Fetal allotransplant recipients are resistant to graft-versus-host disease.

In utero hematopoietic cell transplantation (IUHCT) is an experimental treatment for congenital hemoglobinopathies, including Sickle cell disease and thalassemias. One of the principal advantages of IUHCT is the predisposition of the developing fetus toward immunologic tolerance. This allows for engraftment across immune barriers without immunosuppression and, potentially, decreased susceptibility to graft-versus-host disease (GVHD). We demonstrate fetal resistance to GVHD following T cell-replete allogeneic hematopoietic cell transplantation compared with the neonate. We show that this resistance is associated with elevated fetal serum interleukin-10 conducive to the induction of regulatory T cells (Tregs). Finally, we demonstrate that the adoptive transfer of Tregs from IUHCT recipients to neonates uniformly prevents GVHD, recapitulating the predisposition to tolerance observed after fetal allotransplantation. These findings demonstrate fetal resistance to GVHD following hematopoietic cell transplantation and elucidate Tregs as important contributors.

Thoracoscopy Approach in Prone Position for Esophagoplasty in Children.

Congenital esophageal stenosis (CES) is a very rare clinical condition found in 1 per 25,000 to 50,000 live births. There are three histological types of CES described: tracheobronchial remnants, fibromuscular stenosis (FMS), and membranous stenosis. The first-line treatment in most cases is the conservative treatment (dilatation with a Savary bougie or balloon), but in some CES types, dilatation may be ineffective or result in esophageal perforation with serious complications or lethal outcome. Resection of the stenotic segment and end-to-end esophageal anastomosis was formerly presented as the most common surgical treatment option for CES. However, esophagoplasty is a safe and feasible alternative for surgical treatment of esophageal stenosis in children. Our aim is to report two cases of FMS submitted to thoracoscopic esophagoplasty. Both cases started with dysphagia and refusal after transition to solid diet, at 6 months old, and the radiological examination showed stricture of the distal esophagus. Esophagoplasty was performed with the patients in prone position. The stenotic esophageal wall was incised longitudinally and transverse synthesis was performed. After surgery, the patients had prompt recovery, without recurrent stenosis, remaining asymptomatic, with good diet acceptance.

Regulatory T cells promote alloengraftment in a model of late-gestation in utero hematopoietic cell transplantation.

In utero hematopoietic cell transplantation (IUHCT) has the potential to cure congenital hematologic disorders including sickle cell disease. However, the window of opportunity for IUHCT closes with the acquisition of T-cell immunity, beginning at approximately 14 weeks gestation, posing significant technical challenges and excluding from treatment fetuses evaluated after the first trimester. Here we report that regulatory T cells can promote alloengraftment and preserve allograft tolerance after the acquisition of T-cell immunity in a mouse model of late-gestation IUHCT. We show that allografts enriched with regulatory T cells harvested from either IUHCT-tolerant or naive mice engraft at 20 days post coitum (DPC) with equal frequency to unenriched allografts transplanted at 14 DPC. Long-term, multilineage donor cell chimerism was achieved in the absence of graft-versus-host disease or mortality. Decreased alloreactivity among recipient T cells was observed consistent with donor-specific tolerance. These findings suggest that donor graft enrichment with regulatory T cells could be used to successfully perform IUHCT later in gestation.

Donor cell engineering with GSK3 inhibitor-loaded nanoparticles enhances engraftment after in utero transplantation.

Host cell competition is a major barrier to engraftment after in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor-loaded nanoparticles conjugated to the surface of donor hematopoietic cells to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post-IUHCT. We also show that the salutary effects of the nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells and achieved by a pseudoautocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor-loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders.

In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment.

In utero transplantation (IUT) of hematopoietic stem cells (HSCs) has been proposed as a strategy for the prenatal treatment of congenital hematological diseases. However, levels of long-term hematopoietic engraftment achieved in experimental IUT to date are subtherapeutic, likely due to host fetal HSCs outcompeting their bone marrow (BM)-derived donor equivalents for space in the hematopoietic compartment. In the present study, we demonstrate that amniotic fluid stem cells (AFSCs; c-Kit+/Lin-) have hematopoietic characteristics and, thanks to their fetal origin, favorable proliferation kinetics in vitro and in vivo, which are maintained when the cells are expanded. IUT of autologous/congenic freshly isolated or cultured AFSCs resulted in stable multilineage hematopoietic engraftment, far higher to that achieved with BM-HSCs. Intravascular IUT of allogenic AFSCs was not successful as recently reported after intraperitoneal IUT. Herein, we demonstrated that this likely due to a failure of timely homing of donor cells to the host fetal thymus resulted in lack of tolerance induction and rejection. This study reveals that intravascular IUT leads to a remarkable hematopoietic engraftment of AFSCs in the setting of autologous/congenic IUT, and confirms the requirement for induction of central tolerance for allogenic IUT to be successful. Autologous, gene-engineered, and in vitro expanded AFSCs could be used as a stem cell/gene therapy platform for the in utero treatment of inherited disorders of hematopoiesis. Stem Cells 2019;37:1176-1188.

Bronchogenic cyst in an unusual location / Cisto broncogênico de localização não habitual

ABSTRACT This article reports the case of a patient with lingual bronchogenic cyst and presents a brief review of discrepancies in the nomenclature of lingual cysts. A 2-year-old male patient was admitted to the pediatric surgery outpatient clinic of a university hospital due to the presence of a 2 cm mass on the dorsal surface of the tongue. The tumor was excised and the anatomopathological report revealed a foregut cyst, bronchogenic subtype. Lingual cysts are rare, especially when compatible with bronchogenic formations. Their pathogenic process is not clear; one of the possibilities is the separation of cells from the primitive gut, before the separation between the esophagus and the trachea. The treatment usually consists of surgical excision.

RESUMEN Este artículo relata el caso de un paciente con quiste broncogénico lingual y presenta una breve revisión de las discrepancias de nomenclatura para quistes linguales. Paciente de sexo masculino, de 2 años de edad, acudió a cirugía pediátrica de un hospital universitario con una masa de 2 cm en la cara dorsal de la lengua. El tumor fue extirpado y el informe anatomopatológico reveló quiste de duplicación, subtipo broncogénico. Quistes linguales no son frecuentes, sobre todo cuando concomitantes con formaciones broncogénicas. Su patogénesis es incierta: una de las posibilidades es la separación de células del intestino primitivo antes de la separación entre esófago y tráquea. El tratamiento, en general, consiste en escisión quirúrgica.

RESUMO Este artigo relata o caso de um paciente com cisto broncogênico lingual e apresenta uma breve revisão das discrepâncias de nomenclatura para cistos linguais. Paciente do sexo masculino, 2 anos de idade, foi admitido no ambulatório de cirurgia pediátrica de um hospital universitário devido à presença de uma massa de 2 cm na face dorsal da língua. O tumor foi excisionado; o laudo anatomopatológico revelou foregut cyst, subtipo broncogênico. Cistos linguais são raros, especialmente quando compatíveis com formações broncogênicas. Seu processo de patogênese é incerto, e uma das possibilidades é a separação de células do intestino primitivo antes da separação entre esôfago e traqueia. O tratamento, comumente, consiste em excisão cirúrgica.