Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent lowIgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.

Mutations in the adenosine deaminase (ADA) gene are responsible for a form of severe combined immunodeficiency (SCID) caused by the lymphotoxic accumulation of ADA substrates, adenosine and 2-deoxy-adenosine. The molecular mechanisms underlying T-cell dysfunction in humans remain to be elucidated. Here, we show that CD4 ؉ T cells from ADA-SCID patients have severely compromised TCR/CD28-driven proliferation and cytokine production, both at the transcriptional and protein levels. Such an impairment is associated with an intrinsically reduced ZAP-70 phosphorylation, Ca 2؉ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-B. Moreover, exposure to 2-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A 2A adenosine receptor signaling engagement and PKA hyperactivation, or in a direct apoptotic effect at higher doses. Conversely, in T cells isolated from patients after gene therapy with retrovirally transduced hematopoietic stem/progenitor cells, the biochemical events after TCR triggering occur properly, leading to restored effector functions and normal sensitivity to apoptosis. Overall, our findings provide a better understanding of the pathogenesis of the immune defects associated with an altered purine metabolism and confirm that ADA gene transfer is an efficacious treatment for ADA-SCID. The trials in this study are enrolled at www.ClinicalTrials. gov as #NCT00598481 and #NCT0059978. IntroductionAdenosine deaminase (ADA) is a key enzyme in the purine pathway, ubiquitously expressed, catalyzing the irreversible deamination of adenosine (Ado) and 2Ј-deoxy-adenosine (dAdo). Genetic defects in ADA gene cause an accumulation of purine metabolites in plasma and cells, leading to an inherited form of severe combined immunodeficiency (SCID). 1,2 Accordingly, broad lymphopenia, absence of humoral-and cellular-mediated immunity, recurrent infections, and failure to thrive are the prominent features of the most severe forms of ADA deficiency. 3,4 In addition, the systemic accumulation of purine metabolites can cause alterations in several organs, including the skeleton, lung, liver, gastrointestinal tract, and central nervous system. 4 The clinical phenotypes usually correlate with the severity of genetic mutations, the residual ADA activity and the extent of substrates accumulations. 5 Conflicting data exist on the relative contribution of ADA metabolites in the pathogenesis of the immune dysfunctions. The biochemical hallmarks of ADA deficiency are consistent with the general belief indicating dAdo as the primary cause of lymphotoxicity in ADA-SCID. Exerting its effects at the nucleoside level or after conversion to dATP, accumulation of intracellular dAdo may interfere with deoxynucleotide synthesis and inhibit S-adenosylmethionine-mediated transmethylation reactions, which are required for cell viability and normal differentiation. 6,7 In developing lymphocytes, dAdo has been reported to induce apoptosis through a pathway involving p53 ...

Conventional MHC-restricted T lymphocytes leave thymus with a naive phenotype and require Ag-dependent stimulation coupled to proliferation to acquire effector functions. Invariant (i)NKT cells are a subset of T lymphocytes considered innate because they display an effector memory phenotype independent of TCR stimulation by foreign Ags. We investigated the effector differentiation program followed by human iNKT cells by studying cells from a relevant set of fetal thymi and umbilical cord blood samples. We find that human fetal iNKT cells have already started a differentiation program that activates the epigenetic and transcriptional control of ifng and il4 genes, leading at birth to cells that express these cytokines upon TCR signaling but independently of proliferation in vitro. Both ex vivo and in vitro analysis of fetal and neonatal iNKT cells delineate an effector differentiation program linked to cell division in vivo, and they identify IL-7 as one of the crucial signals driving this program in the apparent absence of Ag stimulation. Consistent with these data, human fetal and neonatal iNKT cells are hyperresponsive in vitro to IL-7 in comparison to conventional T cells, owing to an increased expression and signaling function of the IL-7 receptor α-chain. The innate nature of human iNKT cells could thus derive from lineage-specific developmental cues that selectively make these cells efficient IL-7 responders following thymic selection.

We report on 12 patients with chronic granulomatous disease transplanted with hematopoietic stem cells from matched unrelated (n = 9) or matched sibling donors (n = 3). The most common infectious complication was pulmonary aspergillosis, which nine patients had previously developed. Only 5 of 12 individuals had normal lung function prior to transplantation. At a mean follow-up of 53 months 9 of the 12 patients are alive including 7 of 9 following matched unrelated donor (MUD) transplantation. One patient died from ARDS, another from systemic BK virus infection, the third from complications of chronic graft-versus-host disease. Seven of nine surviving patients have normal lung function now. HSCT from a MUD is an option worth considering when no matched family donor is available. Restricted lung function prior to HSCT does not appear to be a limiting factor for such treatment.