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Antigens derived from engulfed apoptotic bodies that are presented by dendritic cells can amplify Ag-specific T-cells. Accelerated co-cultured DC (acDC) strategy keeps lymphocytes in contact with differentiating DCs. Therefore, Ag-specific T-cell activation can occur during DC maturation. Our aim was to prepare DCs by acDC method and check the subsequent engulfment of the apoptotic body by acDC. We have proposed that this method could be feasible if we transfect the apoptotic bodies with the antigen. DCs were prepared using acDC method and their maturation markers were confirmed by flow cytometry. Ultraviolet was used for inducing apoptosis in the PBMCs and induction of apoptosis checked by propidium iodide and 7-aminoactinomycin D staining. Flow cytometry and immunohistochemistry were used for checking the uptake of apoptotic bodies by the DCs. The alloreactivity against apoptotic bodies was examined by enzyme-linked immunospot (ELISPOT) assay. Results showed that 40.4% of DCs could efficiently engulf the apoptotic bodies. The results indicated that acDC method is capable to isolate a high yield of DCs, and these cells could properly engulf the apoptotic bodies, more works should be performed to use this method for Ag discovery through delivering the Ag by apoptotic bodies into the DCs.

International audience; The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+ T cells reactive to ZnT8186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+ T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.

The human leukocyte antigen (HLA)-A2-restricted zinc transporter (ZnT)8186–194 and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. Here, we show that clonal ZnT8186–194-reactive CD8+ T cells express private T-cell receptors and display equivalent functional properties in T1D and healthy subjects. Ex-vivo analyses further revealed that CD8+ T cells reactive to ZnT8186–194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186–194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children vs. adults, irrespective of disease status. Moreover, some ZnT8186–194-reactive CD8+ T-cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. While ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expressions levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186–194-reactive cells were enriched in the pancreata of T1D donors vs. non-diabetic and type 2 diabetic controls. Thus, islet-reactive CD8+ T cells circulate in most individuals, but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T-cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a pro-inflammatory islet microenvironment.

International audience; In vivo electroporation (EP) is used to enhance the uptake of nucleic acids and its association with DNA vaccination greatly stimulates immune responses to vaccine antigens delivered through the skin. However, the effect of EP on cutaneous cell behavior, the dynamics of immune cell recruitment and local inflammatory factors, have not been fully described. Here, we show that intradermal DNA vaccination combined with EP extends antigen expression to the epidermis and the subcutaneous skin muscle in non-human primates. In vivo fibered confocal microscopy and dynamic ex vivo imaging revealed that EP promotes the mobility of Langerhans cells (LC) and their interactions with transfected cells prior to their migration from the epidermis. At the peak of vaccine expression, we detected antigen in damaged keratinocyte areas in the epidermis and we characterized recruited immune cells in the skin, the hypodermis and the subcutaneous muscle. EP alone was sufficient to induce the production of pro-inflammatory cytokines in the skin and significantly increased local concentrations of Transforming Growth Factor (TGF)-alpha and IL-12. Our results show the kinetics of inflammatory processes in response to EP of the skin, and reveal its potential as a vaccine adjuvant. Among the various vaccination approaches against infectious diseases such as human immunodeficiency virus (HIV), deoxyribonucleic acid (DNA) vaccines have several advantages: they are easily produced, provide opportunities for molecular engineering, lack anti-vector immunity, and have the potential to promote both cellular and humoral immune responses 1. However, despite their high immunogenicity in murine models, DNA vaccines have shown poor efficacy in large animal models and humans 2. New strategies to improve DNA vaccines include the optimization of transcriptional control elements and codons 3-5 , the use of adjuvants, such as Toll-like receptor (TLR) ligands 6 , cytokine expressing plasmids 7-9 or apoptosis-based adjuvants 10-12 and the choice of an appropriate delivery system such as local electroporation (EP) 13-15. In particular, EP has been largely used to enhance plasmid DNA uptake and increase the number of antigen-producing cells 16, 17. In addition, EP modifies blood vessel permeability and facilitates leukocyte extrava-sation in the exposed area 18. However, the effects of EP on cutaneous antigen presenting cells (APCs) and on the dynamics of cell recruitment at the vaccine site have not been fully described. In a previous study, we demonstrated that intradermal (id) administration of the auxo-GTU ®-multiHIV plasmid (GTU for Gene Transport Unit) combined with noninvasive EP induces a strong and persistent poly-functional T-cell response in macaques 19. Here, we investigated the early events that occur in the skin and the 1 CEA-Université Paris Sud 11-INSERM U1184, DRF/Jacob/Immunology of Viral infections and Autoimmune Diseases (IMVA), IDMIT infrastructure, 92265, Fontenay-aux-Roses

Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8The combinatorial HLA-A2 multimer assay was applied in five participating centres using centralised reagents and blinded replicate samples. In preliminary experiments, samples from healthy donors were analysed using recall antigen multimers. In subsequent experiments, samples from healthy donors and individuals with type 1 diabetes were analysed using beta cell antigen and recall antigen multimers.The combinatorial assay was successfully implemented in each participating centre, with CVs between replicate samples that indicated good reproducibility for viral epitopes (mean %CV = 33.8). For beta cell epitopes, the assay was very effective in a single-centre setting (mean %CV = 18.4), but showed sixfold greater variability across multi-centre replicates (mean %CV = 119). In general, beta cell antigen-specific CD8Our results suggest that, although combinatorial multimer assays are challenging, they can be implemented in multiple laboratories, providing relevant T cell frequency measurements. Assay reproducibility was notably higher in the single-centre setting, suggesting that biomarker analysis of clinical trial samples would be most successful when assays are performed in a single laboratory. Technical improvements, including further standardisation of cytometry platforms, will likely be necessary to reduce assay variability in the multi-centre setting.

Insulin is the hormone produced by pancreatic β-cells, with a central role in carbohydrate and fat metabolism. Together with its precursors preproinsulin and proinsulin, insulin is also a key target antigen (Ag) of the autoimmune islet destruction leading to type 1 diabetes. Being recognized by both autoantibodies (aAbs) and autoreactive T cells, insulin plays a triggering role, at least in rodent models, in diabetes pathogenesis. It is expressed not only by β-cells but also in the thymus, where it plays a major role in central tolerance mechanisms. We will summarize current knowledge concerning insulin, its role in β-cell autoimmunity as initial target Ag, its recognition by aAbs and autoreactive T cells, and the detection of these immune responses to provide biomarkers for clinical trials employing insulin as an immune modulatory agent.

Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-week-old NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8(+) T cells recognizing the immunodominant epitopes insulin B(15-23) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214). Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high- but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.

The central role of T cells in type 1 diabetes pathogenesis is well established, but these cells continue to pose numerous challenges in understanding their dynamics and in following their modifications. Important progress has been recently made in pinpointing some novel antigens targeted by pathogenic T cells and the epitope sequences recognized. Studies on the interplay between effector T cells, their regulatory counterparts, and cells of the innate immune system have unraveled novel pathways and may inspire new therapeutic approaches. At the same time, the appreciation of the plasticity of regulatory T cells has raised important caveats on their use for cell-based therapies. Continuous development of T-cell assays exploring both pathogenic and regulatory players will be critical to "take the temperature" of undergoing disease progression and reversal.

International audience; Central tolerance plays a key role in modulating immune responses to self and exogenous antigens. The absence of self-antigen expression, as in patients with genetic deficiencies, prevents the development of antigen-specific immune tolerance. Hence, a substantial number of patients develop neutralizing antibodies to the corresponding protein therapeutics after replacement treatment. In this context, the administration of missing antigens during fetal development, a key period for self-tolerance establishment, should confer early and long-lasting antigen-specific tolerance. To this end, we exploited the physiological pathway of the neonatal Fc receptor (FcRn) through which maternal immunoglobulins are transplacentally transferred to fetuses. We demonstrate that Fc-fused antigens administered to pregnant mice reach fetal lymphoid organs in an FcRn-dependent manner, accumulate in antigen-presenting cells of myeloid origin, and promote the generation of both thymic and peripheral antigen-specific regulatory T cells. This strategy was successfully pursued in a mouse model of hemophilia A, where maternofetal transfer of the Fc-fused immunodominant domains of coagulation factor VIII conferred antigen-specific tolerance. Transplacental tolerance induction with Fc-fused proteins may thus prove valuable to prevent alloimmunization after replacement protein therapy for congenital deficiencies.

The first signs of autoimmune activation leading to β-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPIB15–23 T-cell receptor–transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4+ regulatory T cells expressing transforming growth factor-β and in increased effector CD8+ T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions.

The assembly of MHC class I molecules with beta(2)-microglobulin and peptides is assisted by the housekeeping chaperones calnexin, calreticulin, and Erp57 and the dedicated accessory protein, tapasin. Tapasin and calreticulin are essential for efficient MHC class I assembly, but their precise action during class I assembly remains to be elucidated. Previous in vitro studies have demonstrated that the lectin calreticulin interacts with monoglucosylated MHC class I heavy chains, whatever their state of assembly with light chains and peptide, and inhibits their aggregation above physiological temperature. We used a soluble single chain HLA-A2/beta(2)-microglobulin molecule, A2SC, to study the effect of calreticulin on the peptide binding capacity of HLA class I molecules. Calreticulin inhibited the formation of A2SC aggregates both when co-expressed in insect cells and during incubations at elevated temperature. Calreticulin dramatically enhanced acquisition of peptide binding capacity when added to denatured A2SC molecules during refolding at 4 degrees C. However, it had no effect on the rapid loss of A2SC peptide binding capacity at physiological temperature. We conclude that calreticulin promotes the folding of HLA class I molecules to a state in which, at low temperature, they spontaneously acquire peptide binding capacity. However, it does not induce or maintain a peptide-receptive state of the class I-binding site, which is likely to be promoted by one or several other components of the class I loading complexes. By being amenable to complementation with additional proteins, the described system should be useful for identification of these components.

One of the hurdles encountered by immunotherapy attempts for type 1 diabetes (T1D) is the delicate ethical issue of minimizing risks for a disease with a normal life expectancy in many patients. For this reason, antigen (Ag)-specific immunotherapies are attractive in view of their selectivity and favorable safety profile (1). However, they have not met expectations in therapeutic trials using insulin (2–4) and GAD (5). These trials face several technical difficulties: the need to produce and administer proteins of suitable quality and quantity; bioavailability issues, as prolonged delivery of small Ag amounts may be more effective at restoring long-term immune tolerance; routes of administration, with the noninvasive oral route being more tolerogenic but suffering considerable Ag degradation; and Ag delivery in a noninflammatory environment to avoid unwanted immunogenic outcomes. The most important issue is the timing of immune intervention, with a panoply of agents effective at preventing disease even in the reductionist NOD mouse model, but only a handful working at reversing established disease, which is the preferred setting for human trials. In this issue, Robert et al. (6) bring Ag-specific therapies into a new dimension by letting genetically modified Lactococcus lactis do the job. L. lactis is a nonpathogenic, noncolonizing, commensal bacterium with a long safety record in the dairy industry. Biological containment of genetically modified strains to avoid environmental propagation can be obtained …

Peptide ligands presented by MHC class I (MHC-I) molecules are produced by degradation of cytosolic and nuclear, but also endoplasmic reticulum (ER)–resident, proteins by the proteasome. However, Ag processing of ER proteins remains little characterized. Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune diabetes, we found that targeting to the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its cellular levels. While proteasome inhibition inhibited degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-targeted proinsulin. This targeting and protein modifications modifying protein half-life also had profound effects on MHC-I presentation and proteolytic processing of proinsulin. Thus, presentation of stable luminal forms was inefficient but enhanced by proteasome inhibition, whereas that of unstable luminal forms and of a cytosolic form were more efficient and compromised by proteasome inhibitors. Distinct stability of peptide MHC complexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activities process the two Ag forms. Thus, both structural features and subcellular targeting of Ags can have strong effects on the processing pathways engaged by MHC-I–restricted Ags, and on the efficiency and regulation of their presentation.

Antigen presentation by MHC class I molecules requires degradation of epitope source proteins in the cytosol. Although the preeminent role of the proteasome is clearly established, evidence suggesting a significant role for proteasome-independent generation of class I ligands has been reported repeatedly. However, an enzyme responsible for such a role has not been identified. Recently insulin-degrading enzyme (IDE) was shown to produce an antigenic peptide derived from the tumor antigen MAGE-A3 in an entirely proteasome-independent manner, raising the question of the global impact of IDE in MHC class I antigen processing. Here we report that IDE knockdown in human cell lines, or knockout in two different mouse strains, has no effect on cell surface expression of various MHC class I molecules, including allomorphs such as HLA-A3 and HLA-B27 suggested to be loaded in an at least a partly proteasome-independent manner. Moreover, reduced or absent IDE expression does not affect presentation of five epitopes including epitopes derived from beta amyloid and proinsulin, two preferred IDE substrates. Thus, IDE does not play a major role in MHC class I antigen processing, confirming the dominant and almost exclusive role of the proteasome in cytosolic production of MHC class I ligands.

Decades of research efforts aimed at upgrading type 1 diabetes (T1DM) treatment did not harvest much success besides improving insulin therapy, which remains the standard of care since 1922. Immunological strategies targeting autoimmune mechanisms, rather than their metabolic consequences, are highly demanded. A dealt of preclinical studies in animal models offered some promises, which were however not maintained once translated into human. All these immune intervention trials evaluated metabolic and clinical endpoints, namely C-peptide secretion, HbA(1c) and insulin requirements. While critical, we argue that these endpoints are insufficient and should be complemented with immune surrogate endpoints, i.e. biomarkers reflecting the immune modifications induced by such treatments. This is even more critical when clinical expectations are not met, in order to sort out the reasons of such failure, i.e. whether immune changes are not accomplished or whether, despite being accomplished, they are insufficient to translate into clinical benefits. Furthermore, these ancillary analyses may give precious indications to design further trials, i.e. to enroll patients with the best odds to respond to therapy and to follow-up their response.

International audience; Synthetic peptides are widely used in immunological research as epitopes to stimulate their cognate T cells. These preparations are never completely pure, but trace contaminants are commonly revealed by mass spectrometry quality controls. In an effort to characterize novel major histocompatibility complex (MHC) Class I-restricted β-cell epitopes in non-obese diabetic (NOD) mice, we identified islet-infiltrating CD8+ T cells recognizing a contaminating peptide. The amount of this contaminant was so small to be undetectable by direct mass spectrometry. Only after concentration by liquid chromatography, we observed a mass peak corresponding to an immunodominant islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)$_{206-214}$ epitope described in the literature. Generation of CD8+ T-cell clones recognizing IGRP$_{206-214}$) using a novel method confirmed the identity of the contaminant, further underlining the immunodominance of IGRP$_{206-214}$. If left undetected, minute impurities in synthetic peptide preparations may thus give spurious results.

Strategies to improve vaccine efficacy are still required, especially in the case of chronic infections, including human immunodeficiency virus (HIV). DNA vaccines have potential advantages over conventional vaccines; however, low immunological efficacy has been demonstrated in many experiments involving large animals and in clinical trials. To improve the immunogenicity of DNA vaccines, we have designed a plasmid vector exploiting the binding capacity of the bovine papillomavirus E2 protein and we have used electroporation (EP) to increase DNA uptake after intradermal inoculation. We demonstrated, in nonhuman primates (NHPs), efficient induction of anti-HIV immunity with an improved DNA vaccine vector encoding an artificial fusion protein, consisting of several proteins and selected epitopes from HIV-1. We show that a DNA vaccine delivery method combining intradermal injection and noninvasive EP dramatically increased expression of the vaccine antigen selectively in the epidermis, and our observations strongly suggest the involvement of Langerhans cells in the strength and quality of the anti-HIV immune response. Although the humoral responses to the vaccine were transient, the cellular responses were exceptionally robust and persisted, at high levels, more than 2 years after the last vaccine boost. The immune responses were characterized by the induction of significant proportions of T cells producing both interferon-gamma and interleukin-2 cytokines, in both subpopulations, CD4(+) and CD8(+). This strategy is an attractive approach for vaccination in humans because of its high efficacy and the possible use of newly developed devices for EP.

Introduction En depit de resultats encourageants obtenus chez la souris NOD, les essais cliniques de prevention du diabete de type 1 par l’insuline sous-cutanee sont restes sans succes. Materiels et methodes Pour expliquer ces divergences, des souris NOD âgees de 3 semaines ont ete traitees pendant 7 semaines par deux differentes doses d’insuline sous-cutanee : une forte dose (0,5 U/souris) utilisee dans des etudes murines anterieures; et une faible dose (0,005 U/souris) equivalente a celle utilisee dans les essais cliniques chez l’homme. Les effets sur l’insulite et le diabete et les modifications immunologiques et metaboliques ont ete suivis pendant et apres traitement. Resultats Le traitement par faible dose d’insuline n’a pas montre d’effet sur l’incidence de la maladie. Le traitement par forte dose retarde mais ne previent pas le diabete, induisant une diminution de l’insulite qui toutefois reapparait apres arret du traitement. Cet effet n’est pas associe a des modifications immunologiques significatives dans l’infiltrat des ilots, ni en terme de composition cellulaire, ni en terme de frequence et de secretion d’IFN-g par les cellules T CD8 + reconnaissant les epitopes immunodominants de l’insuline B15–23 et de la proteine islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) 206–214. Les retards du diabete et de l’insulite sont associes a des niveaux de glucose sanguin et de peptide C endogene diminues, mais qui reviennent rapidement a la normale apres interruption du traitement. Conclusion Un traitement prophylactique par l’insuline a forte dose – mais pas a faible dose – retarde l’apparition du diabete et est associe a des changements metaboliques suggerant une « mise au repos » des cellules beta, qui toutefois ne persistent pas au-dela du traitement. Ces resultats ont d’importantes implications pour la conception d’essais cliniques bases sur une therapie prophylactique par l’insuline.

International audience; Insulin Degrading Enzyme (IDE) is a protease conserved through evolution with a role in diabetes and Alzheimer's disease. The reason underlying its ubiquitous expression including cells lacking identified IDE substrates remains unknown. Here we show that the fission yeast IDE homologue (Iph1) modulates cellular sensitivity to endoplasmic reticulum (ER) stress in a manner dependent on TORC1 (Target of Rapamycin Complex 1). Reduced sensitivity to tunicamycin was associated with a smaller number of cells undergoing apoptosis. Wild type levels of tunicamycin sensitivity were restored in iph1 null cells when the TORC1 complex was inhibited by rapamycin or by heat inactivation of the Tor2 kinase. Although Iph1 cleaved hallmark IDE substrates including insulin efficiently, its role in the ER stress response was independent of its catalytic activity since expression of inactive Iph1 restored normal sensitivity. Importantly, wild type as well as inactive human IDE complemented gene-invalidated yeast cells when expressed at the genomic locus under the control of iph1(+) promoter. These results suggest that IDE has a previously unknown function unrelated to substrate cleavage, which links sensitivity to ER stress to a pro-survival role of the TORC1 pathway.

Introduction Le diabete de type 1 (DT1) est une pathologie auto-immune resultant d’une rupture de la tolerance immunitaire envers des antigenes β-cellulaires, en premier lieu la preproinsuline (PPI). Hypotheses : 1) le transfert physiologique des IgG maternels envers la progeniture pourrait permettre l’introduction de la PPI a l’aide d’un fragment Fc d’Ig ; 2) cette introduction precoce pourrait « eduquer » le systeme immunitaire par le developpement d’une tolerance a la PPI et, de ce fait, proteger du DT1. Materiels et methodes Nous avons introduit une proteine PPI-Fc dans la progeniture des souris G9C8 Cα-/- NOD, qui sont transgeniques pour un recepteur des cellules T reconnaissant la PPI. Ce traitement est fait : 1) par l’intermediaire des meres gestantes, injectees en i.v. ; et/ou 2) par gavage des nouveaux-ne. Resultats La PPI-Fc se lie au recepteur Fc neonatal (FcRn) exprime a la surface des syncytiotrophoblastes placentaires et/ou de l’epithelium digestif. La portion Fc est essentielle pour le transfert, car la PPI seule n’est pas transferee. La PPI-Fc se concentre selectivement chez les fœtus et les nouveaux-ne, notamment dans le thymus et la rate principalement par l’intermediaire des cellules dendritiques. Une seule injection de 100 μg de la PPI-Fc montre deja une protection significative sur la survenue du DT1 chez les souriceaux. Conclusion L’ajout du fragment Fc permet le transfert de la PPI des meres a leur progeniture et induit une protection efficace du DT1 a de moindres doses. Compte tenu du fait que le FcRn est exprime chez l’homme jusqu’a l’âge adulte, le traitement par voie orale pourrait etre facilement adopte en essai clinique.

Background We recently demonstrated that intradermal (ID) injection with electroporation (EP) of a new HIV DNA vaccine (auxo-GTU®MultiHIV) induced particularly strong and very long lasting specific T-cell responses (1044 ± 400 SFC per million PBMCs 3 years after vaccination) in macaques. Therefore we get interested to characterize the localization and expression of the auxo-GTU®MultiHIV vaccine as well as local involvement of immune cells at the sites of injection and in draining lymph nodes (LN).

Background Langerhans cells (LC), skin residential cells, are shown to induce specific CD8+ T cell response upon activation. Targeting vaccine antigens to LC with specific antibodies could elucidate specific CD8+ response. Therefore we propose the intra-dermal injection of mAb specific for C-type lectin Langerin, expressed on LC in epidermis, fused to HIV Gag p24 protein, as type of T-cell based vaccine. The present work emphasizes molecular and cellular immune mechanisms triggered in the skin by intra-dermal vaccination.

Mallone et al. use peptidomics and transcriptomics to identify the epitopes presented by β cells that trigger type 1 diabetes (T1D) autoimmunity. Multiple pathways, including conventional processing and mRNA and peptide splicing, are involved in epitope generation and presentation; these epitopes are selectively recognized by pancreas-infiltrating CD8+ T lymphocytes in T1D patients., SCOPUS: ar.j, info:eu-repo/semantics/published