41 research outputs found
Quelle rĂ©gulation pour lâarrĂȘt dâun protocole de recherche clinique de thĂ©rapie gĂ©nique somatique ? Ătat des lieux auprĂšs des cliniciens-chercheurs europĂ©ens
Depuis 2002, le dĂ©bat sur les risques associĂ©s Ă la thĂ©rapie gĂ©nique est initiĂ© suite Ă lâannonce
que deux enfants inclus dans un essai thérapeutique impliquant une thérapie génique ont
développé des effets indésirables important. En Janvier 2005, le débat sur les risques reprit suite
Ă lâinterruption du protocole sur les enfants bulle du Pr Fischer Ă lâhĂŽpital Necker de Paris. Nous
avons donc étudié le processus impliqué ainsi que la réflexion éthique associée aux décisions
dâarrĂȘt de protocole de recherche. Notre travail a Ă©tĂ© menĂ© par une Ă©quipe pluridisciplinaire
combinant chercheurs en santé, généticiens et éthiciens. Nous avons étudié la participation des
chercheurs, des patients, des institutions officielles, des comitĂ©s dâĂ©thique ainsi que des
associations de patients dans le processus de dĂ©cision dâinterruption dâun protocole de recherche.Nous avons Ă©galement analysĂ© les critĂšres jugĂ©s les plus pertinents dans lâarrĂȘt dâun protocole
de recherche. Enfin nous avons analysé le point de vue des personnes directement impliquées
dans la thĂ©rapie gĂ©nique au moyen dâun questionnaire. Toutes les personnes contactĂ©es ont
présenté un poster de recherche au congrÚs de la Société Européenne de Thérapie Génique. 62
personnes dâautant dâĂ©quipes de recherche diffĂ©rentes, de 17 pays, sur les 350 contactĂ©s ont
rĂ©pondu. Selon eux, la dĂ©cision dâarrĂȘt dâun protocole de recherche doit ĂȘtre prise suite Ă une
consultation des chercheurs, des patients, du ministĂšre de tutelle, dâune agence nationale de
rĂ©gulation ou dâun comitĂ© dâĂ©thique ; la lĂ©gitimitĂ© Ă©tant accordĂ©e Ă des dĂ©cisions prises en
commun par les chercheurs, les patients et les comitĂ©s dâĂ©thique. Les incidents sĂ©rieux et de façon
plus surprenante, les incidents moins graves sont jugés comme étant des critÚres suffisants pour
interrompre un essai. Nous avons fini par analyser les conséquences éthiques, telles que balance
bĂ©nĂ©fice/risque, processus de rĂ©gulation ou responsabilitĂ©, de ces critĂšres sur lâarrĂȘt dâun protocole
de recherche.In 2002, the debate on the risks of gene therapy was initiated following the annoucement that two
children included in a clinical trial developed serious adverse effects. In January 2005, the debate
was reignited following the interruption of the âbubble kids protocolâ at the HĂŽpital Necker in Paris.
We have thus investigated the ethical stakes involved in decisions to stop protocols. This work was
carried out by a multidisciplinary team combining ethics researchers and geneticists. We studied
the specific participation of researchers, patients, official institution, ethics committees and patient
associations in the processes that can lead to an interruption of trial.We also analysed the criterion
judged most relevant for halting a trial. Finally, we analyzed the perspective of the actors implicated
directly in the provision of gene therapy, by means of a questionnaire. All the individuals contacted
had presented a scientific poster at the European Society of Gene Therapy. 62 out of 350 persons,
from 17 countries, responded to our questionnaire. According to these respondants, decisions to stop
a trial should be taken after consultation with researchers, patients, the ministry, national agencies
or ethics committees. Legitimacy was accorded to joint decision-making by researchers, patients and
committees. Serious incidents, and surprisingly less serious incidents, clearly emerge as criterion for
stopping a trial. We conclude by analyzing the ethical consequences, such as risk/benefit ratios,
regulatory processes and responsibility, associated with these criterions and decisions to stop a trial
Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency
Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype
Identification of CD4âCD8â Double-Negative Natural Killer T Cell Precursors in the Thymus
BACKGROUND: It is well known that CD1d-restricted Valpha14 invariant natural killer T (NKT) cells are derived from cells in the CD4(+)CD8(+) double-positive (DP) population in the thymus. However, the developmental progression of NKT cells in the earlier stages remains unclear, and the possible existence of NKT cell presursors in the earlier stages than DP stage remains to be tested. PRINCIPAL FINDINGS: Here, we demonstrate that NKT cell precursors that express invariant Valpha14-Jalpha18 transcripts but devoid of surface expression of the invariant Valpha14 receptor are present in the late CD4(-)CD8(-) double-negative (DN)4 stage and have the potential to generate mature NKT cells in both in vivo and in vitro experimental conditions. Moreover, the DN4 population in CD1d knock-out (CD1dKO) mice was similar to those with an NKT cell potential in wild-type (WT) C57BL/6 (B6) mice, but failed to develop into NKT cells in vitro. However, these precursors could develop into NKT cells when co-cultured with normal thymocytes or in an in vivo experimental setting, indicating that functional NKT cell precursors are present in CD1dKO mice. CONCLUSIONS: Together, these results demonstrate that thymic DN4 fraction contains NKT cell precursors. Our findings provide new insights into the early development of NKT cells prior to surface expression of the invariant Valpha14 antigen receptor and suggest the possible alternative developmental pathway of NKT cells
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PRKDC mutations associated with immunodeficiency, granuloma and aire-dependent autoimmunity
Analyse moléculaire de patients présentant un déficit immunitaire combiné avec microcéphalie associé à un défaut général de la réparation de l'ADN
Analyse moléculaire de patients présentant un déficit immunitaire combiné avec microcéphalie associé à un défaut général de la réparation de l'ADN. Les cassures double-brin d'ADN (dsb) formées au cours de la recombinaison V(D)J sont modifiées et ligaturées par des facteurs généraux de la réparation de l'ADN du non homologous end joining (NHEJ), avec six protéines connues impliquées:Ku70/Ku86/DNAPKcs, Artemis et Xrcc4/Lig4. Dans un premier temps, nous avons montré que des mutations hypomorphes de Lig4 peuvent entraßner un déficit immunitaire sévÚre avec radiosensibilité (RS-SCID) chez l'homme, caractérisé par un défaut de la recombinaison V(D)J in vitro, qui est complémenté par la forme sauvage de Lig4. DeuxiÚmement, nous avons identifié un nouveau facteur V(D)J/NHEJ grùce à l'analyse fonctionnelle et génétique d'un groupe de patients présentant un phénotype similaire à celui des patients déficients e Lig4. Nous avons nommé ce facteur Cernunnos, dont le gÚne codant est muté chez tous les patients analysés. Le défaut du NHEJ observé dans les cellules de ces patients est complémenté par la forme sauvage de Cernunnos.PARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF
Distinct effects of DNA-PKcs and Artemis inactivation on signal joint formation in vivo.
International audienceThe assembly of functional immune receptor genes via V(D)J recombination in developing lymphocytes generates DNA double-stranded breaks intermediates that are repaired by non-homologous end joining (NHEJ). This repair pathway requires the sequential recruitment and activation onto coding and signal DNA ends of several proteins, including the DNA-dependent protein kinase and the nuclease Artemis. Artemis activity, triggered by the DNA-dependent protein kinase, is necessary to process the genes hairpin-sealed coding ends but appears dispensable for the ligation of the reciprocal phosphorylated, blunt-ended signal ends into a signal joint. The DNA-dependent protein kinase is however present on signal ends and could potentially recruit and activate Artemis during signal joint formation. To determine whether Artemis plays a role during the resolution of signal ends during V(D)J recombination, we analyzed the structure of signal joints generated in developing thymocytes during the rearrangement of T cell receptor genes in wild type mice and mice mutated for NHEJ factors. These joints exhibit junctional diversity resulting from N nucleotide polymerization by the terminal nucleotidyl transferase and nucleotide loss from one or both of the signal ends before they are ligated. Our results show that Artemis participates in the repair of signal ends in vivo. Furthermore, our results also show that while the DNA-dependent protein kinase complex protects signal ends from processing, including deletions, Artemis seems on the opposite to promote their accessibility to modifying enzymes. In addition, these data suggest that Artemis might be the nuclease responsible for nucleotide loss from signal ends during the repair process