Mye-EUNITER
 

Louvet, Cedric

Models available:

  • Tolerance induction by anti-CD28 antibodies after kidney allograft, in the rat LEW.1W to LEW.1A combination. We described that after selective costimulation blockade with antagonist anti-CD28 antibodies (1 week treatment), allografts are accepted long-term and that the mechanism of action involves upregulation of iNOS-producing monocytic myeloid-derived suppressor cells (MDSC; Dugast et al, J. Immunol. 2008).
  • Induction of EL4-ova melanoma rejection in mice by transfer of OT1 T cells expressing an ectopic Cystathionase (CSE) transgene. We described that CSE enzyme is down regulated in transplant tolerance (Vuillefroy de Silly et al, Blood 2012) and that a mechanism of action of MDSC implies down modulation of CSE, which prevents T cells growth. Therefore our hypothesis is that ectopic expression of CSE by T cells would make them resistant to the suppressive action of MDSC. This represents a potential therapeutic strategy for the treatment of solid tumors (where action of T cells is blunted by MDSC).

Cells available:

  • Monocytic myeloid-derived suppressor cells (MDSC) defined as CD11b+ classII- cells expressing CD172a, upregulated in blood and infiltrating the tolerated kidney. These cells present immunosuppressive properties ex-vivo, depending on iNOS. In tolerant animals, they also repress transcription of RANTES, contributing to low CCL5 levels in the periphery and establishing a blood-to-allograft gradiant that was shown to attract intragraft regulatory T cells (Dilek et al, J. Immunol. 2012).
  • These MDSC also overexpress Bcl-XL. The scientific question is twice: 1) is the overexpression of Bcl-XL contributing to their peripheral accumulation? 2) What signal controls their suppressive activity?
  • For the CSE project, the scientific question is whether ectopic expresison of CSE in tumor-directed CD8+ T cells woiuld make them resistant to the suppressive action of MDSC.

Technology available:

  • Microsurgery (kidney transplantation)
  • Flow cytometry
  • Cell sorting
  • RT-PCR
  • Transcriptome analysis
  • Suppression assays (effector T cell proliferation)
  • Lentiviral T cell transfection

Key publications related to Mye-EUNITER:

  1. Haspot F, Seveno C, Dugast AS, et al. Anti-CD28 Antibody-Induced Kidney Allograft Tolerance Related to Tryptophan Degradation and TCR Class II B7 Regulatory Cells. Am J Transplant. 2005;5(10):2339-2348.

  2. Dugast AS, Haudebourg T, Coulon F, et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol. 2008;180(12):7898-7906.

  3. Dilek N, Poirier N, Usal C, Martinet B, Blancho G, Vanhove B. Control of Transplant Tolerance and Intragraft Regulatory T Cell Localization by Myeloid-Derived Suppressor Cells and CCL5. J Immunol. 2012.

  4. Vuillefroy de Silly R, Coulon F, Poirier N, et al. Transplant tolerance is associated with reduced expression of cystathionine-gamma-lyase that controls IL-12 production by dendritic cells and TH-1 immune responses. Blood. 2012;119(11):2633-2643.

  5. Dilek N, Vuillefroy de Silly R, Blancho G, Vanhove B. Myeloid-derived suppressor cells: mechanisms of action and recent advances in their role in transplant tolerance. Front Immunol. 2012;3:208. 

Contact details:

INSERM UMR1064
CHU Hoitel Dieu, 30 Bl J. Monnet
44093 Nantes
Tel: +33(0)240 08 74 17
Fax: +33(0)240 08 74 11
cedric.louvet@univ-nantes.fr