Contributions
Abstract: P1776
Type: Poster Sessions
Abstract Category: N/A
Genetic engineering of T-cells expressing either recombinant TCR (T-cell receptor) or CAR (chimeric antigen receptor) is a powerful and precise tool to therapeutically redirect immune responses, for instance arming the immune system to destroy cancer cells or calming it to stop tissue destruction in autoimmune diseases.
The Foxp3-expressing regulatory CD4 T cells (Tregs) can inhibit autoreactive effector T cells in physiological conditions. However, an imbalance in this immune homeostasis contributes to autoimmune pathogenesis. In the blood of MS patients, the frequency of Tregs is not reduced but their functional properties are altered. Restoring disease-relevant Tregs could therefore be a therapeutic strategy in MS. Importantly, in EAE (experimental autoimmune encephalomyelitis), adoptive transfer of ex vivo expanded myelin-reactive Tregs cures recipient mice from EAE. However, autoantigen-specific Tregs are rare and remain difficult to isolate.
In our laboratory, a library of MOG (Myelin oligodendrocyte glycoprotein)-reactive or MOG/NFM (Neurofilament medium) cross-reacting TCR has been established. We have applied a protocol to engineer polyclonal Tregs to express autoantigen-specific MHC-class II-restricted recombinant TCR. These engineered polyclonal Tregs are redirected to self antigen(s) such as MOG or MOG/NFM and used for adoptive transfer to achieve targeted immune suppression in a mouse model of multiple sclerosis. In particular, we are testing whether engineered Tregs expressing MOG/NFM cross-reacting TCR provide enhanced protection against CD4 or CD8 effector T cell-mediated immunopathology targeting MOG or an unrelated myelin antigen.
In in vitro suppression assay, these engineered Tregs inhibit the proliferation of 2D2 CD4 conventional T cells when co-cultured and stimulated with MOG(35-55) peptide. Upon adoptive transfer, these engineered Tregs persist beyond 30 days post injection, and significantly improved the course of EAE in recipient C57BL/6 mice, while polyclonal Tregs transduced with control vector had no protective effect nor persisted.
These results should break a stranglehold and make the application of autologous cellular therapy using self-reactive engineered Tregs closer to the clinic.
Disclosure: Nothing
Abstract: P1776
Type: Poster Sessions
Abstract Category: N/A
Genetic engineering of T-cells expressing either recombinant TCR (T-cell receptor) or CAR (chimeric antigen receptor) is a powerful and precise tool to therapeutically redirect immune responses, for instance arming the immune system to destroy cancer cells or calming it to stop tissue destruction in autoimmune diseases.
The Foxp3-expressing regulatory CD4 T cells (Tregs) can inhibit autoreactive effector T cells in physiological conditions. However, an imbalance in this immune homeostasis contributes to autoimmune pathogenesis. In the blood of MS patients, the frequency of Tregs is not reduced but their functional properties are altered. Restoring disease-relevant Tregs could therefore be a therapeutic strategy in MS. Importantly, in EAE (experimental autoimmune encephalomyelitis), adoptive transfer of ex vivo expanded myelin-reactive Tregs cures recipient mice from EAE. However, autoantigen-specific Tregs are rare and remain difficult to isolate.
In our laboratory, a library of MOG (Myelin oligodendrocyte glycoprotein)-reactive or MOG/NFM (Neurofilament medium) cross-reacting TCR has been established. We have applied a protocol to engineer polyclonal Tregs to express autoantigen-specific MHC-class II-restricted recombinant TCR. These engineered polyclonal Tregs are redirected to self antigen(s) such as MOG or MOG/NFM and used for adoptive transfer to achieve targeted immune suppression in a mouse model of multiple sclerosis. In particular, we are testing whether engineered Tregs expressing MOG/NFM cross-reacting TCR provide enhanced protection against CD4 or CD8 effector T cell-mediated immunopathology targeting MOG or an unrelated myelin antigen.
In in vitro suppression assay, these engineered Tregs inhibit the proliferation of 2D2 CD4 conventional T cells when co-cultured and stimulated with MOG(35-55) peptide. Upon adoptive transfer, these engineered Tregs persist beyond 30 days post injection, and significantly improved the course of EAE in recipient C57BL/6 mice, while polyclonal Tregs transduced with control vector had no protective effect nor persisted.
These results should break a stranglehold and make the application of autologous cellular therapy using self-reactive engineered Tregs closer to the clinic.
Disclosure: Nothing