Case Report: Primary immunodeficiency -severe autoimmune enteropathy in a pediatric heart transplant recipient treated with abatacept and alemtuzumab

Disorders of immune dysregulation following heart transplantation in children have been reported; however, the management of such disorders remains uncertain and challenging. In this case report, we describe a clinical course of a child with severe autoimmune enteropathy after a heart transplant in infancy and detail a treatment approach with abatacept and alemtuzumab. A 21-month-old girl with a medical history of congenital dilated cardiomyopathy and heart transplantation at 2 months was evaluated for chronic hematochezia. The patient underwent an extensive workup, including endoscopic biopsy which showed crypt apoptosis, similar to that seen with graft-versus-host disease (GVHD). Results of her immune workup were consistent with status post-thymectomy but also demonstrated evidence of immune dysregulation. Specifically, her immune phenotype at diagnosis demonstrated T-cell lymphopenia, restricted TCR repertoire and skewing of T-cell compartment toward memory phenotype, increase in serum soluble ILR2a, and hypergammaglobulinemia. In the absence of response to more standard immune modulation, the patient was treated with CTLA4-Ig (abatacept), followed by a combination of abatacept and a JAK inhibitor and, finally, a combination of abatacept and alemtuzumab. Following therapy with alemtuzumab, the patient achieved remission for the first time in her life. Her clinical course was complicated by a relapse after 6 months which again readily responded to alemtuzumab. Ultimately, despite these remissions, the patient suffered an additional relapse. This case highlights the challenges of neonatal thymectomy and adds new insights into the pathogenesis, diagnosis, and management of severe autoimmune enteropathy in pediatric heart transplant recipients

Direct nitric oxide detection in aqueous solution by copper(II) fluorescein complexes

A series of FLn (n = 1-5) ligands, where FLn is a fluorescein modified with a functionalized 8-aminoquinoline group as a copper-binding moiety, were synthesized, and the chemical and photophysical properties of the free ligands and their copper complexes were investigated. UV-visible spectroscopy revealed a 1:1 binding stoichiometry for the Cu(II) complexes of FL1, FL3, and FL5 in pH 7.0 buffered aqueous solutions. The reactions of FL2 or FL4 with CuCl2, however, appear to produce a mixture of 1:1 and 1:2 complexes, as suggested by Job's plots. These binding modes were modeled by the synthesis and X-ray crystal structure determination of Cu(II) complexes of 2-[(quinolin-8-ylamino)methyl]phenol (modL), employed as a surrogate of the FLn ligand family. Two kinds of crystals, [Cu(modL) 2](BF4)2 and [Cu2(modL???) 2-(CH3OH)](BF4)2 (modL??? = 2-[(quinolin-8-ylamino)methyl]phenolate), were obtained. The structures suggest that one oxygen and two nitrogen atoms of the FLn ligands most likely bind to Cu(II). Introduction of nitric oxide (NO) to pH 7.0 buffered aqueous solutions of Cu(FLn) (1 ??M CuCl2 and 1 ??M FL n) at 37 ??C induces an increase in fluorescence. The fluorescence response of Cu(FLn) to NO is direct and specific, which is a significant improvement over commercially available small molecule-based probes that are capable of detecting NO only indirectly. The NO-triggered fluorescence increase of Cu(FL5) occurs by reduction of Cu(II) to Cu(I) with concomitant dissociation of the N-nitrosated fluorophore ligand from copper. Spectroscopic and product analyses of the reaction of the FL5 copper complex with NO indicated that the N-nitrosated fluorescein ligand (FL 5-NO) is the species responsible for fluorescence turn-on. Density functional theory (DFT) calculations of FL5 versus FL5-NO reveal how N-nitrosation of the fluorophore ligand brings about the fluorescence increase. The copper-based probes described in the present work form the basis for real-time detection of nitric oxide production in living cells.close13413