TLR9 activation is required for cytotoxic response elicited by baculovirus capsid display.

Although the baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) infects lepidopteran invertebrates as natural hosts, represents an efficient vector for vaccine development. Baculovirus surface display induces strong humoral responses against viruses and parasites. A novel strategy based on capsid display carrying foreign antigens in the AcMNPV particle further improved the immune response by eliciting CD8+ T cell activation. In this study, we analyze the intracellular mechanisms and signalling pathways involved in CD8+ T cell activation by capsid display. Our results show that baculovirus can attach to the cell surface, enter dendritic cells (DCs), transit within endocytic vesicles and escape to the cytosol for further degradation by the proteasome. We found that the availability of viral proteins, endosomal acidification, and proteasome activity are needed for efficient Major Histocompatibility Complex class-I presentation by baculovirus carrying Ovalbumin in the viral capsid. Importantly, we demonstrated with this strategy that the induction of cytotoxic T cells and IL-12 production by DCs are TLR9-dependent and STING-independent. Finally, our study shows differential intracellular processing for capsid and surface baculovirus proteins in DCs and highlights the role of different danger receptors during cytotoxic T cell priming through the capsid display delivery system, which could lead to improved baculovirus-based vaccines development.

IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8+ T-cell responses.

Antitumor immunity is mediated by Th1 CD4+ and CD8+ T lymphocytes, which induce tumor-specific cytolysis, whereas Th17 CD4+ T cells have been described to promote tumor growth. Here, we explored the influence of IL-17 on the ability of therapeutic vaccines to induce the rejection of tumors in mice using several adjuvants known to elicit either Th1 or Th17-type immunity. Immunization of mice with Th1-adjuvanted vaccine induced high levels of IFN-γ-producing T cells, whereas injection with Th17-promoting adjuvants triggered the stimulation of both IL-17 and IFN-γ-producing T cells. However, despite their capacity to induce strong Th1 responses, these Th17-promoting adjuvants failed to induce the eradication of tumors. In addition, the systemic administration of IL-17A strongly decreases the therapeutic effect of Th1-adjuvanted vaccines in two different tumor models. This suppressive effect correlated with the capacity of systemically delivered IL-17A to inhibit the induction of CD8+ T-cell responses. The suppressive effect of IL-17A on the induction of CD8+ T-cell responses was abolished in mice depleted of neutrophils, clearly demonstrating the role played by these cells in the inhibitory effect of IL-17A in the induction of antitumor responses. These results demonstrate that even though strong Th1-type responses favor tumor control, the simultaneous activation of Th17 cells may redirect or curtail tumor-specific immunity through a mechanism involving neutrophils. This study establishes that IL-17 plays a detrimental role in the development of an effective antitumor T cell response and thus could strongly affect the efficiency of immunotherapy through the inhibition of CTL responses.

The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients.

Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830-844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA-DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.

Persistence of Integrase-Deficient Lentiviral Vectors Correlates with the Induction of STING-Independent CD8+ T Cell Responses.

Lentiviruses are among the most promising viral vectors for in vivo gene delivery. To overcome the risk of insertional mutagenesis, integrase-deficient lentiviral vectors (IDLVs) have been developed. We show here that strong and persistent specific cytotoxic T cell (CTL) responses are induced by IDLVs, which persist several months after a single injection. These responses were associated with the induction of mild and transient maturation of dendritic cells (DCs) and with the production of low levels of inflammatory cytokines and chemokines. They were independent of the IFN-I, TLR/MyD88, interferon regulatory factor (IRF), retinoic acid induced gene I (RIG-I), and stimulator of interferon genes (STING) pathways but require NF-κB signaling in CD11c+ DCs. Despite the lack of integration of IDLVs, the transgene persists for 3 months in the spleen and liver of IDLV-injected mice. These results demonstrate that the capacity of IDLVs to trigger persistent adaptive responses is mediated by a weak and transient innate response, along with the persistence of the vector in tissues.

Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses.

We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a ß-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323-339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.

Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells.

Cross-presentation allows exogenous antigen presentation in association with major histocompatibility complex class I molecules, a process crucial for the priming of CD8+ T-cell responses against viruses and tumors. By contrast to conventional dendritic cells (cDC), which cross-present antigens in the steady state, plasmacytoid dendritic cells (pDC) acquire this ability only after stimulation by Toll-like receptor (TLR) ligands. The intracellular pathways accounting for this functional difference are still unknown. Here we show that the induction of cross-presentation by pDCs is regulated by mitochondria through a reactive oxygen species (ROS)-dependent mechanism, involving pH alkalization and antigen protection. The reduction of mitochondrial ROS production dramatically decreases the cross-presentation capacity of pDCs, leading to a strong reduction of their capacity to trigger CD8+ T-cell responses. Our results demonstrate the importance of mitochondrial metabolism in pDC biology, particularly for the induction of adaptive immune responses.

Tumor-Derived TGFß Alters the Ability of Plasmacytoid Dendritic Cells to Respond to Innate Immune Signaling.

A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDCs generally correlates with a poor prognosis, suggesting that pDCs may play an important role in the host-tumor relationship. Here, we analyze the influence of pDCs in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDCs showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDCs to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGFß is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that natural killer (NK) cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the cross-talk among pDCs, NK, and regulatory T cells in the promotion of tumor growth and their role in the development of antitumor immune responses.Significance: These findings highlight the importance of pDCs in the cross-talk between tumor cells and the immune system. Cancer Res; 78(11); 3014-26. ©2018 AACR.

Lack of MHC class II molecules favors CD8+ T-cell infiltration into tumors associated with an increased control of tumor growth.

Regulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as for preventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. In the TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstrated that the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declines with tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, we demonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression of immunosuppressive molecules. Both intratumoral effector CD4+ T-cells (Teffs) and Tregs expressed high levels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restore the therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited to the tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4+ effector T-cells. We demonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which were recruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with a strong increase in the intratumoral recruitment of CD8+ T-cells. In addition, in mice that spontaneously rejected their tumors, the infiltration of E7-specific CD8+ T-cells was significantly higher than in MHC-II KO mice with a growing tumor. These results demonstrate that tumor-specific CD8+ T-cells can be efficiently activated and recruited in the absence of MHC class II molecules and of CD4+ T-cell help.

Symptom fluctuations, self-esteem, and cohesion during group cognitive behaviour therapy for early psychosis.

Group cohesion has been linked to positive changes in self-esteem and in symptoms during group psychotherapy in people with psychosis. These changes may be linked to changes in symptoms as fluctuations in self-esteem have been linked to symptom fluctuations. OBJECTIVE: We aimed to determine the relationship between these three factors - group cohesion, self-esteem, and symptoms - during group cognitive behaviour therapy for psychosis (GCBTp). We hypothesized that group cohesion would precede changes in symptoms and self-esteem and that improvements in self-esteem would precede improvements in symptoms. DESIGN: This is an uncontrolled longitudinal study recruiting from a convenience sample within two early psychosis clinics. METHODS: Sixty-six individuals from first episode of psychosis treatment programmes participated in this study and received 24 sessions of a validated GCBTp protocol. Participants answered a brief questionnaire at the end of each session, measuring their group cohesion, self-esteem, and perception of their symptoms as worse, same, or better than usual. RESULTS: Orthogonal polynomial contrasts for time effects were estimated with a mixed model for repeated measures with a random cluster effect and revealed a quartic trend regarding changes in symptoms over the 24 sessions. Self-esteem, symptoms, and group cohesion were strongly linked during a given session. Also, self-esteem changes predicted changes in symptoms up to two sessions later, and symptoms changes predicted self-esteem changes at the next session. Group cohesion preceded improvements in both self-esteem and symptoms; self-esteem also predicted improvements in group cohesion. CONCLUSION: These results suggest that self-esteem and symptoms influence each other during therapy, with improvements in one leading to improvements in the other. Group cohesion also appears to be an essential prerequisite to positive changes in self-esteem and symptoms during GCBTp. PRACTITIONER POINTS: This study emphasizes the interrelation between self-esteem improvements and symptom improvements, with improvements in one leading to improvements in the other, during group CBT for psychosis. Group cohesion, in this study, is a predictor of self-esteem and symptom improvements, suggesting that a special attention should be given to developing a strong alliance and group cohesion early on during CBT for psychosis.

Feasibility and Accessibility of a Tailored Intervention for Informal Caregivers of People with Severe Psychiatric Disorders: a Pilot Study.

OBJECTIVES: This study aimed to assess the acceptability and feasibility of a new tailored intervention for informal caregivers: the Ensemble (Together) program. METHODS: An open pre-post within-subject comparison pilot study was conducted. Twenty-one informal caregivers completed the five-session Ensemble program. Two measurement tools were used: The Brief Symptom Inventory (BSI) and the Life Orientation Scale (LOT-R). RESULTS: The results showed that informal caregivers were in need of individual support and were ready to participate in the Ensemble program independent of the patient's diagnosis or stage of illness. The participants were very satisfied, and 95.4% completed the program. The preliminary results also showed that in five sessions, informal caregivers' Global Severity Index measured by the BSI and their optimism about their future (measured by the LOT-R) were significantly improved. CONCLUSION: This pilot study provided preliminary results concerning the feasibility and acceptability of the tailored Ensemble program and indicates the need for a randomized trial. The Ensemble program is appropriate for both the acute and chronic phases of disease. Individualized brief and useful interventions for informal caregivers may provide more positive outcomes in care.

Corrigendum: A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies.

[This corrects the article on p. 641 in vol. 7, PMID: 28082980.].

Large-scale synthesis and structural analysis of a synthetic glycopeptide dendrimer as an anti-cancer vaccine candidate.

Herein, we report a new process that enables the gram-scale production of a fully synthetic anti-cancer vaccine for human use. This therapeutic vaccine candidate, named MAG-Tn3, is a high-molecular-weight tetrameric glycopeptide encompassing carbohydrate tumor-associated Tn antigen clusters and peptidic CD4+ T-cell epitopes. The synthetic process involves (i) the stepwise solid-phase assembly of protected amino acids, including the high value-added Tn building blocks with only 1.5 equivalents, (ii) a single isolated intermediate, and (iii) the simultaneous deprotection of 36 hindered protective groups. The resulting MAG-Tn3 was unambiguously characterized using a combination of techniques, including a structural analysis by nuclear magnetic resonance spectroscopy. The four peptidic chains are flexible in solution, with a more constrained but extended conformation at the Tn3 antigen motif. Finally, we demonstrate that, when injected into HLA-DR1-expressing transgenic mice, this vaccine induces Tn-specific antibodies that mediate the killing of human Tn-positive tumor cells. These studies led to a clinical batch of the MAG-Tn3, currently investigated in breast cancer patients (phase I clinical trial). The current study demonstrates the feasibility of the multigram-scale synthesis of a highly pure complex glycopeptide, and it opens new avenues for the use of synthetic glycopeptides as drugs in humans.

CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host-pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Δppe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Δppe25-pe19 vaccine candidate. We provide evidence that the Mtb Δppe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Δppe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens.

B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer.

Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient µMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in µMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines.

The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity.

Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.

A Universal Influenza Vaccine Can Lead to Disease Exacerbation or Viral Control Depending on Delivery Strategies.

The development of influenza A virus (IAV) vaccines, which elicits cross-strain immunity against seasonal and pandemic viruses is a major public health goal. As pigs are susceptible to human, avian, and swine-adapted IAV, they would be key targets of so called universal IAV vaccines, for reducing both the zoonotic risk and the economic burden in the swine industry. They also are relevant preclinical models. However, vaccination with conserved IAV antigens (AGs) in pigs was reported to elicit disease exacerbation. In this study, we assessed whether delivery strategies, i.e., dendritic cell (DC) targeting by the intradermal (ID) or intramuscular (IM) routes, impact on the outcome of the vaccination with three conserved IAV AGs (M2e, NP, and HA2) in pigs. The AGs were addressed to CD11c by non-covalent binding to biotinylated anti-CD11c monoclonal antibody. The CD11c-targeted AGs given by the ID route exacerbated disease. Conversely, CD11c-targeted NP injected by the IM route promoted T cell response compared to non-targeted NP. Furthermore, the conserved IAV AGs injected by the IM route, independently of DC targeting, induced both a reduction of viral shedding and a broader IgG response as compared to the ID route. Our findings highlight in a relevant animal species that the route of vaccine delivery impacts on the protection induced by conserved IAV AGs and on vaccine adverse effects. Finally, our results indicate that HA2 stands as the most promising conserved IAV AG for universal vaccine development.

The Quest for Anticancer Vaccines: Deciphering the Fine-Epitope Specificity of Cancer-Related Monoclonal Antibodies by Combining Microarray Screening and Saturation Transfer Difference NMR.

The identification of MUC1 tumor-associated Tn antigen (αGalpNAc1-O-Ser/Thr) has boosted the development of anticancer vaccines. Combining microarrays and saturation transfer difference NMR, we have characterized the fine-epitope mapping of a MUC1 chemical library (naked and Tn-glycosylated) toward two families of cancer-related monoclonal antibodies (anti-MUC1 and anti-Tn mAbs). Anti-MUC1 mAbs clone VU-3C6 and VU-11E2 recognize naked MUC1-derived peptides and bind GalNAc in a peptide-sequence-dependent manner. In contrast, anti-Tn mAbs clone 8D4 and 14D6 mostly recognize the GalNAc and do not bind naked MUC1-derived peptides. These anti-Tn mAbs show a clear preference for glycopeptides containing the Tn-Ser antigen rather than the Tn-Thr analogue, stressing the role of the underlying amino acid (serine or threonine) in the binding process. The reported strategy can be employed, in general, to unveil the key minimal structural features that modulate antigen-antibody recognition, with particular relevance for the development of Tn-MUC1-based anticancer vaccines.

Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication.

The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines.

Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells.

BACKGROUND: Early life is characterized by a high susceptibility to infection and a TH2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for TH1 activation, but their translation to the field of pediatric vaccines is facing the impairment of neonatal innate TLR responses. OBJECTIVE: We sought to analyze C-type lectin receptor pathways as an alternative or a coactivator to TLRs for neonatal dendritic cell activation for TH1 polarization. METHODS: Neonatal monocyte-derived dendritic cells (moDCs) were exposed to various combinations of TLR agonists with or without Dectin-1 agonist. IL-12 and IL-23 responses were analyzed at the transcriptional and protein levels after stimulation. The intracellular pathways triggered by combined TLR plus Dectin-1 stimulation was determined by using pharmacologic inhibitors. The capacity of neonatal moDCs to differentiate naive CD4 TH cells was evaluated in cocultures with heterologous neonatal naive T cells. Curdlan was finally tested as an adjuvant within a subunit tuberculosis vaccine in neonatal mice. RESULTS: Simultaneous coactivation through Dectin-1 and TLRs induced robust secretion of IL-12p70 by neonatal moDCs by unlocking transcriptional control on the p35 subunit of IL-12. Both the spleen tyrosine kinase and Raf-1 pathways were involved in this process, allowing differentiation of neonatal naive T cells toward IFN-γ-producing TH1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce TH1 responses after vaccination of neonatal mice. CONCLUSION: Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and TH1 polarization of neonatal T cells. Dectin-1 agonists represent a promising TH1 adjuvant for pediatric vaccination.

Understanding process in group cognitive behaviour therapy for psychosis.

BACKGROUND: Group cognitive behaviour therapy for psychosis (GCBTp) has shown to be effective in diminishing symptoms, as well as in improving other psychosocial dimensions such as self-esteem. But little is known regarding the processes that generate these therapeutic improvements and might be harnessed to further improve its effectiveness. OBJECTIVES: The current study aimed at investigating these processes, particularly those linked to interpersonal relationships. DESIGN: The participants were all assessed at baseline, were given 24 sessions of GCBTp over the course of 3 months and were assessed again at post-treatment as well as 6 months later (9 months from baseline). METHOD: Sixty-six individuals with early psychosis took part in a study of GCBTp where therapist alliance and group cohesion were assessed at three time points during the therapy, and punctual (each session) self-perceptions on symptoms and optimism were collected. RESULTS: Improvements in symptoms (BPRS), self-esteem (SERS-SF) and in self-perceived therapeutic improvements (CHOICE) were linked to specific aspects of the alliance, group cohesion, as well as optimism. The variables retained were not always overall scores, suggesting the importance of the variables at key moments during the therapy. CONCLUSIONS: The results clearly demonstrate the importance of the alliance and group cohesion, together significantly explaining improvements measured at post-therapy or follow-up. PRACTITIONER POINTS: This study has attempted to focus mostly on relational aspects, as well as on self-perceptions, in the context of a GCBTp for individuals with early psychosis. This study also showed that these therapeutic relationships are especially useful when they are more stable and at specific moments during the therapy, namely when more difficult psychological work is done.