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.

Bladder Urothelial Carcinoma in a Child: Case Report and Review of Literature.

Bladder urothelial carcinoma (UC) it is the fifth most prevalent carcinoma in humans, nevertheless in children and young adults it's very rare. It usually occurs in older adults. Literature on UC in pediatric population is limited and important information (risk factors, follow-up protocols, etc.) are poorly defined. We present an 11-year-old boy with a painful macroscopic hematuria. Ultrasound revealed a heterogeneous intravesical mass without extravesical extension, which was confirmed by computed tomography (CT) and magnetic resonance imaging (MRI). The first biopsy was compatible with urothelial papilloma. After 1 year, he returned with a bigger mass. Transurethral resection of the bladder (TURB) was performed and immunohistochemistry showed low-grade papillary UC with a high-grade component, with tumor free margin. Tumor had mutations in the BRAF and KRAS genes. Two and a half years after the resection the patient has no recurrence. Less than 1% of bladder UC occur in the first two decades of life. Gross hematuria is a common symptom. Ultrasound is generally the first diagnostic tool. MRI is also helpful, but cystoscopy allows definitive diagnosis. Transurethral resection of the bladder (TURB) is the standard treatment, with good results and low recurrence rate, and it was the treatment of choice for our patient, that remains free of disease. The BRAF and KRAS gene mutations were never described before in pediatric UC. There are only few cases in literature of pediatric UC that present a tumor genetic profile; therefore, our case report adds more information to this very rare disease in children.

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.