IN VITRO-GENERATED MYELOID-DERIVED SUPPRESSOR CELLS (MDSC) PREVENT MURINE GRAFT-VERSUS-HOST DISEASE (GVHD) BY INDUCING TYPE 2 T CELLS WITHOUT DISABLING ANTI-TUMOR CYTOTOXICITY
(Abstract release date: 05/21/15)
EHA Library. Strauss G. 06/13/15; 103059; S495
Disclosure(s): University Medical Center UlmDepartment of Pediatrics and Adolescent Medicine
Prof. Dr. Gudrun Strauss
Contributions
Contributions
Abstract
Abstract: S495
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room Lehar 3 + 4
Background
Allogeneic bone marrow transplantation (BMT) is a curative treatment modality for hematopoietic malignancies such as acute and chronic leukemias and lymphomas. Mature donor T cells in the allograft support engraftment, promote early T cell immunity of the recipient and mediate the graft-versus-tumor (GVT) effect. However, these donor T cells are also responsible for the induction of graft-versus-host disease (GVHD) by destroying recipient tissue such as liver, skin, and bowel. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells preventing T cell activation, proliferation and functions.
Aims
Therefore, we tested whether and how in vitro-generated MDSCs suppress GVHD development without disabling the GVT effect in allogeneic BMT models.
Methods
Results
In-vitro generated MDSCs efficiently suppressed alloantigen-specific T cell proliferation in vitro. Transplantation of 1x107 MDSCs together with allogeneic BM and spleen cells efficiently prevented clinical GVHD and attenuated histological GVHD. MDSCs expanded in vivo and invaded lymphatic and GVHD target organs and were still detectable 30 days after BMT. MDSC-mediated GVHD suppression was antigen-independent since transplantation of MHC class I deficient MDSCs prevented GVHD development comparable to wild type MDSCs. Inhibition of GVHD required the presence of MDSCs during T cell priming because transplantation of MDSCs one week after BMT was ineffective in GVHD prevention. Interestingly, MDSC treatment did not significantly reduce allogeneic T cell numbers in lymphoid and GVHD target organs or change their homing behavior. However, MDSCs skewed allogeneic T cells towards type 2 T cells up-regulating Th2-specific transcription factors and cytokines. Polarization towards type 2 T cell immunity was indispensable for GVHD prevention since MDSC-treatment failed to prevent GVHD when allogeneic STAT6-deficient T cells, which are unable to differentiate into Th2 cells, were transplanted. However, MDSC-mediated type 2 T cell polarization did not abrogate anti-tumor cytotoxicity of alloantigen-specific T cells since syngeneic thymoma tumor cells were efficiently eradicated.
Summary
Therefore, MDSC-induced Th2 polarization might be exploited in clinical settings for GVHD prophylaxis while simultaneously maintaining anti-tumor cytotoxicity.
Keyword(s): Allo BMT, Graft-versus-host disease (GVHD), Graft-versus-tumor effect, Immunosuppression
Session topic: Stem cell transplantation: Experimental
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room Lehar 3 + 4
Background
Allogeneic bone marrow transplantation (BMT) is a curative treatment modality for hematopoietic malignancies such as acute and chronic leukemias and lymphomas. Mature donor T cells in the allograft support engraftment, promote early T cell immunity of the recipient and mediate the graft-versus-tumor (GVT) effect. However, these donor T cells are also responsible for the induction of graft-versus-host disease (GVHD) by destroying recipient tissue such as liver, skin, and bowel. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells preventing T cell activation, proliferation and functions.
Aims
Therefore, we tested whether and how in vitro-generated MDSCs suppress GVHD development without disabling the GVT effect in allogeneic BMT models.
Methods
MDSCs were generated in vitro by culturing BM cells in the presence of GM-CSF and G-CSF. After 4 days more than 90% of the cells exhibited the CD11b+Gr-1+ MDSC phenotype. To test, whether and how MDSCs prevent GVHD, we transplanted allogeneic BM and spleen cells in lethally irradiated recipient mice in combination with in vitro-generated MDSCs and analyzed survival and allogeneic T phenotype and functions. By co-injection of syngeneic tumor cells, the effect of MDSC-treatment on the anti-tumor capacity of allogeneic T cells was analyzed.
Results
In-vitro generated MDSCs efficiently suppressed alloantigen-specific T cell proliferation in vitro. Transplantation of 1x107 MDSCs together with allogeneic BM and spleen cells efficiently prevented clinical GVHD and attenuated histological GVHD. MDSCs expanded in vivo and invaded lymphatic and GVHD target organs and were still detectable 30 days after BMT. MDSC-mediated GVHD suppression was antigen-independent since transplantation of MHC class I deficient MDSCs prevented GVHD development comparable to wild type MDSCs. Inhibition of GVHD required the presence of MDSCs during T cell priming because transplantation of MDSCs one week after BMT was ineffective in GVHD prevention. Interestingly, MDSC treatment did not significantly reduce allogeneic T cell numbers in lymphoid and GVHD target organs or change their homing behavior. However, MDSCs skewed allogeneic T cells towards type 2 T cells up-regulating Th2-specific transcription factors and cytokines. Polarization towards type 2 T cell immunity was indispensable for GVHD prevention since MDSC-treatment failed to prevent GVHD when allogeneic STAT6-deficient T cells, which are unable to differentiate into Th2 cells, were transplanted. However, MDSC-mediated type 2 T cell polarization did not abrogate anti-tumor cytotoxicity of alloantigen-specific T cells since syngeneic thymoma tumor cells were efficiently eradicated.
Summary
Therefore, MDSC-induced Th2 polarization might be exploited in clinical settings for GVHD prophylaxis while simultaneously maintaining anti-tumor cytotoxicity.
Keyword(s): Allo BMT, Graft-versus-host disease (GVHD), Graft-versus-tumor effect, Immunosuppression
Session topic: Stem cell transplantation: Experimental
Abstract: S495
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room Lehar 3 + 4
Background
Allogeneic bone marrow transplantation (BMT) is a curative treatment modality for hematopoietic malignancies such as acute and chronic leukemias and lymphomas. Mature donor T cells in the allograft support engraftment, promote early T cell immunity of the recipient and mediate the graft-versus-tumor (GVT) effect. However, these donor T cells are also responsible for the induction of graft-versus-host disease (GVHD) by destroying recipient tissue such as liver, skin, and bowel. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells preventing T cell activation, proliferation and functions.
Aims
Therefore, we tested whether and how in vitro-generated MDSCs suppress GVHD development without disabling the GVT effect in allogeneic BMT models.
Methods
Results
In-vitro generated MDSCs efficiently suppressed alloantigen-specific T cell proliferation in vitro. Transplantation of 1x107 MDSCs together with allogeneic BM and spleen cells efficiently prevented clinical GVHD and attenuated histological GVHD. MDSCs expanded in vivo and invaded lymphatic and GVHD target organs and were still detectable 30 days after BMT. MDSC-mediated GVHD suppression was antigen-independent since transplantation of MHC class I deficient MDSCs prevented GVHD development comparable to wild type MDSCs. Inhibition of GVHD required the presence of MDSCs during T cell priming because transplantation of MDSCs one week after BMT was ineffective in GVHD prevention. Interestingly, MDSC treatment did not significantly reduce allogeneic T cell numbers in lymphoid and GVHD target organs or change their homing behavior. However, MDSCs skewed allogeneic T cells towards type 2 T cells up-regulating Th2-specific transcription factors and cytokines. Polarization towards type 2 T cell immunity was indispensable for GVHD prevention since MDSC-treatment failed to prevent GVHD when allogeneic STAT6-deficient T cells, which are unable to differentiate into Th2 cells, were transplanted. However, MDSC-mediated type 2 T cell polarization did not abrogate anti-tumor cytotoxicity of alloantigen-specific T cells since syngeneic thymoma tumor cells were efficiently eradicated.
Summary
Therefore, MDSC-induced Th2 polarization might be exploited in clinical settings for GVHD prophylaxis while simultaneously maintaining anti-tumor cytotoxicity.
Keyword(s): Allo BMT, Graft-versus-host disease (GVHD), Graft-versus-tumor effect, Immunosuppression
Session topic: Stem cell transplantation: Experimental
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room Lehar 3 + 4
Background
Allogeneic bone marrow transplantation (BMT) is a curative treatment modality for hematopoietic malignancies such as acute and chronic leukemias and lymphomas. Mature donor T cells in the allograft support engraftment, promote early T cell immunity of the recipient and mediate the graft-versus-tumor (GVT) effect. However, these donor T cells are also responsible for the induction of graft-versus-host disease (GVHD) by destroying recipient tissue such as liver, skin, and bowel. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells preventing T cell activation, proliferation and functions.
Aims
Therefore, we tested whether and how in vitro-generated MDSCs suppress GVHD development without disabling the GVT effect in allogeneic BMT models.
Methods
MDSCs were generated in vitro by culturing BM cells in the presence of GM-CSF and G-CSF. After 4 days more than 90% of the cells exhibited the CD11b+Gr-1+ MDSC phenotype. To test, whether and how MDSCs prevent GVHD, we transplanted allogeneic BM and spleen cells in lethally irradiated recipient mice in combination with in vitro-generated MDSCs and analyzed survival and allogeneic T phenotype and functions. By co-injection of syngeneic tumor cells, the effect of MDSC-treatment on the anti-tumor capacity of allogeneic T cells was analyzed.
Results
In-vitro generated MDSCs efficiently suppressed alloantigen-specific T cell proliferation in vitro. Transplantation of 1x107 MDSCs together with allogeneic BM and spleen cells efficiently prevented clinical GVHD and attenuated histological GVHD. MDSCs expanded in vivo and invaded lymphatic and GVHD target organs and were still detectable 30 days after BMT. MDSC-mediated GVHD suppression was antigen-independent since transplantation of MHC class I deficient MDSCs prevented GVHD development comparable to wild type MDSCs. Inhibition of GVHD required the presence of MDSCs during T cell priming because transplantation of MDSCs one week after BMT was ineffective in GVHD prevention. Interestingly, MDSC treatment did not significantly reduce allogeneic T cell numbers in lymphoid and GVHD target organs or change their homing behavior. However, MDSCs skewed allogeneic T cells towards type 2 T cells up-regulating Th2-specific transcription factors and cytokines. Polarization towards type 2 T cell immunity was indispensable for GVHD prevention since MDSC-treatment failed to prevent GVHD when allogeneic STAT6-deficient T cells, which are unable to differentiate into Th2 cells, were transplanted. However, MDSC-mediated type 2 T cell polarization did not abrogate anti-tumor cytotoxicity of alloantigen-specific T cells since syngeneic thymoma tumor cells were efficiently eradicated.
Summary
Therefore, MDSC-induced Th2 polarization might be exploited in clinical settings for GVHD prophylaxis while simultaneously maintaining anti-tumor cytotoxicity.
Keyword(s): Allo BMT, Graft-versus-host disease (GVHD), Graft-versus-tumor effect, Immunosuppression
Session topic: Stem cell transplantation: Experimental
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