Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human-derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation-related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs.

Long-Term Adherence and Risk of Allergic Reactions in Patients Who Attained Milk Oral Immunotherapy Maintenance.

BACKGROUND: Oral immunotherapy (OIT) has emerged as the most popular therapy for food allergy. However, data on the long-term adherence and efficacy of this approach are sparse. OBJECTIVE: We aimed to assess the long-term adherence rates to OIT protocol and the associated risk of allergic reactions. METHODS: Patients who completed milk OIT and reached a maintenance dose of 200 mL of milk were surveyed biannually on their dairy consumption and occurrence of allergic reactions. A survival analysis was performed to evaluate the association between the risk of reaction and the adherence to OIT maintenance protocol. RESULTS: The cohort consisted of 50 patients. Only 56% of the cohort adhered to the protocol, which consisted of ingesting a minimum of 200 mL of milk at least 3 times per week. Adherent patients had a significantly reduced risk of allergic reactions as well as a reduced incidence of anaphylaxis, health care/emergency room visits, and epinephrine/antihistamine administration. CONCLUSIONS: The findings demonstrate the importance of consistent maintenance dose consumption in the management of food allergies, with regular milk consumption contributing to the maintenance of unresponsiveness and decreased risk of allergic symptoms.

Gut Immunomodulation with Vedolizumab prior to Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients with Inflammatory Bowel Disease.

Inborn errors of immunity (IEI) are often associated with inflammatory bowel disease (IBD). IEI can be corrected by allogeneic hematopoietic stem cell transplantation (HSCT); however, peritransplantation intestinal inflammation may increase the risk of gut graft-versus-host disease (GVHD). Vedolizumab inhibits the homing of lymphocytes to the intestine and may attenuate gut GVHD, yet its role in preventing GVHD in pediatric patients with IEI-associated IBD has not been studied. Here we describe a cohort of pediatric patients with IEI-associated IBD treated with vedolizumab before and during allogeneic HSCT. The study involved a retrospective chart review of pediatric patients with IEI-associated IBD treated with vedolizumab at 6 weeks, 4 weeks, and 1 week before undergoing HSCT. The conditioning regimen consisted of treosulfan, fludarabine, and cyclophosphamide with rabbit antithymocyte globulin, and GVHD prophylaxis included tacrolimus and steroids. Eleven patients (6 females) with a median age of 5 years (range, 0.4 to 14 years) with diverse IEI were included. IBD symptoms were characterized by abdominal pain, loose stools, and blood in stools. Four patients had developed a perianal fistula, and 1 patient had a rectal prolapse. One patient had both a gastrostomy tube and a jejunal tube in situ. Treatment of IBD before HSCT included steroids in 11 patients, anakinra in 2, infliximab in 4, sulfasalazine in 2, mesalazine in 2, and vedolizumab. IBD symptoms were considered controlled in the absence of abdominal pain, loose stools, or blood in stools. Graft sources for HSCT were unrelated donor cord in 5 patients (2 with a 5/8 HLA match, 2 with a 7/8 match, and 1 with a 6/8 match), peripheral blood stem cells in 5 patients (2 haploidentical, 1 with a 9/10 HLA match, and 2 with a 10/10 match), and bone marrow in 1 patient (10/10 matched sibling donor). The median number of vedolizumab infusions was 4 (range, 3 to 12) before HSCT and 1 (range, 1 to 3) after HSCT, and all were reported to be uneventful. All patients had engrafted. Acute GVHD occurred in 4 patients and was limited to grade I skin GVHD only. Chronic GVHD occurred in 1 patient and again was limited to the skin. There was no gut GVHD. Three patients experienced cytomegalovirus viremia, and 2 patients had Epstein-Barr virus viremia. At the time of this report, all patients were alive with no evidence of IBD at a median follow-up of 15 months (range, 3 to 39 months). Administration of vedolizumab pre- and post-HSCT in pediatric patients with IEI-associated IBD is well tolerated and associated with a low rate of gut GVHD. These findings provide a platform for the prospective study and use of vedolizumab for GVHD prophylaxis in pediatric patients with known intestinal inflammation as a pre-HSCT comorbidity.

Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study.

BACKGROUND: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. OBJECTIVES: We sought to study HCT for p47phox CGD in North America. METHODS: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. RESULTS: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person-years (P = .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, ≥95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. CONCLUSIONS: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.