Anti-idiotypic monoclonal antibody AB3, reacting with the primary antigen (CEA), can localize in human colon-carcinoma xenografts as efficiently as AB1.

BALB/c mice were immunized with anti-idiotypic monoclonal (MAb) antibody (anti-Id or Ab2) directed against an AB1 MAb anti-carcinoembryonic (CEA) in order to obtain AB3 MAbs (anti-anti-Id). AB3 MAbs were shown to recognise the primary antigen (CEA) and one of them was tested extensively in vitro and in vivo. This AB3 MAb was shown to bind specifically to CEA on frozen sections of a human colon carcinoma by immunoperoxidase. Scatchard plot analyses showed that the affinity of this AB3 was of the same order of magnitude as the AB1. In vivo experiments, in nude mice bearing CEA-producing human colon-carcinoma xenografts showed that up to 30% of the intravenously injected dose of 125I-labelled AB3 were localized per gram of tumour tissue. Furthermore, calculation of the ratios of AB3 concentration in the tumour over those in normal organs such as lung, liver, kidney, spleen and bone gave relatively high values similar to results obtained with AB1. All together our results show that AB3 can localize as efficiently and specifically in the tumour as AB1, despite the fact that the mice from which it was derived were immunized with a mouse MAb (AB2) and had never been exposed to CEA.

The anti-lymphoma activity of APO866, an inhibitor of nicotinamide adenine dinucleotide biosynthesis, is potentialized when used in combination with anti-CD20 antibody.

Abstract APO866 is an inhibitor of nicotinamide adenine dinucleotide (NAD) biosynthesis that exhibits potent anti-lymphoma activity. Rituximab (RTX), an anti-CD20 antibody, kills lymphoma cells by direct apoptosis and antibody- and complement-dependent cell-mediated cytotoxicities, and has clinical efficacy in non-Hodgkin cell lymphomas. In the present study, we evaluated whether RTX could potentiate APO866-induced human B-lymphoma cell death and shed light on death-mediated mechanisms associated with this drug combination. We found that RTX significantly increases APO866-induced death in lymphoma cells from patients and lines. Mechanisms include enhancement of autophagy-mediated cell death, activation of caspase 3 and exacerbation of mitochondrial depolarization, but not increase of reactive oxygen species (ROS) production, when compared with those induced by each drug alone. In vivo, combined administration of APO866 with RTX in a laboratory model of human aggressive lymphoma significantly decreased tumor burden and prolonged survival over single-agent treatment. Our study demonstrates that the combination of RTX and APO866 optimizes B-cell lymphoma apoptosis and therapeutic efficacy over both compounds administered separately.

Effect of vitamin D on EBV-specific CD8+T cells in patients with early multiple sclerosis

Introduction: Infection with Epstein-Barr Virus (EBV) and a lack invitamin D are emerging as the twomost significant environmental triggersof multiple sclerosis (MS). Sincewe and others have shown that CD8+T cells are important immune mediatorsof the inflammatory response inMS, we examined whether vitamin Ddirectly affects the CD8+ T cell response.We also explored if vitaminDmodulates the EBV-specific CD8+ Tcell response. Methods: PBMC of 10patients with early MS and 10 healthycontrols (HC) were stimulated eitherwith a pool of EBVimmunodominantpeptides or anti-CD3/anti-CD28 beads.Cytokine secretion was assessed witha Cytometric Beads Array (CBA),ELISA and intracellular cytokinestaining. To examine whether vitaminD could directly modulate CD8+ Tcell immune responses, we depletedCD4+ T cells using a negative selection.Results: We found that vitaminD-treated PBMC stimulated eitherwith the EBV peptide pool or anti-CD3/anti-CD28 beads adopted ananti-inflammatory profile: significantdecrease in IFN-and TNF secretion,contrasting with a significant increasein IL-5 and TGF-secretion. At baseline,but also after vitamin D stimulation,IL-5 was significantly less producedby stimulated CD8+ T cells ofearly MS than HC. Finally, using depletionof CD4+ T cells, we couldshow that vitaminDcan directlymodulateCD8+ T cells. Discussion: Ourdata suggest that vitaminDconfers ananti-inflammatory profile to CD8+ Tcells, without the help of CD4+ Tcells. Even if vitamin D has a significanteffect on CD8+ T cells of earlyMS patients, this "rescuing" effect isof smaller magnitude than in HC subjects.Finally, vitamin D does influencethe CD8+ T cell response toEBV in early MS patients, suggestingthat there is an interplay betweenthese two major environmental factorsof MS.

Use of radiolabelled monoclonal anti-CEA antibodies for the detection of human carcinomas by external photoscanning and tomoscintigraphy

Paul Ehrlich's inspired concept of 'magic bullets' for the cure of diseases has been revitalized by recent advances in immunology1. In particular, the development of cell fusion technology allowing the production of monoclonal antibodies (Mabs) with exquisite specificities2 triggered new hopes that we may now have the perfect carrier molecules with which to deliver cytotoxic drugs3 or toxins4 to the hidden cancer cells. This article reviews data on one aspect of the magic bullet concept, the use of radiolabelled antibodies as tracers for tumour localization. It will also discuss the very recent clinical use of 131I-labelled Mabs against carcinoembryonic antigen (CEA)5 to detect carcinoma either by conventional external photoscanning or by single photon emission computerized tomography (SPELT). This alliance of the most modern tools from immunology (Mabs) and nuclear medicine (SPELT) appears promising as a way to improve the sensitivity of 'immunoscintigraphy'. However, this approach is not yet ready, for widespread clinical use.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.

Nouveaux traitements de l'hépatite C: aspects pharmacologiques et potentiel d'interaction [New hepatitis C treatments: pharmacological considerations and potential for drug interactions].

Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed.

Anti-TNF-alpha therapy in patients with chronic non-infectious uveitis: the experience of Jules Gonin Eye Hospital.

BACKGROUND: The purpose of this study is to describe the experience of Jules Gonin Eye Hospital on the long-term outcome of anti-TNF-alpha therapy in chronic non-infectious uveitis. PATIENTS AND METHODS: We identified and followed those patients with chronic non-infectious uveitis who received systemic anti-TNF-alpha therapy. Anti-TNF-alpha therapy was administered when no response had been obtained with classical immunosuppressive therapies or in the presence of severe rheumatoid disease. RESULTS: Fifteen patients (28 eyes), 7 male and 8 female (mean age, 43 years; range: 7 to 70 years) were identified. Diagnoses included HLA-B27-associated anterior uveitis (n = 4), sarcoidosis (n = 2), juvenile idiopathic arthritis (n = 2), idiopathic retinal vasculitis with uveitis (n = 2), pars planitis (n = 2), Adamantiades-Behçet disease (n = 1), birdshot retinochoroidopathy (n = 1), and Crohn's disease (n = 1). Mean duration of ocular disease was 8 years (range: 1 to 29 years). Treatment with infliximab (n = 11), etanercept (n = 2), or adalimumab (n = 2) was initiated. One patient with etanercept was switched to infliximab due to lack of clinical response. Clinical and angiographic regression of uveitis was observed within the first two months of therapy in all patients, and was maintained throughout the entire follow-up period (mean 18 months; range: 3 - 72 months). Recurrence was observed in 3 patients, and resolved after adjustment of therapy. Adverse events were recorded in only one patient (arterial hypotension). CONCLUSIONS: In this series of patients with chronic non-infectious uveitis, anti-TNF-alpha therapy was effective and safe. Further clinical studies are needed to determine an adequate duration of therapy.

Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies.

The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments.

Production et évaluation de l'anticorps NIMP-R14 pour dépléter chroniquement les neutrophiles chez un modèle expérimental d'athérosclérose avancée : la souris ApoE-/- 2 reins-1clip (2K1C)

L'athérosclérose (ATS) est une maladie artérielle inflammatoire chronique à l'origine des nombreuses maladies cardiovasculaires que sont l'infarctus du myocarde, l'accident vasculaire cérébral ou encore l'artériopathie oblitérante des membres inférieurs. L'ATS se définit comme la formation de plaques fibro-lipidiques dans l'intima des artères. Les facteurs de risque majeurs associés à l'ATS sont l'hypertension, l'hypercholestérolémie, le tabagisme, le diabète, la sédentarité, ou encore des prédispositions génétiques. L'ATS peut être asymptomatique durant des années ou alors engendrer des complications aiguës pouvant parfois mettre le pronostic vital en jeu. Les complications les plus graves surviennent principalement lors de la rupture d'une plaque athéromateuse dite vulnérable ou instable. En effet, cette dernière peut se rompre et entraîner la formation d'un thrombus artériel occlusif avec, pour conséquence, l'ischémie/nécrose des tissus en aval. Prévenir le développement de la plaque vulnérable et/ou la « stabiliser » permettrait donc de prévenir les complications cliniques de l'ATS. Cet objectif requiert une connaissance éclairée des mécanismes cellulaires et moléculaires impliqués dans la physiopathologie de l'ATS et de la plaque vulnérable. Les travaux expérimentaux menés au sein du laboratoire du service d'angiologie du CHUV sous la direction du Prof. Lucia Mazzolai ont montré que l'angiotensine II (ang II), produit final de la cascade du système rénine-angiotensine, joue un rôle majeur dans la « vulnérabilité » des plaques athéromateuses (1). Ces travaux ont été réalisés à partir d'un modèle animal original développant des plaques d'ATS vulnérables dépendantes de l'ang II: la souris ApoE-/- 2 reins-1 clip (2K1C). Plus récemment, le laboratoire d'angiologie a mis en évidence une implication directe des leucocytes, plus précisément des macrophages et des lymphocytes T CD4+, dans l'athérogenèse ang II-dépendante (2,3). Dernièrement, des travaux ont également suggéré un rôle possible des granulocytes neutrophiles dans l'ATS (4,5,6,7). Toutefois, les études sont encore limitées de sorte que le rôle exact des neutrophiles dans l'ATS et plus spécialement dans l'ATS induite par l'ang II reste à démontrer. Une des recherches actuelles menée dans le laboratoire est donc d'étudier le rôle des neutrophiles dans le développement de la plaque athéromateuse vulnérable à partir du modèle animal, la souris ApoE-/- 2K1C. Pour évaluer le rôle direct des neutrophiles chez notre modèle animal, nous avons choisi comme méthode la déplétion des neutrophiles circulants par l'utilisation d'un anticorps spécifique. Il a été reporté dans la littérature que l'anticorps monoclonal NIMP-R14 3 permettait de dépléter sélectivement in vivo les neutrophiles dans différents modèles murins (8,9). Cependant, ces études ont utilisé cet anticorps anti-neutrophiles majoritairement sur des périodes expérimentales de durées relativement limitées (12-14 jours) et la question s'est donc posée de savoir si cet anticorps pouvait aussi dépléter les neutrophiles chez notre modèle animal, qui requiert une période expérimentale de 4 semaines pour développer des plaques vulnérables (1). Le but de ce travail a donc été de produire l'anticorps NIMP-R14 et d'évaluer son efficacité chez la souris ApoE-/- 2K1C qui développe des plaque d'ATS vulnérables dépendantes de l'ang II.

The impact of fasting on the interpretation of triglyceride levels for predicting myocardial infarction risk in HIV-positive individuals: the D:A:D study.

We assessed whether fasting modifies the prognostic value of these measurements for the risk of myocardial infarction (MI). Analyses used mixed effect models and Poisson regression. After confounders were controlled for, fasting triglyceride levels were, on average, 0.122 mmol/L lower than nonfasting levels. Each 2-fold increase in the latest triglyceride level was associated with a 38% increase in MI risk (relative rate, 1.38; 95% confidence interval, 1.26-1.51); fasting status did not modify this association. Our results suggest that it may not be necessary to restrict analyses to fasting measurements when considering MI risk.

Radioimmunotherapy combined with maintenance anti-CD20 antibody may trigger long-term protective T cell immunity in follicular lymphoma patients.

Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.