Bulk T-cell receptor sequencing confirms clonality in pediatric eosinophilic esophagitis and identifies a food-specific repertoire.

BACKGROUND: Eosinophilic esophagitis (EoE) involves a chronic immune-mediated response to dietary antigens. Recent work identifies T-cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food-specific T-cell repertoire. We sought to confirm T-cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. METHODS: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non-EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V-J-CDR3s were assessed based on specific food triggers. RESULTS: Active EoE biopsies from children but not adults displayed decreased unique TCRα/ß clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non-EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre-diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). CONCLUSION: We confirmed relative clonality in children but not adults with active EoE and identified potential food-specific TCRs, particularly for milk-triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers.

Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms After Dilation in Adults With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and peak esophageal eosinophils per high-power field (eos/hpf). METHODS: Adults enrolled in a multisite prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsy specimens. Patients were stratified based on dilation status as absent, performed 1 year or less before endoscopy, and performed more than 1 year before endoscopy. Assessments included Spearman correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf. RESULTS: Among 100 patients (n = 61 males; median age, 37 y), 15 and 40 patients underwent dilation 1 year or less and more than 1 year before index endoscopy, respectively. In nondilated patients, the association between eos/hpf and symptoms was moderate (ρ = 0.49; P < .001); for a 10-eos/hpf increase, the predicted EEsAI increased by 2.69 (P = .002). In patients dilated 1 or less and more than 1 year before index endoscopy, this association was abolished (ρ = -0.38; P = .157 for ≤1 y and ρ = 0.02; P = .883 >1 y); for a 10-eos/hpf increase, the predicted EEsAI changed by -1.64 (P = .183) and 0.78 (P = .494), respectively. Dilation modified the association between symptoms and eos/hpf (P = .005 and P = .187 for interaction terms of eos/hpf and dilation 1 or less years before and more than 1 year before index endoscopy, respectively). CONCLUSIONS: In nondilated EoE adults, eos/hpf correlate modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than 1 year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up evaluation.

Noninvasive biomarkers identify eosinophilic esophagitis: A prospective longitudinal study in children.

BACKGROUND: Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil-associated proteins to diagnose EoE and predict esophageal eosinophilia. METHODS: Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein-1 (MBP-1), galectin-10 (CLC/GAL-10), Eotaxin-2 and Eotaxin-3, and urine osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. RESULTS: Of 183 specimens were collected from 56 EoE patients and 15 non-EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre- and post-treatment specimens. Plasma (CLC/GAL-10, ECP, EDN, Eotaxin-3, MBP-1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL-10, Eotaxin-3, ECP, EDN, MBP-1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL-10, ECP, and MBP-1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC, CLC/GAL-10, ECP, EDN, OPN, and MBP-1 each predicted esophageal eosinophil counts utilizing mixed models controlled for age, gender, treatment, and atopy; AEC combined with MBP-1 best predicted the counts. CONCLUSIONS: We identified novel panels of eosinophil-associated proteins that along with AEC are superior to AEC alone in distinguishing EoE from controls and predicting esophageal eosinophil counts.

Mast Cell Infiltration Is Associated With Persistent Symptoms and Endoscopic Abnormalities Despite Resolution of Eosinophilia in Pediatric Eosinophilic Esophagitis.

OBJECTIVES: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs. METHODS: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical remission (CR) patients were identified, with absence of endoscopic abnormalities and symptoms. RESULTS: MC/hpf were increased in HI-EoE compared with control (17 ± 11 vs 8 ± 6, P < 0.0). Patients with persistent endoscopic abnormalities had increased total (20 ± 12 vs 13 ± 10, P = 0.001) and degranulated (8 ± 6 vs 5 ± 4, P = 0.002) MC/hpf, with no difference in eosinophils. MC/hpf predicted furrowing (odds ratio = 1.06, P = 0.01) and rings (odds ratio = 1.05, P = 0.03) after controlling for treatment type, proton-pump inhibitor, eosinophils, and duration of therapy. Patients with persistent basal zone hyperplasia and dilated intercellular spaces had increased MC/hpf. Eosinophils were weakly correlated with MC/hpf in the mid (r = 0.30, P < 0.001) and distal (r = 0.29, P < 0.001) esophagus. Clinical remission patients had lower MC/hpf compared with patients with persistent symptoms and/or endoscopic abnormalities. DISCUSSION: MC density is increased in patients with endoscopic and epithelial abnormalities, as well as a few symptoms, despite resolution of esophageal eosinophilia after treatment. This association warrants further study to ascertain whether MCs play an eosinophil independent role in EoE.

Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites.

BACKGROUND: Patient-reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology. OBJECTIVE: We sought to understand (1) the potential of caregiver report to predict patient self-reported symptoms and (2) the correlation of patient-reported outcome domains with histology. METHODS: Patients with EoE (n = 310) and their parents participating in the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) observational clinical trial were queried for baseline patient symptoms and quality of life (QOL) by using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2 (PEESSv2.0), and the Pediatric QOL EoE module (PedsQL-EoE), and biopsy specimens were analyzed by using the EoE Histology Scoring System. RESULTS: PEESSv2.0 parental and child reports aligned across all domains (r = 0.68-0.73, P < .001). PedsQL-EoE reports correlated between parents and children across ages and multiple domains (r = 0.48-0.79, P < .001). There was a tight correlation between symptoms on PEESSv2.0 and their effects on QOL both on self-report and parental report (P < .001). Self-reported symptoms on PEESSv2.0 (positively) and PedsQL-EoE (inversely) showed a weak correlation with proximal, but not distal, peak eosinophil counts and features and architectural tissue changes on the EoE Histology Scoring System (P < .05). CONCLUSIONS: Parents of children with EoE aged 3 to 18 years accurately reflected their children's disease symptoms and QOL. Self- and parent-reported symptoms correlate with proximal esophageal histology. Our data suggest that parental report in young children can function as an adequate marker for self-reported symptoms and that self-reported symptoms can reflect changes in tissue histology in the proximal esophagus. These findings should be considered during clinical trials for drug development.

Eosinophilic Esophagitis Reference Score Accurately Identifies Disease Activity and Treatment Effects in Children.

BACKGROUND & AIMS: The endoscopic reference score (EREFS) is used to determine severity of 5 endoscopic findings: edema, rings, exudates, furrows, and strictures. Little is known about the relationship between EREFSs and histologic markers of disease activity in children with eosinophilic esophagitis (EoE). We aimed to determine whether the EREFS can be used to identify children with EoE and how it changes with treatment. METHODS: We performed a prospective study of consecutive children (ages 2-17 years) undergoing diagnostic or post-treatment endoscopy scored real-time with EREFS from December 2012 through 2016. Findings from 192 diagnostic endoscopies and 229 post-treatment endoscopies were evaluated, from 371 children. Incident EoE cases were diagnosed based on 2011 consensus guidelines. Patients were treated with either elimination diet or topical steroids. Subjects who underwent endoscopy for symptoms of esophageal dysfunction but had normal esophageal findings from histology analysis were used as controls. EREFS and receiver operating characteristic curves were determined for incident EoE cases (n = 77) vs controls (n = 115), patients with active EoE (n = 101) vs inactive EoE after treatment (n = 128), and paired pre- and post-treatment cases of EoE (n = 85). Component and composite scores were correlated with eosinophilia. RESULTS: Visual detection of more than 1 esophageal abnormality during the diagnostic endoscopy identified children with EoE with 89.6% sensitivity and 87.9% specificity. EREFS correlated with peak level of eosinophilia (P < .001) at all esophageal levels. Children who responded to therapy had mean EREFSs of 0.5 compared to 2.4 in non-responders. In comparing pre-treatment vs post-treatment data from 85 patients, we found a significant reduction in the composite EREFS (from 2.4 to 0.7) (P < .001) among patients who responded to treatment; 92% of responders had a reduced EREFSs after treatment. EREFSs identified children with EoE with an area under the curve value (AUC) of 0.93. EREFSs identified children with active EoE following treatment with an AUC of 0.81 before treatment and an AUC of 0.79 after treatment. CONCLUSIONS: In a prospective study of children undergoing diagnostic or post-treatment endoscopy, we found the EREFS to accurately identify those with EoE. Children who responded to therapy had lower EREFS scores than non-responders. EREFSs can be used to measure outcomes of pediatric patients, in conjunction with histology findings, and assess treatments for children with EoE.

Efficacy of a 4-Food Elimination Diet for Children With Eosinophilic Esophagitis.

BACKGROUND & AIMS: A 6-food elimination diet induces remission in most children and adults with eosinophilic esophagitis (EoE). The effectiveness of empiric elimination of only 4 foods has not been studied in children. We performed a prospective observational outcome study in children with EoE treated with dietary exclusion of cow's milk, wheat, egg, and soy. The objective was to assess the clinical, endoscopic, and histologic efficacy of this treatment in EoE. METHODS: We recruited children (1-18 years old, diagnosed per consensus guidelines) from 4 medical centers. Study participants (n = 78) were given a proton pump inhibitor twice daily and underwent a baseline esophagogastroduodenoscopy. Subjects were instructed on dietary exclusion of cow's milk, wheat, egg, and soy. Clinical, endoscopic, and histologic assessments were made after 8 weeks. Responders had single foods reintroduced for 8 weeks, with repeat endoscopy to assess for recurrence of active disease. The primary endpoint was histologic remission (fewer than 15 eosinophils per high-powered field). Secondary endpoints included symptom and endoscopic improvements and identification of foods associated with active histologic disease. RESULTS: After 8 weeks on 4-food elimination diet, 50 subjects were in histologic remission (64%). The subjects' mean baseline clinical symptoms score was 4.5, which decreased to 2.3 after 8 weeks of 4-food elimination diet (P < .001). The mean endoscopic baseline score was 2.1, which decreased to 1.3 (P < .001). After food reintroduction, the most common food triggers that induced histologic inflammation were cow's milk (85%), egg (35%), wheat (33%), and soy (19%). One food trigger that induced recurrence of esophageal inflammation was identified in 62% of patients and cow's milk-induced EoE was present in 88% of these patients. CONCLUSIONS: In a prospective study of children with EoE, 8 weeks of 4-food elimination diet induced clinical, endoscopic, and histologic remission in more than 60% of children with EoE. Although less restrictive than 6-food elimination diet, 4-food elimination diet was nearly as effective, and can be recommended as a treatment for children with EoE.

Educational Module Improves Emergency Department Evaluation for Suspected Constipation.

OBJECTIVES: To determine abdominal radiograph use and frequency of digital rectal examinations in children presenting to the emergency department (ED) with abdominal pain and suspected constipation and to determine the impact of an educational module on their use. STUDY DESIGN: Retrospective chart review of patients evaluated at a pediatric ED because of the complaint of abdominal pain who had the discharge diagnosis of constipation over two 2-month periods, one before and one after an educational module. RESULTS: Comparing pre- and posteducational module periods, there was a significant decrease in abdominal radiograph utilization (69.5% vs 26.4%, respectively, P ≤ .001) and significant increase in performance of digital rectal examination (22.9% vs 47.3%, respectively, P ≤ .001). We demonstrated a 33.6% reduction in abdominal radiograph in children who had a digital rectal examination as part of their examination. Overall, we demonstrated a 43.1% decrease in patients receiving an abdominal radiograph. When time and costs of an abdominal radiograph are considered, this results in significant cost savings. CONCLUSIONS: An educational module reviewing the established criteria for the diagnosis of constipation and presented to ED providers results in increased use of digital rectal examination and decreased use of abdominal radiograph in patients evaluated for abdominal pain and ultimately diagnosed with constipation. The change also was associated with reduction in cost and time and radiation exposure in the ED for these patients.

Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis.

OBJECTIVES: Cow's-milk protein is one of the food antigens responsible for causing eosinophilic esophageal inflammation in a majority of children. We describe our experience with treating eosinophilic esophagitis (EoE) in children by eliminating only cow's milk from their diets. METHODS: This retrospective study assessed the short-term clinical and histological response to eliminating cow's-milk protein from the diet of children with EoE. Only patients undergoing a subsequent upper endoscopy to assess their histological response were included in this analysis. RESULTS: We identified 17 (12 boys and 5 girls) children with EoE who excluded only cow's milk from their diet. Remission was induced in 11 of 17 (65%) patients; within the remission group, 7 (41%) achieved complete histological remission and 4 patients (24%) were in significant histological remission. The mean peak pre- and posttreatment counts for those in remission were 76 ±â€Š40 and 2 ±â€Š4 (P < 0.01), respectively. CONCLUSIONS: Elimination of cow's milk-induced clinical and histological remission in 65% (95% confidence interval 42%-88%) of children with EoE in whom it was attempted. This approach offers distinct advantages over other dietary treatment approaches for the initial management of children with EoE. The role of eliminating cow's milk alone for the treatment of EoE warrants further prospective study.

Eosinophilic esophagitis: updated consensus recommendations for children and adults.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.

4. Gastrointestinal mucosal immunity.

Mucosal surfaces constitute a large host-environmental interface that must be protected from pathogenic organisms. The mucosal immune system has evolved as a distinct immune organ functioning independently from its systemic counterpart. The mucosal immune system has the difficult task of mounting protective responses to invading microorganisms while maintaining a state of nonresponsiveness to commensal bacteria and food antigens. The system has unique cellular components and functional aspects that permit it to carry out this dual role.

Direct evidence of mast cell participation in acute acid-induced esophageal inflammation in mice.

OBJECTIVES: Mast cells have been implicated in the pathogenesis of esophagitis resulting from gastroesophageal acid reflux, but their precise role has been difficult to define. We proposed to directly examine the contribution of mast cells to neutrophil infiltration in a mouse model of acid-induced esophageal injury. MATERIALS AND METHODS: Normal and mast cell-deficient (Kit) mice underwent either a surgical procedure to induce acute acid reflux injury of the esophagus or sham surgery. Neutrophil infiltration in the esophagus was determined by morphometrical quantification. To further delineate the involvement of mast cells, acid-induced esophageal injury was elicited in mast cell-deficient mice that had undergone mast cell reconstitution by bone marrow transplantation. RESULTS: Normal mice exhibited significant neutrophil infiltration into the esophagus as a result of acid-induced injury. The neutrophil accumulation was significantly diminished in mast cell-deficient mice. However, the neutrophil infiltration that resulted from acid-induced injury in mast cell-reconstituted Kit mice was similar to that seen in normal mice. CONCLUSIONS: Our findings provide direct evidence that mast cells participate in the recruitment of neutrophils during acid-induced esophageal injury in mice.

Gastrointestinal symptoms in children with an autism spectrum disorder and language regression.

Few studies have compared gastrointestinal problems in children with an autism spectrum disorder with and without a history of language regression. A cross-sectional study was conducted with structured interviews in 100 children with autism spectrum disorder, using a gastrointestinal questionnaire and a familial autoimmune questionnaire. By parental report, children with language regression more frequently exhibited an abnormal stool pattern (40% vs 12%, P = 0.006) and had an increased family history of celiac disease or inflammatory bowel disease (24% vs 0%, P = 0.001) and of rheumatoid arthritis (30% vs 11%, P = 0.03). Among 35 children with a family history of autoimmune disease, an abnormal stool pattern was reported more frequently in those with language regression (78% vs 15%, P = 0.001) than in those without. An association was observed between children with language regression, a family history of autoimmune disease, and gastrointestinal symptoms. Additional studies are needed to examine a possible shared autoimmune process.

Transcription factor network downstream of protease activated receptors (PARs) modulating mouse bladder inflammation.

BACKGROUND: All four PARs are present in the urinary bladder, and their expression is altered during inflammation. In order to search for therapeutic targets other than the receptors themselves, we set forth to determine TFs downstream of PAR activation in the C57BL/6 urinary bladders. METHODS: For this purpose, we used a protein/DNA combo array containing 345 different TF consensus sequences. Next, the TF selected was validated by EMSA and IHC. As mast cells seem to play a fundamental role in bladder inflammation, we determined whether c-kit receptor deficient (Kit w/Kit w-v) mice have an abrogated response to PAR stimulation. Finally, TFEB antibody was used for CHIP/Q-PCR assay and revealed up-regulation of genes known to be downstream of TFEB. RESULTS: TFEB, a member of the MiTF family of basic helix-loop-helix leucine zipper, was the only TF commonly up-regulated by all PAR-APs. IHC results confirm a correlation between inflammation and TFEB expression in C57BL/6 mice. In contrast, Kit w/Kit w-v mice did not exhibit inflammation in response to PAR activation. EMSA results confirmed the increased TFEB binding activity in C57BL/6 but not in Kit w/Kit w-v mice. CONCLUSION: This is the first report describing the increased expression of TFEB in bladder inflammation in response to PAR activation. As TFEB belongs to a family of TFs essential for mast cell survival, our findings suggest that this molecule may influence the participation of mast cells in PAR-mediated inflammation and that targeting TFEB/MiTF activity may be a novel approach for the treatment of bladder inflammatory disorders.

The ontogeny and developmental physiology of gastric acid secretion.

The production of acid by the stomach is a tightly controlled physiological process that involves neural and hormonal mechanisms and the input of several epithelial cell types. The past several years have seen significant advances in our understanding of the molecular ontogenesis of the stomach and the factors controlling stomach innervation, as well as the differentiation of gastric epithelial cell lineages and their respective hormones/factors that influence acid production. The programmed development of each of these elements is exquisitely regulated and allows human neonates to produce gastric acid; it also helps us define expectations of acid production in preterm infants at all gestational ages.

Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease.

This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.

Regulation of Mast Cell Proliferation, Maturation and Function by Stem Cell Factor, a Ligand for the c-kit Receptor.

Mast cell development in mice is critically regulated by stem cell factor (SCF), a product of fibroblasts and other cell types which is a ligand for the tyrosine kinase receptor protein encoded by the proto-oncogene c-kit. In mice, recombinant SCF influences the migration, proliferation and maturation of cells in the mast cell lineage. Recombinant SCF also promotoes mast cell development in rats and nonhuman primates. Recombinant SCF can induce c-kit receptor-dependent activation and mediator release from some populations of mouse mast cells. In isolated human skin mast cells, recombinant SCF can induce mediator release directly and augment the cells' ability to release mediators in response to stimulation through the FcεRI receptor. These findings suggest that changes in levels of endogenous SCF may contribute to the alterations in the numbers of mast cells which have been observed in association with a variety of disease processes and other biological responses. They also raise the possibility that endogenous SCF may contribute to the regulation of mast cell function unter physiological or pathological conditions, and during IgE-dependent immunological responses.