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  1. Article ; Online: Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway.

    Molina, Megan S / Hoffman, Emely A / Stokes, Jessica / Kummet, Nicole / Simpson, Richard J / Katsanis, Emmanuel

    PloS one

    2022  Volume 17, Issue 8, Page(s) e0273075

    Abstract: The immediate precursor to murine type 1 conventional DCs (cDC1s) has recently been established and named "pre-cDC1s". Mature CD8α+ cDC1s are recognized for suppressing graft-versus-host disease (GvHD) while promoting graft-versus-leukemia (GvL), however ...

    Abstract The immediate precursor to murine type 1 conventional DCs (cDC1s) has recently been established and named "pre-cDC1s". Mature CD8α+ cDC1s are recognized for suppressing graft-versus-host disease (GvHD) while promoting graft-versus-leukemia (GvL), however pre-cDC1s have not previously been investigated in the context of alloreactivity or anti-tumor responses. Characterization of pre-cDC1s, compared to CD8α+ cDC1s, found that a lower percentage of pre-cDC1s express PD-L1, yet express greater PD-L1 by MFI and a greater percent PIR-B, a GvHD-suppressing molecule. Functional assays were performed ex vivo following in vivo depletion of CD8α+ DCs to examine whether pre-cDC1s play a redundant role in alloreactivity. Proliferation assays revealed less allogeneic T-cell proliferation in the absence of CD8α+ cDC1s, with slightly greater CD8+ T-cell proliferation. Further, in the absence of CD8α+ cDC1s, stimulated CD8+ T-cells exhibited significantly less PD-1 expression compared to CD4+ T-cells, and alloreactive T-cell death was significantly lower, driven by reduced CD4+ T-cell death. Tumor-killing assays revealed that T-cells primed with CD8α-depleted DCs ex vivo induce greater killing of A20 B-cell leukemia cells, particularly when antigen (Ag) is limited. Bulk RNA sequencing revealed distinct transcriptional programs of these DCs, with pre-cDC1s exhibiting activated PD-1/PD-L1 signaling compared to CD8α+ cDC1s. These results indicate distinct T-cell-priming capabilities of murine pre-cDC1s compared to CD8α+ cDC1s ex vivo, with potentially clinically relevant implications in suppressing GvHD while promoting GvL responses, highlighting the need for greater investigation of murine pre-cDC1s.
    MeSH term(s) Animals ; B7-H1 Antigen/metabolism ; CD8-Positive T-Lymphocytes ; Dendritic Cells ; Graft vs Host Disease ; Mice ; Mice, Inbred C57BL ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/metabolism
    Chemical Substances B7-H1 Antigen ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2022-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0273075
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation.

    Stokes, Jessica / Molina, Megan S / Hoffman, Emely A / Simpson, Richard J / Katsanis, Emmanuel

    Cancers

    2021  Volume 13, Issue 7

    Abstract: Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in ... ...

    Abstract Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
    Language English
    Publishing date 2021-04-03
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13071702
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia.

    Stokes, Jessica / Hoffman, Emely A / Molina, Megan S / Kummet, Nicole / Simpson, Richard J / Zeng, Yi / Katsanis, Emmanuel

    Oncoimmunology

    2020  Volume 9, Issue 1, Page(s) 1758011

    Abstract: Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our ... ...

    Abstract Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.
    MeSH term(s) Animals ; Bendamustine Hydrochloride/pharmacology ; Female ; Graft vs Host Disease ; Graft vs Leukemia Effect ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/radiation effects ; Transplantation Conditioning ; Whole-Body Irradiation
    Chemical Substances Bendamustine Hydrochloride (981Y8SX18M)
    Language English
    Publishing date 2020-04-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-4011
    ISSN (online) 2162-402X
    ISSN 2162-4011
    DOI 10.1080/2162402X.2020.1758011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3.

    Molina, Megan S / Stokes, Jessica / Hoffman, Emely A / Eremija, Jelena / Zeng, Yi / Simpson, Richard J / Katsanis, Emmanuel

    Frontiers in immunology

    2020  Volume 11, Page(s) 1410

    Abstract: Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an ... ...

    Abstract Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.
    MeSH term(s) Allografts ; Animals ; Basic-Leucine Zipper Transcription Factors/metabolism ; Bendamustine Hydrochloride/pharmacology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/radiation effects ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation/adverse effects ; Mice ; Repressor Proteins/metabolism ; Transplantation Conditioning/methods ; Whole-Body Irradiation
    Chemical Substances Basic-Leucine Zipper Transcription Factors ; Repressor Proteins ; SNFT protein, mouse ; Bendamustine Hydrochloride (981Y8SX18M)
    Language English
    Publishing date 2020-07-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.01410
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death.

    Molina, Megan S / Hoffman, Emely A / Stokes, Jessica / Kummet, Nicole / Smith, Kyle A / Baker, Forrest / Zúñiga, Tiffany M / Simpson, Richard J / Katsanis, Emmanuel

    Frontiers in immunology

    2021  Volume 12, Page(s) 699128

    Abstract: The growth factor Flt3 ligand (Flt3L) is central to dendritic cell (DC) homeostasis and development, controlling survival and expansion by binding to Flt3 receptor tyrosine kinase on the surface of DCs. In the context of hematopoietic cell ... ...

    Abstract The growth factor Flt3 ligand (Flt3L) is central to dendritic cell (DC) homeostasis and development, controlling survival and expansion by binding to Flt3 receptor tyrosine kinase on the surface of DCs. In the context of hematopoietic cell transplantation, Flt3L has been found to suppress graft-versus-host disease (GvHD), specifically
    MeSH term(s) Animals ; Apoptosis/immunology ; Bendamustine Hydrochloride/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Female ; Graft vs Host Disease/immunology ; Humans ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Transplantation Conditioning/methods ; fms-Like Tyrosine Kinase 3/immunology ; fms-Like Tyrosine Kinase 3/metabolism
    Chemical Substances Bendamustine Hydrochloride (981Y8SX18M) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
    Language English
    Publishing date 2021-06-24
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.699128
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells.

    Stokes, Jessica / Hoffman, Emely A / Molina, Megan S / Eremija, Jelena / Larmonier, Nicolas / Zeng, Yi / Katsanis, Emmanuel

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2018  Volume 25, Issue 3, Page(s) 405–416

    Abstract: Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we ... ...

    Abstract Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11b
    MeSH term(s) Animals ; Bendamustine Hydrochloride/therapeutic use ; Cell Count ; Combined Modality Therapy/methods ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation/adverse effects ; Mice ; Myeloid-Derived Suppressor Cells/cytology ; Myeloid-Derived Suppressor Cells/drug effects ; Myeloid-Derived Suppressor Cells/radiation effects ; Transplantation Conditioning/methods ; Whole-Body Irradiation
    Chemical Substances Bendamustine Hydrochloride (981Y8SX18M)
    Language English
    Publishing date 2018-10-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474865-4
    ISSN 1523-6536 ; 1083-8791
    ISSN (online) 1523-6536
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2018.10.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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