[Show abstract][Hide abstract] ABSTRACT: Adoptive transfer of in vitro activated and expanded antigen-specific cytotoxic T lymphocytes (CTLs) is a promising therapeutic strategy for infectious diseases and cancers. Obtaining in vitro a sufficient amount of highly specific cytotoxic cells and capable of retaining cytotoxic activity in vivo remains problematic. We studied the role of Toll-Like Receptor-8 (TLR8) engagement on peripheral CTLs activated with melanoma antigen MART-1-expressing artificial antigen-presenting cells (AAPCs). After a 3-week co-culture, 3–27% of specific CTLs were consistently obtained. CTLs expressed TLR8 in the intracellular compartment and at the cell surface. Specific CTLs activated with a TLR8 agonist (CL075) 24 h before the end of the culture displayed neither any change in their production levels of molecules involved in cytotoxicity (IFN-γ, Granzyme B, and TNF-α) nor major significant change in their cell surface phenotype. However, these TLR8-stimulated lymphocytes displayed increased cytotoxic activity against specific peptide-pulsed target cells related to an increase in specific anti-melanoma CTL functional avidity. TLR8 engagement on CTLs could, therefore, be useful in different immunotherapy strategies.
[Show abstract][Hide abstract] ABSTRACT: Regulatory B cells (B-reg) produce IL-10 and suppress inflammation in both mice and humans, but limited data on the phenotype and function of these cells have precluded detailed assessment of their contribution to host immunity. In this article, we report that human B-reg cannot be defined based on a phenotype composed of conventional B cell markers, and that IL-10 production can be elicited in both the CD27(+) memory population and naive B cell subset after only a brief stimulation in vitro. We therefore sought to obtain a better definition of IL-10-producing human B-regs using a multiparameter analysis of B cell phenotype, function, and gene expression profile. Exposure to CpG and anti-Ig are the most potent stimuli for IL-10 secretion in human B cells, but microarray analysis revealed that human B cells cotreated with these reagents resulted in only ∼0.7% of genes being differentially expressed between IL-10(+) and IL-10(-) cells. Instead, connectivity map analysis revealed that IL-10-secreting B cells are those undergoing specific differentiation toward a germinal center fate, and we identified a CD11c(+) B cell subset that was not capable of producing IL-10 even under optimal conditions. Our findings will assist in the identification of a broader range of human pro-B-reg populations that may represent novel targets for immunotherapy.
The Journal of Immunology 07/2014; 193(5). DOI:10.4049/jimmunol.1303214 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) may relapse following introduction of drugs structurally unrelated to the initial culprit drug. Objective
To assess the frequency and characteristics of recurrent drug eruptions in patients with history of DRESS. Methods
Patients who had developed adverse cutaneous reaction after DRESS occurrence were recruited from the regional database of Upper Normandy in France. Rate of recurrences were compared with patients with Toxic Epidermal Necrolysis (TEN) and Stevens–Johnson syndrome (SJS) patients during the same time frame. ResultsOf the 60 cases of DRESS collected, 15 (25%) with recurrences were retained for analysis. Seven patients had a single recurrence, whereas eight patients had several relapses. In the patients with pre-existing DRESS, recurrences were incomplete, corresponding to cutaneous rash in 13 cases and associated with eosinophilia in seven cases. Internal organ involvement was observed in two cases. In contrast, a single recurrence was found out of 61 patients with TEN/SJS. Conclusion
Incomplete recurrences with structurally unrelated culprit drugs are a frequent phenomenon in DRESS patients.
Journal of the European Academy of Dermatology and Venereology 03/2014; 29(4). DOI:10.1111/jdv.12419 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have identified a spliced mRNA transcript of CD20 (named D393-CD20) which was associated with resistance to RTX in primary B cell from patients with lymphoma and leukaemia. In the present work, we wished to investigate whether D393-CD20 variant was expressed by B cells from patients with pemphigus. Ten patients with bullous pemphigoid and twenty-five patients with pemphigus were included. All patients were responder to conventional immunosuppressive agents or rituximab (n=11). Efficacy of B-cell activation by Pokeweed Mitogen was assessed by CD86 expression using a FACS Canto II flow cytometer. mRNA CD20 expression study was then performed using RT-PCR assay allowing first to discriminate wild type (wt)-CD20 and D393-CD20 transcript. Although wt-CD20 expression was always detected, we were unable to detect D393-CD20, even after B cell activation or RTX treatment. Our results suggest that D393-CD20 transcript may be a molecular marker of B cell malignancies rather than auto-immune disease like pemphigus. Further study of RTX-non responders or -escaping PV patients are thus still required to appreciate whether D393-CD20 expression may be detected under the pressure of RTX therapy. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19CD27 naïve B cells to CD19CD27 memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10-secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G-positive (IgG) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.
Science translational medicine 03/2013; 5(175):175ra30. DOI:10.1126/scitranslmed.3005166 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have reviewed 47 drug rash with eosinophilia and systemic symptoms (DRESS) cases associated to strontium ranelate reported up to March 2011 to the Marketing Holder. The main signs were skin rash, fever, face oedema hypereosinophilia and liver involvement. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained, and DRESS was identified as the direct cause of death in one case. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. Because DRESS is a severe drug reaction, the occurrence of a rash in a patient treated with strontium ranelate should lead to prompt and permanent treatment discontinuation. INTRODUCTION: This study aims to describe cases of DRESS reported to the Marketing Authorisation Holder worldwide for patients receiving strontium ranelate by practitioner or by regulatory authorities. METHODS: Spontaneously reported hypersensitivity events from the strontium ranelate pharmacovigilance database since marketing authorisation (2004) to March 2011 were reviewed by an expert committee. Cases of DRESS were classified as established, probable, possible or no DRESS according to expert judgement. National incidences of DRESS were estimated in relation to the number of newly treated patients. RESULTS: Up to March 2011, 325 cases of strontium ranelate-induced hypersensitivity events were assessed from which 47 DRESS cases were confirmed. Mean age was 68.7 years and besides skin rash, the main signs and symptoms were hypereosinophilia, liver involvement, fever and face oedema. Median time to skin reaction was 33.5 days after treatment start. Most patients (62 %) recovered at the time of reporting or were recovering. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained. Relapses were observed in a single case. The mortality rate was 8.5 %. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. CONCLUSION: DRESS is a well-identified and characterised adverse reaction to strontium ranelate. This risk should be integrated in the risk-benefit balance evaluation of patient treatment, and the occurrence of a rash should lead to prompt and permanent treatment discontinuation with careful follow-up.
Osteoporosis International 01/2013; 24(5). DOI:10.1007/s00198-013-2265-1 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The syndrome termed 'Drug Reaction with Eosinophilia and Systemic Symptoms' (DRESS) is an unpredictable, life-threatening condition associated with adverse reactions to therapy. Although the etiology of DRESS is poorly understood, genetic susceptibility markers have been identified within the HLA complex and there are several prevailing models of pathogenesis. Modification of host antigens by haptens (drugs or their metabolites), or non-covalent drug binding to endogenous proteins (the p-i concept), may drive pro-inflammatory immune responses in patients. Alternatively, a viral trigger for DRESS has been proposed based on the concomitant detection of herpesviruses and the recent demonstration of Epstein-Barr virus-specific immune responses in DRESS patients. In the present review, we discuss the latest findings concerning the pathogenesis of drug reactions and known risk factors for DRESS.
Current opinion in immunology 10/2012; 24(6). DOI:10.1016/j.coi.2012.07.010 · 7.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as "no," "possible," "probable," or "definite" to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as "probable/definite" DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with "probable/definite" DRESS cases, whereas skin rash was described in almost all of the cases, including "possible cases." Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.
The American journal of medicine 07/2011; 124(7):588-97. DOI:10.1016/j.amjmed.2011.01.017 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug-induced hypersensitivity syndrome or DRESS is an uncommon but potentially severe cutaneous adverse drug reaction. This cutaneous drug adverse reaction has some particular characteristics: a small number of culprit drugs, long delay (three to six weeks) for development after the first drug intake, responsibility of some viruses, especially Human Herpesvirus 6 (HHV6). The awareness of this cutaneous adverse reaction has increased during the last years with a better knowledge including the relationship between some drugs and reactivation of Herpesviruses, antiviral immune response, and genetic background. The identification of DRESS is important for rheumatologist who is often using drugs at risk for DRESS (allopurinol, salazopyrine, antiépileptiques…). This recognition enables a rapid diagnosis and a proper management of this syndrome.
Revue du Rhumatisme Monographies 06/2011; 78(3):197-200. DOI:10.1016/j.monrhu.2011.03.004
[Show abstract][Hide abstract] ABSTRACT: The inflammation which occurs around the silicone prosthesis is a complex process that can provoke the failure of the device and compromise the health of the implanted patient. Toll-like receptors (TLRs), which are transmembrane proteins, are now known to act in the innate immune response and in endogenous inflammation. The aim of our study was to assess the role of TLR4 in the foreign body reaction to a silicone shell prosthesis. Disks of shell silicone prosthesis were implanted in the subcutaneous tissue of C57BL6-TLR4-/- and C57BL6-WT mice. At day 14, inflammatory cell infiltrate and vessel sections around the prosthesis were less numerous in TLR4-/- than in WT mice. A histomorphometric analysis showed that the capsule around the implant was 1.96-fold less thick in depleted TLR4 than in wild-type mice. In addition, vascular endothelial growth factor and transforming growth factor 1 were underexpressed in the surrounding tissue of the prosthesis in TLR4-/- mice. Our study suggests, from this foreign body response model against silicone in mice, that TLR4 plays a key role in the reaction process around silicone implants.
[Show abstract][Hide abstract] ABSTRACT: Le syndrome d’hypersensibilité médicamenteuse ou DRESS (drug reaction with eosinophilia and systemic symptoms) est une toxidermie grave. Il se traduit par l’association d’une fièvre élevée, d’un rash cutané avec oedème du visage, d’une
polyadénopathie, d’une éosinophilie et/ou de lymphocytes atypiques. La gravité est liée à la survenue d’atteintes viscérales
(hépatite, hémophagocytose, encéphalite, pneumopathie, insuffisance rénale, pancréatite, thyroïdite…) qui peuvent évoluer
vers un tableau de défaillance multiviscérale et conduire à un transfert en réanimation. Ce syndrome occupe une place particulière
dans les toxidermies. Il s’agit en effet d’un syndrome lié à une réponse immunologique contre des réactivations virales (human herpesvirus 6, human herpesvirus 7, virus Epstein-Barr et cytomégalovirus) induites par la prise de certains médicaments. Le DRESS doit aujourd’hui être considéré
comme une maladie virale où certains médicaments jouent un rôle inducteur de réactivations virales sur un terrain prédisposé
génétiquement qui reste à identifier. Le DRESS est un modèle d’étude d’un domaine de la médecine encore peu connu: la possible
synergie entre médicaments et virus.
Drug-induced hypersensitivity syndrome or DRESS (drug reaction with eosinophilia and systemic symptoms) is a severe drug-induced reaction. Its features include high fever, rash, facial oedema, lymphadenopathies, eosinophilia,
and atypical lymphocytes. Its severity is due to the development of visceral manifestations (hepatitis, hemophagocytic syndrome,
encephalitis, pneumonitis, renal failure, pancreatitis, and thyroiditis) and may lead to multiple organ failure and a transfer
to the intensive care unit. This syndrome has some specificities among the cutaneous adverse drug reaction. DRESS is the consequence
of an immune response directed against viral reactivations (Human Herpesviurs 6, Human Herpesvirus 7, Epstein-Barr virus,
cytomegalovirus). These viral reactivations are induced by a few drugs. DRESS should be considered as a viral disease in which
some drugs stimulate viral reactivations in a genetically predisposed background. DRESS is a model to study a medical area
that is still unrecognized: the link between drugs and viruses.
Human herpesvirus 6–
KeywordsDRESS–Human Herpesvirus 6–Herpesvirus–Multiorgan failure