Fifty parents were approached to request permission for their infant to participate in the Transition of the Preterm Infant to an Open Crib research utilization project. All parents agreed. Most parents were enthusiastic about the project and viewed the possible outcome of participation as enhancing the care and recovery of their infant. Some parents delayed granting permission until convinced of the successful results by observing other infants in the project. Some parents granted permission based on trust and faith in the care-giving system.

Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains.

BACKGROUND: Commensal bacteria such as probiotics that are neuroactive acutely affect the amplitudes of intestinal migrating motor complexes (MMCs). What is lacking for an improved understanding of these motility effects are region specific measurements of velocity and frequency. We have combined intraluminal pressure recordings with spatiotemporal diameter maps to analyze more completely effects of different strains of beneficial bacteria on motility. METHODS: Intraluminal peak pressure (PPr) was measured and video recordings made of mouse ex vivo jejunum and colon segments before and after intraluminal applications of Lactobacillus rhamnosus (JB-1) or Lactobacillus reuteri (DSM 17938). Migrating motor complex frequency and velocity were calculated. KEY RESULTS: JB-1 decreased jejunal frequencies by 56% and 34% in colon. Jejunal velocities increased 171%, but decreased 31% in colon. Jejunal PPr decreased by 55% and in colon by 21%. DSM 17938 increased jejunal frequencies 63% and in colon 75%; jejunal velocity decreased 57%, but increased in colon 146%; jejunal PPr was reduced 26% and 12% in colon. TRAM-34 decreased frequency by 71% and increased velocity 200% for jejunum, but increased frequency 46% and velocity 50% for colon; PPr was decreased 59% for jejunum and 39% for colon. CONCLUSIONS & INFERENCES: The results show that probiotics and other beneficial bacteria have strain and region-specific actions on gut motility that can be successfully discriminated using spatiotemporal mapping of diameter changes. Effects are not necessarily the same in colon and jejunum. Further research is needed on the detailed effects of the strains on enteric neuron currents for each gut region.

Autonomic nervous system regulates secretion of anti-inflammatory prohormone SMR1 from rat salivary glands.

The autonomic nervous system regulates the secretion of bioactive proteins and peptides from salivary glands that can be important in systemic physiological responses. The prohormone submandibular rat-1, which is highly expressed in rat submandibular glands, can be cleaved to produce polypeptides with analgesic and anti-inflammatory activities. Human genes related to submandibular rat-1 have conserved biological functions and are potentially important in pain suppression, erectile function, and inflammation. In this study we describe the differential expression and posttranslational modification of submandibular rat-1 protein in salivary glands, the urogenital tract, lung, blood, and saliva in male Sprague-Dawley and Brown Norway rats. Submandibular rat-1 protein is secreted into saliva after the administration of beta-adrenergic or cholinergic agonists. Removal of the sympathetic ganglion that innervates the salivary glands results in increased levels of submandibular rat-1 protein in salivary glands. The secretion of submandibular rat-1 in response to physiological stress may provide a large pool of submandibular rat-1-derived peptide products that can promote analgesia and decrease inflammation locally and systemically. This pathway may be conserved among mammals and may constitute an important anti-inflammatory and analgesic response to stress.

Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.

BACKGROUND AND AIMS: Probiotic bacteria are being investigated as possible treatments for many intestinal disorders. The present study aimed to explore the effects of live, heat killed, or gamma irradiated Lactobacillus reuteri on cardio-autonomic response and single fibre unit discharge in dorsal root ganglia to colorectal distension in healthy Sprague-Dawley rats housed under conventional conditions. The effects of this treatment on somatic pain were also examined. METHODS: 1x10(9) bacteria were given by gavage for nine days. Colorectal distension occurred under anaesthesia. Heart rate was measured through continuous electrocardiography. Single fibre unit discharge was recorded from the 6th left lumbar dorsal root ganglion. Somatic pain was evaluated by the tail flick and paw pressure tests. RESULTS: Colorectal distension caused a pressure dependent bradycardia in the control (native medium) group. Treatment with live, heat killed, or gamma irradiated bacteria as well as their products (conditioned medium) prevented the pain response even during the maximum distension pressure (80 mm Hg). Both viable and non-viable bacteria significantly decreased dorsal root ganglion single unit activity to distension. No effects on somatic pain were seen with any treatment. CONCLUSIONS: Oral administration of either live or killed probiotic bacteria or conditioned medium inhibited the constitutive cardio-autonomic response to colorectal distension in rats through effects on enteric nerves. These data may provide a novel explanation for beneficial probiotic effects on visceral pain.

Clinical consequences of mast cell heterogeneity.

The heterogeneous morphological, biochemical and functional characteristics of mast cells from different species and from different tissue sites in the same species have been described for over 30 years. Far from being mere histochemical or pharmacological curiosities these differences have far reaching implications for therapeutic practice. This review concentrates on two important areas affected by mast cell heterogeneity, those of adverse reactions to therapeutic agents and the efficacy of anti-allergy therapy. In vitro studies of preformed and de novo synthesised mediator release have demonstrated a wide variability in the response of basophils and isolated mast cells to anti-allergy drugs and therapeutic agents such as radiographic contrast media, general anaesthetics, opioids and muscle relaxants. This heterogeneity is not limited to the mast cell's tissue of origin as there is also variability in the response of basophils and mast cells from different donors to the same drug or agent. These data have considerable clinical implications for the study of adverse drug reactions and the design of novel anti-allergic drugs.