Antiviral immunity, Biotherapy and Vaccines  - INSERM U668  


  HEADDr. GOUGEON Marie-Lise / mlgougeo@pasteur.fr
  MEMBERSBRANDT Maryse / Dr. BRISTEAU-LEPRINCE Anne / LEMERCIER Brigitte, LIM Annick / MELKI Marie-Thérèse / Dr. POIRIER Béatrice / Dr. PONCET Pascal / Dr. SAIDI Héla


  Annual Report

Our research unit is involved in basic immunology, studying innate and adaptive immune responses specific for viruses and tumor cells in human hosts. Moreover, we are deeply involved in clinical immunology participating to phase I/II vaccine and immunotherapy trials. Some of them evaluate new vaccine candidates, developed by research teams in Pasteur Institute against malaria, shigellosis, anthrax or cancer.

Apoptosis as a viral strategy to escape immune attack

We discovered that HIV is inducing in vivo inappropriate programmed cell death (apoptosis) in non-infected lymphocytes from the host, thus impairing both T cell homeostasis and HIV-specific T cell immunity, leading to AIDS (Reviewed in ML Gougeon, Nature Rev Immunol, 2003, 3:392-405). We demonstrated the important role of death receptors, including Fas and TNF-Rs, and of the co-receptor CXCR4 in HIV-dependent triggering of cell death. In patients, we found that several mechanisms of CD4/CXCR4-induced cell death were operative, including caspase-independent death. This last year we investigated the HIV strategies involved in the destruction of dendritic cells.

Impact of NK-DC cross-talk on maturation and death of infected DC

DC are qualitatively and quantitatively altered during HIV infection. We have addressed the question of the impact of the cross-talk with NK cells on these alterations. We showed that NK cells facilitate both HIV transmission by DC, and virus persistence in infected DC, contributing to the constitution of reservoirs.

iNKR expression by virus-specific CTL impairs the control of viral replication

CD8+ T-cells with cytotoxic (CTL) activity play a pivotal role in controlling viral infections. However, in most patients chronically infected with HIV, the CTL response is inefficient in the control of viral replication. We discovered that HIV-specific CTLs express MHC class-I specific inhibitory receptors, normally expressed on NK cells (iNKRs), which inhibit their activation and functions in response to HIV peptides. The expression of iNKRs is driven by HIV viral load and contributes to the impairment of CTL functions .

Molecular characterization of TCR repertoire diversity. Implementation in clinical studies

Immunoscope technology is a RT-PCR based approach that allows both to estimate the human aß TCR diversity with V(J)C primers, and to target specific clonotypes in a complex population. With this approach, we provided new insights into the repertoire diversity of regulatory T cells, the positive impact of anti-CD20 therapy on autoimmune diseases, and the identification of autoimmune clones.

An Immunomonitoring laboratory for the evaluation of immunity in vaccine and clinical trials.

We have settled a number of high-tech methods to measure parameters of specific immunity induced in vivo by vaccine candidates or immunotherapy. Among several trials, we have tested in 2007 a new vaccine candidate against Shigellosis in healthy volunteers.

Keywords: adaptive immunity, apoptosis, NK cells, dendritic cells, HIV, AIDS, autoimmunity, TCR repertoire, immunomonitoring



  Publications

Gougeon ML. 2003. Apoptosis as an HIV strategy to escape immune attack.Nature Rev. Immunol 3 :392-405 (PMID : 12766761)

Vignard V, Lemercier B, Lim A, Pandolfino MC, Guilloux Y, Khammari A, Rabu C, Echasserieau K, Lang F, Gougeon ML, Dreno B, Jotereau F, Labarriere N. 2005. Adoptive transfer of tumor-reactive Melan-A-specific CTL clones in melanoma patients is followed by increased frequencies of additional Melan-A-specific T cells. J Immunol. 2005 175(7):4797-805 (PMID 16177129)

Fazilleau N, Delarasse C, Motta I, Fillatreau S, Gougeon ML, Kourilsky P, Pham-Dinh D, Kanellopoulos JM. 2007. T cell repertoire diversity is required for relapses in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J Immunol 178(8):4865-75 (PMID: 17404267) Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D, Jacquot S, Gougeon ML, Bedane C, Muller R, Dreno B, Doutre MS, Delaporte E, Pauwels C, Franck N, Caux F, Picard C, Tancrede-Bohin E, Bernard P, Tron F, Hertl M, Musette P. 2007. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 357(6):545-52 (PMID 17687130)

Fazilleau N, Bachelez H, Gougeon ML, Viguier M. 2007. Cutting edge: size and diversity of CD4+CD25high Foxp3+ regulatory T cell repertoire in humans: evidence for similarities and partial overlapping with CD4+CD25- T cells. J Immunol 179(6):3412-6 (PMID: 17785774)





Activity Reports 2007 - Institut Pasteur
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