|Director : LEMONNIER François (firstname.lastname@example.org)|
The work of the laboratory aims, using different approaches, especially the production of genetically modified strains of mice (knock-out mice lacking selectively or globally H-2 class I or class II molecules, HLA class I or class II transgenic mice) at a) the analysis of the mechanisms involved in the education, the peripheral mobilization and the long term maintenance of cytolytic CD8+ and helper CD4+ T lymphocytes, b) the identification of viral or tumoral peptides presented to cytolytic and helper T lymphocytes, c) the evaluation and optimization of their vaccine potential and d) finally, the evaluation of the auto agressive potential.
Introduction of cytolytic T lymphocytes recognizing a HLA class Ib molecule deprived of bound peptide (P. Rohrlich, H. Firat)
Immunizing mice expressing a single type of HLA class I molecule (HLA-A0201), with transfected cells expressing also a single species of HLA class Ib molecule (the human HFE molecule implicated in the control of iron metabolism), CD8+, TcRaß+ cytolytic T lymphocytes recognizing specifically HFE through their T cell receptor for the antigen, were induced despite the fact that HFE molecules, as documented crystographically, are totally deprived of bound peptide.
Cytolytic T cell responses against leukemic cells (H. Firat, P. Langlade-Demoyen)
The junctional sequences corresponding to the 12-21 translocation (acute lymphoblastic leukemia) and the Philadelphia translocation (myeloblastic leukemia) give rise to neo antigenic peptides which can be presented to CD8+ cytolytic T cells by some HLA class I molecules and can induce in patients leukemia cell specific cytolytic responses.Using HLA-class I transgenic, H-2 class I KO mice, strategies susceptible to induce potent leukemic cell specific cytolytic responses were comparatively evaluated.
Vaccine potential of HLA-A0201- and HLA-B702-restricted epitopic peptides of viral or human tumor origin (P. Langlade-Demoyen, S. Cardinaud, P. Rohrlich)
The vaccine potential of HIV 1, CMV and human tumor-derived epitopic peptides reported in the literature as efficiently presented by either HLA-A0201 or HLA-B0702 molecules have been compared using transgenic mice expressing HLA-A0201 molecules in the complete absence of H-2 class I molecules or the HLA-B0702 molecules in a H-2Kb, H-2Db double KO context. Following these studies, it was possible to establish a hierarchy in terms of immunogenicity of these peptides, to optimize the immunogenicity of those which were poorly immunogenic in their native configuration, to compare vaccine strategies and to demonstrate that a polyepitope construct could induce multiepitopic, long-lasting cytolytic responses in a single mouse. The studies currently performed have resulted in the identification of new epitopic peptides in the viral proteins (TAT, REV, VPU, VPR) expressed in the early phase of the HIV 1 replication cycle. These studies should result in the construction of a polyallelic (HLA-A02.01, HLA-B07.02) polyepitope construct of inter est for 60% of the individuals of the different human populations.
Creation of new HLA-class I transgenic, H-2 class I KO and HLA class II transgenic, H-2 class II KO mice (A. Pajot, Y.C. Lone)
Monochain constructs (by covalent linkage of human ß2-microglobulin to the first domain of HLA class I heavy chain) have been realized for the HLA-A*01.03, -A*03.01, -A*24.02, HLA-B*08.01, -B*27.05, -B*35.01, -B*44.02, HLA-Cw*07.01, -Cw*07.02 genes. The functionality of these constructs has been checked by transfection of cells and they are currently introduced in mouse oocytes to create the corresponding transgenic strains.
Constructions coding for the HLA class II DPß401, DPa103 have been realized to derive HLA class II transgenic, H-2 class II KO mice in order to identify HIV 1-derived epitopic peptides presented by these DP molecules which are expressed by approximately 60% of individuals in human populations.
|Publications of the unit on Pasteur's references database|
|Office staff||Researchers||Scientific trainees||Other personnel|
SAUZET Nicole, IP
LEMONNIER François, DR1 INSERM, Head of Unit IP
LANGLADE-DEMOYEN Pierre, IP
LONE Yu Chun , CNRS
CARDINAUD Sylvain, student
FIRAT Hüseyin, PhD
MATTEI Stefano, post-doctoral fellow
PAJOT Anthony, student
ROHRLICH Pierre, PhD
GARCIA-PONS François, IP