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ABSTRACT: The protective host immune response to viral infections requires both effective innate and adaptive immune responses. Cross-talk between the two responses is coordinated by the chemokine network and professional APCs such as dendritic cells (DCs). In mice, subpopulations of myeloid DCs in peripheral tissues such as lungs and in blood express CX3CR1 depending on the inflammation state. We thus examined the host response of mice deficient in the chemokine receptor CX3CR1 to an intranasal vaccinia virus infection. CX3CR1-deficient mice displayed significantly more severe morbidity and mortality compared with control wild-type mice within 10 d following vaccinia virus infection. CX3CR1(-/-) mice had increased viral loads and a reduced T cell response compared with wild-type mice. Finally, an adoptive transfer of CX3CR1(+/+) DCs completely protected CX3CR1(-/-) mice to a previously lethal infection. This study therefore opens up the possibility of novel antiviral therapeutics targeting lung DC recruitment.
The Journal of Immunology 01/2012; 188(3):952-6. · 5.79 Impact Factor
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ABSTRACT: Skin routes of immunization such as subcutaneous (SC), intradermal (ID) and transcutaneous (TC) administration are utilized for vaccination against various pathogens, without understanding their potential impact on the outcome of immune responses. We demonstrated that SC immunization induced HIV-1 p24 specific IgG in absence of antigen-specific CD8 T cells, whereas the ID route induced both cellular and humoral responses. Interestingly, TC application through empty hair follicular ducts, targeting epidermal Langerhans Cells (LCs), induced major CD8 effector cells, in the absence of IgG. However, high levels of mucosal IgA, were localized in the stratified epithelium of the vagina after TC prime. We propose that re-directing the immune responses by targeting differential skin immunization routes, offers enormous potential for innovative vaccination strategies, especially against HIV.
Vaccine 05/2011; 29(37):6379-91. · 3.77 Impact Factor
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Clément Cochain,
Mathieu P Rodero,
José Vilar,
Alice Récalde,
Adèle L Richart,
Céline Loinard,
Yasmine Zouggari,
Coralie Guérin,
Micheline Duriez, Behazine Combadière,
Lucie Poupel,
Bernard I Lévy,
Ziad Mallat,
Christophe Combadière,
Jean-Sébastien Silvestre
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ABSTRACT: Monocyte systemic levels are known to be a major determinant of ischaemic tissue revascularization, but the mechanisms mediating mobilization of different monocyte subsets-Ly6C(hi) and Ly6C(lo)-to the blood and their respective role in post-ischaemic neovascularization are not clearly understood. Here, we hypothesized that distinct chemokine/chemokine receptor pathways, namely CCL2/CCR2, CX3CL1/CX3CR1, and CCL5/CCR5, differentially control monocyte subset systemic levels, and might thus impact post-ischaemic vessel growth.
In a model of murine hindlimb ischaemia, both Ly6C(hi) and Ly6C(lo) monocyte circulating levels were increased after femoral artery ligation. CCL2/CCR2 activation enhanced blood Ly6C(hi) and Ly6C(lo) monocyte counts, although the opposite effect was seen in mice with CCL2 or CCR2 deficiency. CX3CL1/CX3CR1 strongly impacted Ly6C(lo) monocyte levels, whereas CCL5/CCR5 had no role. Only CCL2/CCR2 signalling influenced neovascularization, which was increased in mice overexpressing CCL2, whereas it markedly decreased in CCL2-/- mice. Moreover, adoptive transfer of Ly6C(hi)-but not Ly6C(lo)-monocytes enhanced vessel growth and blood flow recovery.
Altogether, our data demonstrate that regulation of proangiogenic Ly6C(hi) monocytes systemic levels by CCL2/CCR2 controls post-ischaemic vessel growth, whereas Ly6C(lo) monocytes have no major role in this setting.
Cardiovascular research 10/2010; 88(1):186-95. · 5.80 Impact Factor
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ABSTRACT: Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-gamma+TNF-alpha+ or IFN-gamma+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination.
The Journal of clinical investigation 04/2010; 120(5):1636-44. · 15.39 Impact Factor
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Behazine Combadière,
Annika Vogt,
Brice Mahé,
Dominique Costagliola,
Sabrina Hadam,
Olivia Bonduelle,
Wolfram Sterry,
Shlomo Staszewski,
Hans Schaefer,
Sylvie van der Werf,
Christine Katlama,
Brigitte Autran,
Ulrike Blume-Peytavi
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ABSTRACT: Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses.
We chose the inactivated influenza vaccine - a conventional licensed tetanus/influenza (TETAGRIP) vaccine - to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination.
This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role.
Clinicaltrials.gov NCT00261001.
PLoS ONE 01/2010; 5(5):e10818. · 4.09 Impact Factor
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ABSTRACT: Chemokine receptors are promising targets for enhancing T-cell immunity and anti-cancer therapy. CCL5 is a potential adjuvant for DNA vaccination. We postulated that CCR5 superagonists could be even more effective. A CCR5 superagonist derived from natural CCL5 by directed in vitro evolution, namely 1P7, is used as a DNA vaccine adjuvant and expressed as fused chemokine-Ig (1P7-Ig). We show that OVA+1P7-Ig DNA co-inoculation induced higher frequencies of OVA-specific CD8 lymphocytes than OVA+CCL5-Ig or controls and gave an even better protection against tumor growth in a CCR5-dependant manner. Our results indicate that CCR5-superagonists may provide potent adjuvants for vaccines.
Vaccine 07/2008; 26(26):3252-60. · 3.77 Impact Factor
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ABSTRACT: Immunization concepts evolve with increasing knowledge of how the immune system works and the development of new vaccination methods. Traditional vaccines are made of live, attenuated, killed or fragmented pathogens. New vaccine strategies can take advantage of particulate compounds--microspheres or nanoparticles--to target antigen-presenting cells better, which must subsequently reach the secondary lymphoid organs, which are the sites of the immune response. The use of the skin as a target organ for vaccine delivery stems from the fact that immature dendritic cells (DCs), which are professional antigen-presenting cells can be found at high density in the epidermis and dermis of human or animal skin. This has led to design various methods of dermal or transcutaneous vaccination. The quality and duration of the humoral and cellular responses to vaccination depend on the appropriate targeting of antigen-presenting cells, of the vaccine dose, route of administration and use of adjuvant. In this review, we will focus on the use of micro- and nano-particles to target the skin antigen-presenting cells and will discuss recent advances in the field of transcutaneous vaccination in animal models and humans.
Comparative Immunology Microbiology and Infectious Diseases 04/2008; 31(2-3):293-315. · 2.34 Impact Factor
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ABSTRACT: Upon antigenic stimulation, establishment of adaptive immune responses that determines vaccine efficacy is dependent on efficient T cell priming. Here, single CX3CL1-Ig DNA administration, a unique ligand of CX3CR1, together with viral or tumor antigens induced a strong in vivo antigen-specific T cell proliferation and effector function that was enough efficient to protect against a tumor challenge. We also showed that early expression of CX3CL1-Ig and antigens in muscle and lymphoid organs induces an increased in vivo migration of myeloid CD14+CD11c+ DC but not lymphoid CD8alpha+CD11c+ DC at these sites. Thus, by effectively directing DC toward lymphoid organs to encounter T cells, CX3CL1-Ig become a new candidate that augments T cell priming and increases efficiency of vaccination.
Vaccine 07/2007; 25(23):4554-63. · 3.77 Impact Factor
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ABSTRACT: CX3CR1 has been described previously as a marker of human cytotoxic effector cells. We evaluated the possibility of using its ligand, CX3CL1, to redirect immune response against tumors. When murine lymphoma cell lines (EL4 and its derivative EG7) stably transfected with human-CX3CL1 were injected s.c. into C57BL/6 mice, the tumor growth was severely impaired when compared with the growth of control cell lines. This antitumor effect of CX3CL1 was also found in T- and B-cell-deficient Rag1-/- mice but vanished in natural killer (NK) cell-deficient beige mice and in CX3CR1-/- mice, suggesting the involvement of CX3CR1-expressing NK cells. In addition, increased NK cell infiltration was observed in CX3CL1-producing tumors compared with controls. The effect of CX3CR1 on tumor growth required host cytotoxic effector cell functions because both IFNgamma-/- and perforin-/- mice were resistant to CX3CL1 antitumor effect. Finally, intratumoral injection of DNA plasmid coding for a chimeric immunoglobulin presenting the CX3CL1 chemokine domain provided strong antitumor activity. Together, these data demonstrate that the CX3CL1 can reduce incidence and size of lymphoma in vivo through increased recruitment of activated NK cytotoxic cells. These findings offer the first evidence of the potential of chimeric immunoglobulin-chemokines in anticancer therapy.
Cancer Research 12/2003; 63(21):7468-74. · 7.86 Impact Factor
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ABSTRACT: The involvement of Fas and caspase activation during naive T cell proliferation is still controversial. To explore this paradox, we used antigenic variation of PCC 88-104 peptide to dissect pathways of TCR signaling leading to cell proliferation. We demonstrated that strong TCR stimulation but not weak TCR stimulation induced T cell proliferation and was dependent on IETD- but independent of DEVD-specific caspases. In addition, altered TCR ligand induced T cell proliferation in the absence of IETD-, DEVD-specific caspase activities and Fas ligand expression. However, AND-TCR-transgenic mice in lpr/lpr background generated recently have no defect T cell proliferation after stimulation by the agonist peptide, demonstrating that antigen-induced T cell proliferation is independent of Fas-activation pathways. Thus, Fas-independent caspase activation is tightly regulated by the strength of antigenic stimulation during T cell proliferation. These data reveal a novel facet of antigenic caspase regulation during naive CD4 T cell proliferation and provide insights into the function of caspases during T cell homeostasis.
European Journal of Immunology 11/2002; 32(10):3007-15. · 5.10 Impact Factor
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ABSTRACT: Degeneracy of the TCR repertoire might allow for cross-recognition of epitope variants. However, it is unclear how the first encounter with HIV Ags determines recognition of emerging epitope variants. This question remains crucial in the choice of HIV vaccine sequences given the virus variability. In this study, we individualized nine natural mutations within an HIV-Nef(180-189) epitope selected from several HIV-infected individuals. These variants of Nef(180-189) sequence display slightly different HLA-A2 binding capacities and stabilities and we have shown that only two induced a strong CTL response in vivo in HLA-A2 transgenic mice after a single injection. We demonstrated that priming with these two immunogenic variants generated a specific pattern of cross-reactive CTL repertoire directed against poorly immunogenic peptides. Thus, the range of peptide variants recognized by HIV-specific CTL depends upon the Ag encountered during primary immunization of CD8 lymphocytes. These data have practical implications in the development of cross-reactive vaccines against HIV.
The Journal of Immunology 11/2002; 169(7):3694-9. · 5.79 Impact Factor
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ABSTRACT: Although the risk of smallpox virus being used as a terrorist weapon is very low, it is mandatory to examine potential vaccination strategies, and also the residual immunization rate in the general population. During revaccination of a national intervention team, the residual immunity of 184 volunteers was determined by assaying T memory cells in the gamma interferon ELISpot test, and central T memory cell responses in a proliferation assay. Three-quarters of the subjects had a proliferative response. This response was lower after the age of 55 years but could be reactivated by revaccination.
Bulletin de l'Académie nationale de médecine 190(4-5):1035-46; discussion 1046-9. · 0.25 Impact Factor
