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Pinkhasov J.,Arizona State University | Alvarez M.L.,Arizona State University | Pathangey L.B.,Mayo Medical School | Tinder T.L.,Mayo Medical School | And 5 more authors.
Cancer Immunology, Immunotherapy | Year: 2010

Since epithelial mucin 1 (MUC1) is associated with several adenocarcinomas at the mucosal sites, it is pertinent to test the efficacy of a mucosally targeted vaccine formulation. The B subunit of the Vibrio cholerae cholera toxin (CTB) has great potential to act as a mucosal carrier for subunit vaccines. In the present study we evaluated whether a MUC1 tandem repeat (TR) peptide chemically linked to CTB would break self-antigen tolerance in the transgenic MUC1-tolerant mouse model (MUC1.Tg) through oral or parenteral immunizations. We report that oral immunization with the CTB-MUC1 conjugate along with mucosal adjuvant, unmethylated CpG oligodeoxynucleotide (ODN) and interleukin-12 (IL-12) did not break self-antigen tolerance in MUC1.Tg mice, but induced a strong humoral response in wild-type C57BL/6 mice. However, self-antigen tolerance in the MUC1.Tg mouse model was broken after parenteral immunizations with different doses of the CTB-MUC1 conjugate protein and with the adjuvant CpG ODN co-delivered with CTB-MUC1. Importantly, mice immunized systemically with CpG ODN alone and with CTB-MUC1 exhibited decreased tumor burden when challenged with a mammary gland tumor cell line that expresses human MUC1. © 2010 Springer-Verlag. Source

Monneret G.,Cellular Immunology Laboratory | Monneret G.,University of Lyon | Monneret G.,A+ Network | Venet F.,Cellular Immunology Laboratory | Venet F.,University of Lyon
Cytometry Part B - Clinical Cytometry | Year: 2016

Septic syndromes remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. While sepsis has, for long, been solely described as inducing a tremendous systemic inflammatory response, novel findings indicate that sepsis indeed initiates a more complex immunologic response that varies over time, with the concomitant occurrence of both pro- and anti-inflammatory mechanisms. As a resultant, after a short proinflammatory phase, septic patients enter a stage of protracted immunosuppression. This is illustrated in those patients by reactivation of dormant viruses (CMV or HSV) or infections due to pathogens, including fungi, which are normally pathogenic solely in immunocompromised hosts. Although mechanisms are not totally understood, these alterations might be directly responsible for worsening outcome in patients who survived initial resuscitation as nearly all immune functions are deeply compromised. Indeed, the magnitude and persistence over time of these dysfunctions have been associated with increased mortality and health-care associated infection rate. Consequently, new promising therapeutic avenues are currently emerging from those recent findings such as adjunctive immunostimulation (IFN-γ, GM-CSF, IL-7, anti-PD1/L1 antibodies) for the most immunosuppressed patients. Nevertheless, as there is no clinical sign of immune dysfunctions, the prerequisite for such therapeutic intervention relies on our capacity in identifying the patients who could benefit from immunostimulation. To date, the most robust biomarkers of sepsis-induced immunosuppression are measured by flow cytometry. Of them, the decreased expression of monocyte HLA-DR appears as a “gold standard.” This review reports on the mechanisms sustaining sepsis-induced immunosuppression and its related biomarkers measurable by flow cytometry. The objective is to integrate the most recent facts in an up-to-date account of clinical results, flow cytometry aspects as well as issues in results standardization for multicenter studies. © 2015 International Clinical Cytometry Society. © 2015 International Clinical Cytometry Society Source

Monneret G.,Cellular Immunology Laboratory | Venet F.,Cellular Immunology Laboratory
Expert Review of Anti-Infective Therapy | Year: 2010

Sepsis still constitutes a public health challenge worldwide since its incidence constantly increases over time but its related mortality remains more or less constant. There is thus an unquestionable and urgent need to develop innovative and efficacious therapies for the treatment of this deadly disease. In this study, the authors propose that injection of mesenchymal stem cells rescues mice from death after septic shock owing to their potent immunosuppressive and anti-inflammatory properties. The authors conclude that immunomodulatory cell therapy may represent an effective treatment for sepsis. While the potential therapeutic value of these cells is not to be challenged, considering the present lack of convincing data about mesenchymal stem cell use in sepsis, we do not believe that they constitute the next topical clinical trial in the field. Rather, recent evidence indicates that most septic patients actually present with profound immune alterations suggesting that anti-inflammatory approaches could deleteriously amplify this state. Therefore, in this article, we propose hypotheses explaining why the future of clinical trials in sepsis immunology will likely rely on stimulating immune functions for rebalancing immune homeostasis. © 2010 Expert Reviews Ltd. Source

Allantaz-Frager F.,bioMerieux | Turrel-Davin F.,bioMerieux | Venet F.,Cellular Immunology Laboratory | Monnin C.,bioMerieux | And 6 more authors.
PLoS ONE | Year: 2013

The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-γ). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic patients' blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-γ. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six new transcripts that could be used for the identification of septic patients eligible for IFNg therapy. Along with the previously identified markers TNFa, IL10 and HLA-DRA, the potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy. © 2013 Allantaz-Frager et al. Source

Papagno L.,University Pierre and Marie Curie | Papagno L.,French Institute of Health and Medical Research | Alter G.,Massachusetts Institute of Technology | Assoumou L.,University Pierre and Marie Curie | And 18 more authors.
AIDS | Year: 2011

Background: HIV-specific T-cell-based vaccines have been extensively studied in both prevention and therapeutic settings, with most studies failing to show benefit, and some suggesting harm. We previously performed a multicenter, double-blind, placebo-controlled phase II clinical trial in which 65 antiretroviral-treated patients were randomized to receive an HIV-1 recombinant canarypox vaccine (vCP1452) or placebo, followed by analytical treatment interruption. Patients exposed to vaccine had higher levels of viral replication and more rapid time to treatment resumption. OBJECTIVE:: In the present study we report the results from extensive immunological investigations to test whether the preferential expansion of HIV-specific CD4, rather than CD8 T cells, could account for these unexpected results. Methods: Polychromatic flow cytometry was used to characterize the functional and phenotypic profile of antigen-specific CD8 and CD4 T cells induced by the immunization. Results: We found a significant increase in HIV-specific CD4 T cells producing IFN-γ and IL-2 in the 4 injections arm compared to the placebo arm following vaccination. In contrast, no difference was observed following vaccination in the phenotype and functional capacity within the CD8 T-cell compartment. Neither HLA biases, nor immune hyper-activation, or Env-specific facilitating antibodies were associated with the enhanced virus rebound observed in vaccinees. Conclusion: Our data suggest that a vaccine-induced transient activation of HIV-specific CD4 but not CD8 T cells may have a detrimental effect on HIV outcomes. These findings may provide a mechanistic basis for higher rates of HIV acquisition or replication that have been associated with some T-cell vaccines. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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