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Modulation de l’effet des lymphocytes T régulateurs par la voie TNFα/TNFR2 : une nouvelle immunothérapie en allogreffe de cellules souches hématopoïétiques

Abstract : Regulatory T cells (Tregs) are key players involved in the modulation of alloreactivity after hematopoietic stem cell transplantation. Indeed, Tregs can prevent graft-versus-host disease (GVHD) in experimental models. Therefore, the therapeutic potential of these cells in GVHD is substantial, as it is in other fields like auto-immunity or oncology. However, many obstacles still make the application of cellular therapy strategies based on the adoptive transfer of Tregs in humans quite complicated. A better understanding of factors and mechanisms that control the proliferation and suppressive capacities of Tregs could allow for a direct and specific targeting of these cells in vivo.In this work, after designing a new clinical grading system for murine GVHD and demonstrating its ease of use, reproducibility and performance, we have shown that the suppressive action of Tregs in GVHD depends on the interaction between TNFα produced by donor conventional T cells (Tconvs) and TNFR2 expressed by Tregs. Using 3 different ways to block this interaction, i.e. with an anti-TNFR2 blocking monoclonal antibody, or Tregs that do not express TNFR2 or donor Tconvs that cannot produce TNFα, we were able to show in each situation that blocking TNF signaling resulted in a loss of protection by Tregs. TNFR2 being highly expressed by Tregs as compared with Tconvs, our results pave the way for in vivo targeting of Tregs through TNFR2, either to activate this receptor with an agonist and therefore stimulate Tregs to control GVHD, or to block the TNFα/TNFR2 axis with an antagonist and in this case inhibit Tregs, which could boost alloreactivity, as expected in some particular settings like post-transplant relapse.
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https://tel.archives-ouvertes.fr/tel-01743736
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Submitted on : Monday, March 26, 2018 - 4:33:03 PM
Last modification on : Wednesday, October 14, 2020 - 4:11:05 AM
Long-term archiving on: : Thursday, September 13, 2018 - 9:14:28 AM

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  • HAL Id : tel-01743736, version 1

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Mathieu Leclerc. Modulation de l’effet des lymphocytes T régulateurs par la voie TNFα/TNFR2 : une nouvelle immunothérapie en allogreffe de cellules souches hématopoïétiques. Médecine humaine et pathologie. Université Paris-Est, 2017. Français. ⟨NNT : 2017PESC0014⟩. ⟨tel-01743736⟩

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