96 results on '"Odette M. Smith"'
Search Results
2. Supplementary Figure 3 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 128KB, Treg depletion from c-Rel deficient donor T-cells results in exacerbated GVHD
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- 2023
3. Supplementary Table 1 and Table 2 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 92K, Table 1. Characteristics of c-Rel inhibitor compounds; Table 2. Roles of c-Rel in T-cell responses and transplantation immunology
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- 2023
4. Supplementary Figure 5 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 135KB, Non-specific negative effect of DMSO on the GVT activity of T-cells
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- 2023
5. Supplementary Figure 6 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 128KB, c-Rel-deficient T-cells are polarized towards Th2 responses during GVHD
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- 2023
6. Supplementary Figure 2 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 191K, Recipients of c-Rel-deficient T-cells exhibit reduced damage of GVHD target organs
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- 2023
7. Supplementary Figure 1 from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Chen Liu, Cecilia Lezcano, George F. Murphy, Chandresh V. Undhad, Dmitry Pankov, Ekaterina Doubrovina, Natalie V. Singer, Mallory L. West, Odette M. Smith, Jennifer E. Oyler, Jennifer J. Tsai, Grégoire Altan-Bonnet, Hsiou-Chi Liou, Samedy Ouk, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
PDF file 121K, IL-2 secretion is enhanced in irradiated recipients transplanted with allogeneic T-cells
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- 2023
8. Supplementary Figure 11 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 inhibits growth of human DLBCL cell lines.
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- 2023
9. Supplementary Figure 8 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
c-Rel is constitutively active in a wide range of human lymphoma types.
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- 2023
10. Supplementary Figure 1 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
Analysis of the biochemical efficacy of IT-901 by electrophoretic mobility shift assay (EMSA) and NF-κB DNA binding ELISA.
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- 2023
11. Supplementary Table 2 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
ROS/RNS induction by IT-901 treatement in normal tissues.
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- 2023
12. Supplementary Figure 6 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
c-Rel inhibitor treatment is associated with partial recovery of lost body weight during severe acute GVHD.
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- 2023
13. Data from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
- Author
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB–dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease. Cancer Res; 76(2); 377–89. ©2016 AACR.
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- 2023
14. Supplementary Figure 4 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
- Author
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 is a more potent c-Rel inhibitor than IT-603.
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- 2023
15. Supplementary Figure 7 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
Effects of IT-901 on lymphocyte subsets in the spleen.
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- 2023
16. Supplementary Figure 3 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 has a superior pharmacokinetic profile.
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- 2023
17. Supplementary Figure 2 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 is a more potent NF-κB inhibitor than IT-603.
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- 2023
18. Supplementary Figure 9 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 mediates anti-lymphoma activity in a xenograft model of EBV-induced lymphoma.
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- 2023
19. Supplementary Table 1 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
IT-901 has no significant adverse effects on major organ functions and blood cell counts.
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- 2023
20. Supplementary Figure 5 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
Treatment with IT-901 for 14 days does not alter lymphocyte numbers.
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- 2023
21. Supplementary Figure 10 from Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
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Johannes L. Zakrzewski, Marcel R.M. van den Brink, Richard J. O'Reilly, Anas Younes, Glenn Heller, Mikhail Doubrovin, Mary I. Scallion, Carly G.K. Ziegler, Fabiana M. Kreines, Emily R. Levy, Odette M. Smith, Jennifer J. Tsai, Samedy Ouk, Enrico Derenzini, Ekaterina Doubrovina, Hsiou-Chi Liou, Andrea Z. Tuckett, and Yusuke Shono
- Abstract
Several NF-κB subunits are constitutively active in activated B-like DLBCL cell lines.
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- 2023
22. Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease
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Enrico Velardi, Alan M. Hanash, Marcel R.M. van den Brink, Lauren F. Young, Robert R. Jenq, Anna Mertelsmann, Jarrod A Dudakov, Odette M. Smith, Margaret O'Connor, and Richard L. Boyd
- Subjects
0301 basic medicine ,Immunology ,Graft vs Host Disease ,Thymus Gland ,Biology ,T-Lymphocytes, Regulatory ,Biochemistry ,Interleukin 22 ,03 medical and health sciences ,Immune system ,Immunity ,medicine ,Animals ,Lymphocytes ,Bone Marrow Transplantation ,Mice, Inbred BALB C ,Innate immune system ,Interleukins ,Innate lymphoid cell ,Cell Biology ,Hematology ,Acquired immune system ,medicine.disease ,Immunity, Innate ,Mice, Inbred C57BL ,Transplantation ,030104 developmental biology ,Graft-versus-host disease ,Signal Transduction - Abstract
Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency.
- Published
- 2017
23. Nrf2 regulates CD4(+) T cell–induced acute graft-versus-host disease in mice
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Salma Youssef, Chen Liu, Marcel R.M. van den Brink, Odette M. Smith, Amanda M. Holland, Alan M. Hanash, Yusuke Shono, Jarrod A Dudakov, Kimon V. Argyropoulos, Fabiana M Kreines, Sophie Lieberman, George F. Murphy, Cecilia Lezcano, Robert R. Jenq, Uttam K. Rao, Il-Kang Na, Jennifer Tsai, Nury L. Yim, Lauren F. Young, Enrico Velardi, Ya-Yuan Fu, and Amina Lazrak
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,NF-E2-Related Factor 2 ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Biochemistry ,digestive system ,environment and public health ,03 medical and health sciences ,Mice ,Downregulation and upregulation ,medicine ,Animals ,Mice, Knockout ,Transplantation ,Chemistry ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Neoplasms, Experimental ,respiratory system ,medicine.disease ,Allografts ,Haematopoiesis ,030104 developmental biology ,Graft-versus-host disease ,surgical procedures, operative ,Acute Disease ,Cancer research ,Experimental pathology ,Stem cell ,CD8 - Abstract
Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2−/− donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2−/− donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2−/− donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.
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- 2018
24. Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
- Author
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Fabiana M Kreines, Richard J. O'Reilly, Carly G. K. Ziegler, Mary I. Scallion, Marcel R.M. van den Brink, Johannes L. Zakrzewski, Anas Younes, Mikhail Doubrovin, Glenn Heller, Hsiou-Chi Liou, Emily R Levy, Jennifer Tsai, Yusuke Shono, Odette M. Smith, Enrico Derenzini, Samedy Ouk, Ekaterina Doubrovina, and Andrea Z. Tuckett
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Pharmacology ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,chemistry.chemical_classification ,Reactive oxygen species ,NF-kappa B ,NF-κB ,medicine.disease ,NFKB1 ,Proto-Oncogene Proteins c-rel ,Lymphoma ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Oncology ,chemistry ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Female ,Signal transduction ,Reactive Oxygen Species ,REL ,Carcinogenesis ,Oxidative stress ,Signal Transduction - Abstract
NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB–dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease. Cancer Res; 76(2); 377–89. ©2016 AACR.
- Published
- 2016
25. Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration
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Nancy R. Manley, Odette M. Smith, Yusuke Shono, Alan M. Hanash, Lauren F. Young, Jason M. Butler, Sophia R. Lieberman, Tobias Wertheimer, Robert R. Jenq, Peipei Guo, Andreas Beilhack, Florent Malard, Christian Brede, Shiyun Xiao, Daniel J. Nolan, Katja J. Ottmüller, Jennifer Tsai, Fabiana M Kreines, Sinéad Kinsella, Enrico Velardi, Amina Lazrak, Brisa Palikuqi, Paul DeRoos, Christopher C. Kloss, Shahin Rafii, Jarrod A Dudakov, Zeinab Mokhtari, Kirsten Cooper, Michael Ginsberg, and Marcel R.M. van den Brink
- Subjects
0301 basic medicine ,T-Lymphocytes ,Immunology ,Endogeny ,Bone Morphogenetic Protein 4 ,Thymus Gland ,Biology ,Article ,Mice ,03 medical and health sciences ,Animals ,Regeneration ,Transcription factor ,Cell Proliferation ,Stem Cells ,Regeneration (biology) ,Endogenous regeneration ,Endothelial Cells ,FOXN1 ,Epithelial Cells ,Forkhead Transcription Factors ,General Medicine ,Cell biology ,Mice, Inbred C57BL ,Thymocyte ,030104 developmental biology ,Bone morphogenetic protein 4 ,Female ,Thymic Damage ,Signal Transduction - Abstract
The thymus is not only extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood, and this capacity diminishes considerably with age. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4) ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance, and regeneration, and its downstream targets such as Dll4, a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity.
- Published
- 2018
26. A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
- Author
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Jennifer Tsai, Natalie V. Singer, Dmitry Pankov, Chandresh V. Undhad, George F. Murphy, Cecilia Lezcano, Yusuke Shono, Odette M. Smith, Grégoire Altan-Bonnet, Ekaterina Doubrovina, Andrea Z. Tuckett, Jennifer E. Oyler, Johannes L. Zakrzewski, Hsiou-Chi Liou, Samedy Ouk, Chen Liu, Marcel R.M. van den Brink, Mallory L. West, and Richard J. O'Reilly
- Subjects
T-Lymphocytes ,Receptors, Antigen, T-Cell ,Graft vs Host Disease ,Biology ,Lymphocyte Activation ,Article ,Small Molecule Libraries ,Mice ,Immune system ,Antigen ,Animals ,Humans ,Transplantation, Homologous ,Mice, Inbred BALB C ,Effector ,Graft vs Tumor Effect ,T-cell receptor ,Hematopoietic Stem Cell Transplantation ,Interleukin ,Proto-Oncogene Proteins c-rel ,Mice, Inbred C57BL ,Transplantation ,Gene Expression Regulation ,Oncology ,Immunology ,Cancer research ,Female ,REL ,Homing (hematopoietic) - Abstract
Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule–based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel–deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity. Significance: Chemical inhibition of c-Rel diminishes alloactivation while preserving antigen-specific TCR activation, revealing the redundancy of c-Rel in T cell–mediated antitumor activity of both mouse and human T cells. Our study provides a highly innovative immunomodulatory approach that has true potential for drug development and clinical application with broad therapeutic implications, including allo-tolerance induction after allo-HSCT, as well as antitumor therapies. Cancer Discov; 4(5); 578–91. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 495
- Published
- 2014
27. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
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David T. Scadden, Marcel R.M. van den Brink, Tobias Wertheimer, Fabiana M Kreines, Odette M. Smith, Jennifer Tsai, Emily R Levy, Andrea Z. Tuckett, Amanda M. Holland, Jarrod A Dudakov, Lauren F. Young, Vionnie W.C. Yu, Mallory L. West, Johannes L. Zakrzewski, Enrico Velardi, Richard L. Boyd, and Natalie V. Singer
- Subjects
Male ,medicine.medical_specialty ,T cell ,Immunology ,Notch signaling pathway ,Thymus Gland ,Biology ,Cell Line ,Hormone Antagonists ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Immunology and Allergy ,Animals ,Humans ,Testosterone ,Lymphopoiesis ,Gonadal Steroid Hormones ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Thymocytes ,Dose-Response Relationship, Drug ,Receptors, Notch ,Calcium-Binding Proteins ,Brief Definitive Report ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Dihydrotestosterone ,Epithelial Cells ,Flow Cytometry ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,HEK293 Cells ,Sex steroid ,Receptors, Androgen ,Benzamides ,Female ,Signal transduction ,Receptors, LHRH ,medicine.drug ,Hormone ,Signal Transduction - Abstract
Velardi et al. show that sex steroids regulate thymopoiesis by directly modulating Notch signaling, and provide a novel clinical strategy to boost immune regeneration., Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose-dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function.
- Published
- 2014
28. Nrf2 is a Critical Mediator of CD4 T Cell-Induced Acute Graft-Versus-Host Disease
- Author
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Yusuke Shono, Ya-Yuan Fu, George F. Murphy, Chen Liu, Marcel R.M. van den Brink, Enrico Velardi, Jarrod A Dudakov, Odette M. Smith, Alan M. Hanash, Kimon V. Argyropoulos, Amina Lazrak, Robert R. Jenq, and Jennifer Tsai
- Subjects
Transplantation ,Mediator ,Cd4 t cell ,business.industry ,Immunology ,Acute graft versus host disease ,Medicine ,Hematology ,business - Published
- 2018
29. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
- Author
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George F. Murphy, Lauren F. Young, Michel Sadelain, Yildirim Dogan, Maxim A. Moroz, Enrico Velardi, Chen Liu, Nury L. Yim, Jennifer Tsai, Uttam K. Rao, Odette M. Smith, Robert R. Jenq, Daniel Tannenbaum, Alan M. Hanash, M. Lia Palomba, Vladimir Ponomarev, Cecilia Lezcano, Arnab Ghosh, Olaf Penack, Martin Sauer, Kelly Piersanti, Marcel R.M. van den Brink, Amanda M. Holland, and Durva Masih
- Subjects
Adoptive cell transfer ,business.industry ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,HEK 293 cells ,General Medicine ,Hematopoietic stem cell transplantation ,medicine.disease ,Cell therapy ,surgical procedures, operative ,Apoptosis ,Cell culture ,Immunology ,medicine ,business ,Antigen-presenting cell - Abstract
Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.
- Published
- 2013
30. The central nervous system is a target of acute graft versus host disease in mice
- Author
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Mallory L. West, Natalie V. Singer, Linda K. Johnson, Marcel R.M. van den Brink, Steffen Hartrampf, Michael H. Albert, Jennifer Tsai, Miklós Tóth, Jarrod A Dudakov, Alan M. Hanash, Bingfang Liu, and Odette M. Smith
- Subjects
Programmed cell death ,Pathology ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Central nervous system ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Biology ,Biochemistry ,Postoperative Complications ,Central Nervous System Diseases ,immune system diseases ,medicine ,Animals ,Transplantation ,Lung ,Hematopoietic Stem Cell Transplantation ,food and beverages ,Cell Biology ,Hematology ,medicine.disease ,surgical procedures, operative ,medicine.anatomical_structure ,Graft-versus-host disease ,Neuroglia ,Bone marrow ,Complication - Abstract
Despite significant advances in prevention and management, graft versus host disease (GVHD) is still a leading complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although skin, gut, liver, thymus, and lung are GVHD targets, neurological complications (NC) have also been reported following allo-HSCT. We demonstrate that the central nervous system (CNS) can be a direct target of alloreactive T cells following allo-HSCT in mice. We found significant infiltration of the CNS with donor T lymphocytes and cell death of neurons and neuroglia in allo-HSCT recipients with GVHD. We also found that allo-HSCT recipients with GVHD had deficits in spatial learning/memory and demonstrated increased anxious behavior. These findings highlight CNS sensitivity to damage caused by alloreactive donor T cells and represent the first characterization of target cell subsets and NC during GVHD. Therefore, these clinically relevant studies offer a novel and rational explanation for the well-described neurological symptoms observed after allo-HSCT.
- Published
- 2013
31. Nrf2 regulates haematopoietic stem cell function
- Author
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Jennifer Tsai, Koichi Takahashi, Alan M. Hanash, Marcel R.M. van den Brink, Malcolm A.S. Moore, Amanda M. Holland, Arnab Ghosh, Mallory L. West, Jae-Hung Shieh, Odette M. Smith, Enrico Velardi, Jarrod A Dudakov, Hien Tran, Yusuke Shono, Natalie V. Singer, and Lauren Florence Young
- Subjects
Chromatin Immunoprecipitation ,Receptors, CXCR4 ,Cell signaling ,Stromal cell ,NF-E2-Related Factor 2 ,Blotting, Western ,Regulator ,Cell Communication ,Biology ,Real-Time Polymerase Chain Reaction ,Transfection ,CXCR4 ,Article ,Mice ,Bone Marrow ,Animals ,RNA, Messenger ,Progenitor cell ,Luciferases ,Bone Marrow Transplantation ,Cell Proliferation ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Biology ,Flow Cytometry ,Hematopoietic Stem Cells ,Hematopoiesis ,Cell biology ,Haematopoiesis ,Female ,Stromal Cells ,Stem cell ,Signal transduction ,Signal Transduction - Abstract
Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 deficiency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function.
- Published
- 2013
32. Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury
- Author
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Yusuke Shono, Kimon V. Argyropoulos, Jennifer Tsai, Amina Lazrak, Lauren F. Young, Enrico Velardi, Shieh Jae-Hung, Stefan Radtke, Zhenmin Lei, Marcel R.M. van den Brink, Hans-Peter Kiem, Robert R. Jenq, Prema Narayan, Fabiana M Kreines, Sophie Lieberman, Malcolm A.S. Moore, Jarrod A Dudakov, Kirsten Cooper, Alan M. Hanash, Tobias Wertheimer, and Odette M. Smith
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Medizin ,General Biochemistry, Genetics and Molecular Biology ,Gonadotropin-Releasing Hormone ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Regeneration ,Lymphopoiesis ,Cell Self Renewal ,Receptor ,Cell Proliferation ,business.industry ,Cell Cycle ,Hematopoietic stem cell ,Cell Differentiation ,General Medicine ,Luteinizing Hormone ,Receptors, LH ,Hematopoietic Stem Cells ,Hematopoiesis ,Haematopoiesis ,Radiation Injuries, Experimental ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Bone marrow ,business ,Luteinizing hormone ,Ex vivo ,Whole-Body Irradiation ,Hormone ,Signal Transduction - Abstract
There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.
- Published
- 2016
33. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice
- Author
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Silvia Caballero, Franck Rapaport, Hendrik Poeck, Ying Taur, Jennifer Tsai, Marco Calarfiore, Sophia R. Lieberman, Marcel R.M. van den Brink, Camilla Borges Ferreira Gomes, Ke Xu, Katya F. Ahr, Sean M. Devlin, Shannon B. Falconer, Chen Liu, Eric G. Pamer, Robert R. Jenq, George F. Murphy, Kori A. Porosnicu Rodriguez, Lauren F. Young, Jonathan U. Peled, Hillary V. Jay, Alan M. Hanash, Boglarka Gyurkocza, Jyotsna Gupta, Eli L. Moss, Ann E. Slingerland, Jarrod A Dudakov, Suelen M. Perobelli, Odette M. Smith, Ami S. Bhatt, Enrico Velardi, Yusuke Shono, and Melissa D. Docampo
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,Antibiotics ,Cilastatin, Imipenem Drug Combination ,Graft vs Host Disease ,Penicillanic Acid ,Hematopoietic stem cell transplantation ,Aztreonam ,Interleukin-23 ,chemistry.chemical_compound ,Feces ,Mice ,immune system diseases ,polycyclic compounds ,Medicine ,Phylogeny ,biology ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Flow Cytometry ,Anti-Bacterial Agents ,Drug Combinations ,surgical procedures, operative ,Piperacillin, Tazobactam Drug Combination ,Cilastatin ,Female ,Anaerobic bacteria ,Akkermansia muciniphila ,medicine.drug ,medicine.drug_class ,Colon ,Cefepime ,Article ,03 medical and health sciences ,Verrucomicrobia ,Animals ,Humans ,Transplantation, Homologous ,Piperacillin ,business.industry ,biology.organism_classification ,Mucus ,Gastrointestinal Microbiome ,Transplantation ,Mice, Inbred C57BL ,Imipenem ,030104 developmental biology ,chemistry ,Immunology ,business - Abstract
After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p
- Published
- 2016
34. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation
- Author
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Eric G. Pamer, Chen Liu, Jarrod A Dudakov, Jenna D. Goldberg, Arnab Ghosh, Clarissa C. Menezes, Asia Gobourne, Alan M. Hanash, Ying Taur, Lauren F. Young, Natalie V. Singer, Robert R. Jenq, Marcel R.M. van den Brink, Michele Equinda, Kazutoshi Aoyama, Carles Ubeda, Mallory L. West, Lauren Lipuma, Bruce R. Blazar, Odette M. Smith, and Raya Khanin
- Subjects
0303 health sciences ,Flora ,biology ,Lactobacillales ,Immunology ,chemical and pharmacologic phenomena ,Inflammation ,Gut flora ,biology.organism_classification ,medicine.disease ,3. Good health ,Transplantation ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,Graft-versus-host disease ,immune system diseases ,030220 oncology & carcinogenesis ,Lactobacillus ,medicine ,Immunology and Allergy ,Microbiome ,medicine.symptom ,030304 developmental biology - Abstract
Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients.
- Published
- 2012
35. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
- Author
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Caroline A. Lindemans, Alan M. Hanash, Marcel R.M. van den Brink, Yuan-Hung Lo, Ya-Yuan Fu, Juliet Ivanov, Richard Kolesnick, Edward E. S. Nieuwenhuis, Marco Calafiore, Margaret O'Connor, Lauren F. Young, Anna Mertelsmann, Robert R. Jenq, Gillian Lawrence, Guoqiang Hua, Enrico Velardi, Shuichiro Takashima, Lukas E. Dow, Odette M. Smith, Noah F. Shroyer, Kevin P. O’Rourke, Maria Laura Martin, Monica Romera-Hernandez, Jarrod A Dudakov, Chen Liu, Tom Cupedo, Michal Mokry, Cardiothoracic Surgery, Hematology, and Erasmus MC other
- Subjects
STAT3 Transcription Factor ,inorganic chemicals ,Paneth Cells ,Graft vs Host Disease ,Biology ,Research Support ,digestive system ,Article ,N.I.H ,Interleukin 22 ,Mice ,Intestinal mucosa ,Research Support, N.I.H., Extramural ,Intestine, Small ,medicine ,Organoid ,Journal Article ,Animals ,Humans ,Regeneration ,Phosphorylation ,Stem Cell Niche ,Intestinal Mucosa ,Non-U.S. Gov't ,Immunity, Mucosal ,Multidisciplinary ,Interleukins ,Stem Cells ,Regeneration (biology) ,Research Support, Non-U.S. Gov't ,Innate lymphoid cell ,Extramural ,Epithelial Cells ,Intestinal epithelium ,Cell biology ,Organoids ,medicine.anatomical_structure ,Immunology ,Paneth cell ,Female ,Stem cell ,Signal Transduction - Abstract
Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch, and epidermal growth factor (EGF) signals supporting Lgr5+ crypt base columnar ISCs for normal epithelial maintenance1,2. However, little is known about the regulation of the ISC compartment after tissue damage. Utilizing ex vivo organoid cultures, we provide evidence that innate lymphoid cells (ILCs), potent producers of Interleukin-22 (IL-22) after intestinal injury3,4, increased the growth of murine small intestine (SI) organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both murine and human intestinal organoids, increasing proliferation, and promoting ISC expansion. IL-22 induced Stat3 phosphorylation in Lgr5+ ISCs, and Stat3 was critical for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after murine allogeneic bone marrow transplantation (BMT) enhanced recovery of ISCs, increased epithelial regeneration, and reduced intestinal pathology and mortality from graft vs. host disease (GVHD). Atoh1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independent of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support intestinal epithelium, activating ISCs to promote regeneration.
- Published
- 2015
36. Inhibition of Neovascularization to Simultaneously Ameliorate Graft-vs-Host Disease and Decrease Tumor Growth
- Author
-
Dingcheng Gao, George F. Murphy, Sydney X. Lu, Chen Liu, David A. Scheinberg, Robert Benezra, Erik Henke, Amanda M. Holland, Glenn Heller, Il-Kang Na, Vivek Mittal, David Suh, Marcel R.M. van den Brink, Chad May, Theresa T. Lu, Odette M. Smith, Robert R. Jenq, Christopher G. King, Arnab Ghosh, and Olaf Penack
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Angiogenesis ,medicine.medical_treatment ,Fluorescent Antibody Technique ,Graft vs Host Disease ,Angiogenesis Inhibitors ,Hematopoietic stem cell transplantation ,Biology ,Neovascularization ,Mice ,Vasculogenesis ,Antigens, CD ,immune system diseases ,Neoplasms ,medicine ,Animals ,Transplantation, Homologous ,Progenitor cell ,Bone Marrow Transplantation ,Neovascularization, Pathologic ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Articles ,Cadherins ,Flow Cytometry ,medicine.disease ,Mice, Inbred C57BL ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Graft-versus-host disease ,Oncology ,Female ,Bone marrow ,medicine.symptom - Abstract
BACKGROUND Blood vessels are formed either by sprouting of resident tissue endothelial cells (angiogenesis) or by recruitment of bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs, vasculogenesis). Neovascularization has been implicated in tumor growth and inflammation, but its roles in graft-vs-host disease (GVHD) and in tumors after allogeneic BM transplantation (allo-BMT) were not known. METHODS We analyzed neovascularization, the contribution of endothelial cells and EPCs, and the ability of anti-vascular endothelial-cadherin antibody, E4G10, to inhibit neovascularization in mice with GVHD after allo-BMT using immunofluorescence microscopy and flow cytometry. We examined survival and clinical and histopathologic GVHD in mice (n = 10-25 per group) in which GVHD was treated with the E4G10 antibody using immunohistochemistry, flow cytometry, and cytokine immunoassay. We also assessed survival, the contribution of green fluorescent protein-marked EPCs to the tumor vasculature, and the ability of E4G10 to inhibit tumor growth in tumor-bearing mice (n = 20-33 per group) after allo-BMT using histopathology and bioluminescence imaging. All statistical tests were two-sided. RESULTS We found increased neovascularization mediated by vasculogenesis, as opposed to angiogenesis, in GVHD target tissues, such as liver and intestines. Administration of E4G10 inhibited neovascularization by donor BM-derived cells without affecting host vascularization, inhibited both GVHD and tumor growth, and increased survival (at 60 days post-BMT and tumor challenge with A20 lymphoma, the probability of survival was 0.29 for control antibody-treated allo-BMT recipients vs 0.7 for E4G10-treated allo-BMT recipients, 95% confidence interval = 0.180 to 0.640, P < .001). CONCLUSIONS Therapeutic targeting of neovascularization in allo-BMT recipients is a novel strategy to simultaneously ameliorate GVHD and inhibit posttransplant tumor growth, providing a new approach to improve the overall outcome of allogeneic hematopoietic stem cell transplantation.
- Published
- 2010
37. Erratum: Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury
- Author
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Yusuke Shono, Fabiana M Kreines, Sophie Lieberman, Shieh Jae-Hung, Kirsten Cooper, Robert R. Jenq, Tobias Wertheimer, Odette M. Smith, Jennifer Tsai, Marcel R.M. van den Brink, Jarrod A Dudakov, Zhenmin Lei, Kimon V. Argyropoulos, Lauren F. Young, Amina Lazrak, Hans-Peter Kiem, Alan M. Hanash, Malcolm A.S. Moore, Enrico Velardi, Prema Narayan, and Stefan Radtke
- Subjects
03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,Nat ,Cancer research ,030212 general & internal medicine ,General Medicine ,Biology ,Luteinizing hormone ,Article ,General Biochemistry, Genetics and Molecular Biology ,Ex vivo - Abstract
There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury, either from cancer therapy or accidental exposure1,2. In addition to their role in promoting sexual dimorphisms, increasing evidence suggests that sex hormones regulate HSC self-renewal, differentiation, and proliferation3–5. We and others previously reported that sex steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice5–7. Here we show that a luteinizing hormone-releasing hormone-antagonist (LHRH-Ant), currently used widely in the clinic for sex steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise lethal dose of total body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids, but instead relied on suppression of luteinizing hormone (LH) levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the luteinizing hormone/choriogonadotropin receptor (LHCGR) and expand ex vitro when stimulated with LH. In contrast, suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting quiescence of HSCs and protecting them from exhaustion. These findings reveal a role for LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after injury.
- Published
- 2018
38. Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice
- Author
-
Amanda J. Pickard, Melissa D. Docampo, Ann E. Slingerland, Curtis J. Bare, Jonathan U. Peled, Yusuke Shono, Christoph K. Stein-Thoeringer, Hillary V. Jay, Justin R. Cross, Eric G. Pamer, Marcel R.M. van den Brink, Enrico Velardi, Odette M. Smith, Benjamin H. Durham, Marina Burgos da Silva, Lorenz Jahn, Robert R. Jenq, David E. Cohen, Jennifer Tsai, Corey D. Holman, Anna Staffas, Amina Lazrak, and Sophie Lieberman
- Subjects
0301 basic medicine ,Bone marrow transplantation ,medicine.drug_class ,Lymphocyte ,Antibiotics ,Systemic immunity ,Biology ,Microbiology ,Mice ,03 medical and health sciences ,Bone Marrow ,Virology ,medicine ,Animals ,Mucosal immunity ,Immunodeficiency ,Bone Marrow Transplantation ,Progenitor ,Nutritional Support ,medicine.disease ,Gastrointestinal Microbiome ,Hematopoiesis ,Haematopoiesis ,Treatment Outcome ,surgical procedures, operative ,030104 developmental biology ,medicine.anatomical_structure ,Models, Animal ,Immunology ,Parasitology - Abstract
Summary Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT. Depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts, while recovery of the hematopoietic stem and progenitor compartments and the erythroid lineage were largely unaffected. Depletion of the intestinal microbiota also reduced dietary energy uptake and visceral fat stores. Caloric supplementation through sucrose in the drinking water improved post-BMT hematopoietic recovery in mice with a depleted intestinal flora. Taken together, we show that the intestinal microbiota contribute to post-BMT hematopoietic reconstitution in mice through improved dietary energy uptake.
- Published
- 2018
39. Nutritional Support From the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice
- Author
-
Marcel R.M. van den Brink, Enrico Velardi, Lorenz Jahn, Robert R. Jenq, Melissa D. Docampo, Eric G. Pamer, Benjamin H. Durham, Christoph K. Stein-Thoeringer, Hillary V. Jay, Anna Staffas, Ann E. Slingerland, Odette M. Smith, Sophie Lieberman, Jennifer Tsai, Jonathan U. Peled, Yusuke Shono, Justin R. Cross, Amanda J. Pickard, Marina Burgos da Silva, and Amina Lazrak
- Subjects
Transplantation ,Haematopoiesis ,Bone marrow transplantation ,business.industry ,Immunology ,Medicine ,Hematology ,business - Published
- 2018
40. Luteinizing Hormone-Releasing Hormone Enhances T Cell Recovery following Allogeneic Bone Marrow Transplantation
- Author
-
Christopher G. King, Jamieson Bretz, Rebecca A. Nejat, Robert M. Samstein, Jarrod A Dudakov, Gabrielle L. Goldberg, Ann P. Chidgey, Marcel R.M. van den Brink, Richard L. Boyd, David Suh, Odette M. Smith, and Selina Chen-Kiang
- Subjects
medicine.medical_specialty ,Myeloid ,Naive T cell ,medicine.medical_treatment ,T cell ,Immunology ,Immunosuppression ,Gonadotropin-releasing hormone ,Biology ,medicine.anatomical_structure ,Endocrinology ,Sex steroid ,Internal medicine ,medicine ,Immunology and Allergy ,Bone marrow ,Luteinizing hormone - Abstract
Posttransplant immunodeficiency, specifically a lack of T cell reconstitution, is a major complication of allogeneic bone marrow transplantation. This immunosuppression results in an increase in morbidity and mortality from infections and very likely contributes to relapse. In this study, we demonstrate that sex steroid ablation using leuprolide acetate, a luteinizing hormone-releasing hormone agonist (LHRHa), increases the number of lymphoid and myeloid progenitor cells in the bone marrow and developing thymocytes in the thymus. Although few differences are observed in the peripheral myeloid compartments, the enhanced thymic reconstitution following LHRHa treatment and allogeneic bone marrow transplantation leads to enhanced peripheral T cell recovery, predominantly in the naive T cell compartment. This results in an increase in T cell function in vivo and in vitro. Graft-versus-host-disease is not exacerbated by LHRHa treatment and graft-versus-tumor activity is maintained. Because LHRHa allows for reversible (and temporary) sex steroid ablation, has a strong safety profile, and has been clinically approved for diseases such as prostate and breast cancer, this drug treatment represents a novel therapeutic approach to reversal of thymic atrophy and enhancement of immunity following immunosuppression.
- Published
- 2009
41. Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation
- Author
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Christine Volk, Christopher G. King, Onder Alpdogan, Gabrielle L. Goldberg, Odette M. Smith, Sydney X. Lu, Miguel-Angel Perales, Robert R. Jenq, Marcel R.M. van den Brink, Nury L. Yim, David Suh, Lucy W. Kappel, Amanda M. Holland, Uttam K. Rao, Adi Diab, Jedd D. Wolchok, Alan N. Houghton, Il-Kang Na, Olaf Penack, and Johannes L. Zakrzewski
- Subjects
Fibroblast Growth Factor 7 ,medicine.medical_treatment ,Immunology ,Thymus Gland ,CD8-Positive T-Lymphocytes ,Biology ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,Biochemistry ,DNA vaccination ,Mice ,chemistry.chemical_compound ,Immune system ,Interferon ,Vaccines, DNA ,medicine ,Animals ,Transplantation, Homologous ,Lymphocyte Count ,Bone Marrow Transplantation ,Transplantation Chimera ,Transplantation ,Forkhead Transcription Factors ,Cell Biology ,Hematology ,Immunotherapy ,Mice, Inbred C57BL ,Survival Rate ,surgical procedures, operative ,medicine.anatomical_structure ,chemistry ,CD4 Antigens ,Female ,Keratinocyte growth factor ,Bone marrow ,Stem cell ,Immunologic Memory ,Cell Division ,CD8 ,Plasmids ,medicine.drug - Abstract
Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.
- Published
- 2009
42. IL-17 contributes to CD4-mediated graft-versus-host disease
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Odette M. Smith, Lucy W. Kappel, Nicholas M. Mark, Jeremy Grubin, David Suh, Cassandra Ligh, Christopher G. King, Gabrielle L. Goldberg, Yoichiro Iwakura, Amanda M. Holland, Chen Liu, Glenn Heller, and Marcel R.M. van den Brink
- Subjects
CD4-Positive T-Lymphocytes ,Immunology ,Graft vs Host Disease ,Biology ,Biochemistry ,Proinflammatory cytokine ,Interleukin 22 ,Interferon-gamma ,Mice ,Interleukin 21 ,Interferon ,medicine ,Animals ,Transplantation, Homologous ,Cytotoxic T cell ,Interferon gamma ,Lymphocytes ,Bone Marrow Transplantation ,Cell Proliferation ,Mice, Knockout ,Transplantation ,Interleukins ,Interleukin-17 ,Cell Biology ,Hematology ,medicine.disease ,surgical procedures, operative ,Graft-versus-host disease ,Female ,Interleukin 17 ,Spleen ,medicine.drug - Abstract
CD4+ interleukin-17 (IL-17)+ T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4+ donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17−/− T-cell recipients. However, upon transfer of murine IL-17−/− CD4+ T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4+ T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17−/− CD4+ T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-γ–secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-γ, IL-4, and IL-6) in recipients of IL-17−/− CD4+ T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.
- Published
- 2009
43. Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation
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Sydney X. Lu, Vanessa M. Hubbard, Gabrielle L. Goldberg, David Suh, S. Önder Alpdogan, Christopher R. King, Suzanne McGoldrick, Jeremy Grubin, Marcel R.M. van den Brink, Adam A. Kochman, Neel Patel, Tulin Budak-Alpdogan, and Odette M. Smith
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Time Factors ,T-Lymphocytes ,T cell ,Immunology ,Graft vs Host Disease ,Apoptosis ,Mice, Transgenic ,Biology ,Biochemistry ,TNF-Related Apoptosis-Inducing Ligand ,Mice ,Interleukin 21 ,medicine ,Animals ,Transplantation, Homologous ,Cytotoxic T cell ,fas Receptor ,Cells, Cultured ,Bone Marrow Transplantation ,Cell Proliferation ,bcl-2-Associated X Protein ,Transplantation ,Mice, Inbred BALB C ,Cell Differentiation ,Cell Biology ,Hematology ,T lymphocyte ,Mice, Inbred C57BL ,Hyaluronan Receptors ,medicine.anatomical_structure ,Cancer research ,Female ,Bone marrow ,Stem cell ,CD8 - Abstract
Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-XL expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)- or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4+ and CD8+ T cells. Transplantation of RAG-2-eGFP–transgenic BM revealed that proliferating eGFPloCD44hi donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFPhiCD44lo recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester–labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44hi phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells.
- Published
- 2008
44. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors
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David Suh, Michel Sadelain, Gabrielle Rizzuto, Christopher R. King, Javier Cabrera-Perez, Sydney X. Lu, Glenn Heller, Gabrielle L. Goldberg, John C. Markley, Robert R. Jenq, Odette M. Smith, Juan Carlos Zúñiga-Pflücker, Johannes L. Zakrzewski, Marcel R.M. van den Brink, Isabelle Riviere, Chen Lu, Amanda M. Holland, Renier J. Brentjens, Jeremy Grubin, and Derek B. Sant'Angelo
- Subjects
medicine.medical_treatment ,Biomedical Engineering ,Bioengineering ,Biology ,Transfection ,Major histocompatibility complex ,Immunotherapy, Adoptive ,Applied Microbiology and Biotechnology ,Article ,Cell Line ,Major Histocompatibility Complex ,Mice ,Cell Line, Tumor ,Neoplasms ,Precursor cell ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Precursor Cells, T-Lymphoid ,T lymphocyte ,Immunotherapy ,Cell culture ,Immunology ,biology.protein ,Molecular Medicine ,Ex vivo ,T-Cell Precursors ,Biotechnology - Abstract
We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.
- Published
- 2008
45. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation
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Marcel R.M. van den Brink, Onder Alpdogan, Vanessa M. Hubbard, Adi Diab, Andrew Chow, Theis H. Terwey, Adam A. Kochman, Sydney X. Lu, David Suh, Eric G. Pamer, G. Heller, Ewa Menet, Juan Carlos Zúñiga-Pflücker, Gabrielle Rizzuto, Theo D. Kim, Odette M. Smith, Javier Cabrera-Perez, Johannes L. Zakrzewski, Jeremy Grubin, Neel Patel, Radhika Radhakrishnan, Miguel-Angel Perales, and Stephanie J. Muriglan
- Subjects
Adoptive cell transfer ,Fibroblast Growth Factor 7 ,T-Lymphocytes ,T cell ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Biology ,Lymphocyte Depletion ,General Biochemistry, Genetics and Molecular Biology ,Mice ,medicine ,Animals ,Regeneration ,Listeriosis ,Stem Cells ,Graft vs Tumor Effect ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Adoptive Transfer ,Coculture Techniques ,Transplantation ,Haematopoiesis ,medicine.anatomical_structure ,Immunology ,Cytokine secretion ,Bone marrow ,Stem cell - Abstract
Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.
- Published
- 2006
46. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration
- Author
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Daniel H.D. Gray, Marcel R.M. van den Brink, Onder Alpdogan, Richard L. Boyd, Sydney X. Lu, Neel Patel, Odette M. Smith, Stephanie J. Muriglan, David Suh, Gabrielle L. Goldberg, Adam A. Kochman, Vanessa M. Hubbard, Jared Feinman, and Jeffrey M. Eng
- Subjects
medicine.medical_specialty ,Fibroblast Growth Factor 7 ,T-Lymphocytes ,Immunology ,Spleen ,Thymus Gland ,Biology ,Fibroblast growth factor ,Biochemistry ,Andrology ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Regeneration ,Lymphopoiesis ,Bone Marrow Transplantation ,Immunobiology ,Mice, Knockout ,Age Factors ,Cell Biology ,Hematology ,Transplantation ,Thymocyte ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Keratinocyte growth factor ,Bone marrow - Abstract
Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)
- Published
- 2006
47. Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy
- Author
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Emily R Levy, Raymond H. Thornton, Johannes L. Zakrzewski, Marcel R.M. van den Brink, Andrea Z. Tuckett, Yusuke Shono, Fabiana M Kreines, and Odette M. Smith
- Subjects
medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Thymus Gland ,Biology ,Biochemistry ,Immunophenotyping ,Mice ,Immunity ,Neoplasms ,medicine ,Animals ,Lymphopoiesis ,Progenitor cell ,Antigens ,Bone Marrow Transplantation ,Immunobiology ,Immunity, Cellular ,Multipotent Stem Cells ,Age Factors ,Cell Biology ,Hematology ,Immunotherapy ,Hematopoietic Stem Cells ,Haematopoiesis ,Disease Models, Animal ,Phenotype ,Multipotent Stem Cell ,Female ,Stem cell ,Whole-Body Irradiation ,Stem Cell Transplantation - Abstract
T-cell deficiency related to disease, medical treatment, or aging represents a major clinical challenge and is associated with significant morbidity and mortality in cancer and bone marrow transplantation recipients. This study describes several innovative and clinically relevant strategies to manipulate thymic function based on an interventional radiology technique for intrathymic injection of cells or drugs. We show that intrathymic injection of multipotent hematopoietic stem/progenitor cells into irradiated syngeneic or allogeneic young or aged recipients resulted in efficient and long-lasting generation of functional donor T cells. Persistence of intrathymic donor cells was associated with intrathymic presence of cells resembling long-term hematopoietic stem cells, suggesting a self-renewal capacity of the intrathymically injected cells. Furthermore, our approach enabled the induction of long-term antigen-specific T-cell–mediated antitumor immunity following intrathymic injection of progenitor cells harboring a transgenic T-cell receptor gene. The intrathymic injection of interleukin-7 prior to irradiation conferred radioprotection. In addition, thymopoiesis of aged mice improved with a single intrathymic administration of low-dose keratinocyte growth factor, an effect that was sustained even in the setting of radiation-induced injury. Taken together, we established a preclinical framework for the development of novel clinical protocols to establish lifelong antigen-specific T-cell immunity.
- Published
- 2014
48. IL-22 Directly Regulates Intestinal Stem Cells, Protecting Epithelium from GvHD and Reducing GvHD Mortality
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Anna Mertelsmann, Marco Calafiore, Laura Martin, Jarrod A Dudakov, Lauren Young, Robert R. Jenq, Gillian Lawrence, Alan M. Hanash, Natalie Luo, Marcel R.M. van den Brink, Guoqiang Hua, Chen Liu, Juliet Ivanov, Richard Kolesnick, Odette M. Smith, Enrico Velardi, Caroline A. Lindemans, and Margaret O'Connor
- Subjects
Interleukin 22 ,Transplantation ,medicine.anatomical_structure ,business.industry ,Immunology ,Medicine ,Hematology ,Stem cell ,business ,Epithelium - Published
- 2015
- Full Text
- View/download PDF
49. Treatment with Antibiotics Containing Activity Against Obligate Anaerobes Worsens GVHD Survival in Mice and Humans after Allogeneic BMT
- Author
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Kenya Honda, Melissa D. Docampo, Marcel R.M. van den Brink, Ying Taur, Robert R. Jenq, Odette M. Smith, Jyotsna Gupta, Yusuke Shono, and Sophia R. Liberman
- Subjects
endocrine system ,Imipenem ,Cefepime ,Immunology ,Population ,Aztreonam ,Biology ,Biochemistry ,Meropenem ,chemistry.chemical_compound ,medicine ,education ,education.field_of_study ,Transplantation ,business.industry ,Imipenem/cilastatin ,Clindamycin ,Cell Biology ,computer.file_format ,Hematology ,surgical procedures, operative ,chemistry ,Anaerobic bacteria ,ABX test ,business ,computer ,medicine.drug - Abstract
A relationship between the microbiota and GVHD has long been suspected but is still not well understood. Recently, several studies have indicated that obligately anaerobic commensal intestinal bacteria may be beneficial for intestinal health. Recent studies have found that obligate anaerobes in the intestine, in particular Clostridial species, are important mediators of intestinal homeostasis and prevent inflammation by upregulating intestinal regulatory T cells (Tregs). In this study we sought to further characterize the relationship between the microbiota and GVHD, focusing on the effects of antibiotics (ABX) with anaerobic coverage. First, we treated healthy 129S1 mice with either ABX that included significant activity against anaerobic bacteria (piperacillin-tazobactam; pip-tazo, imipenem-cilastatin; imipenem or ones with reduced activity (cefepime, aztreonam). Mice were treated by subcutaneous injections of each antibiotic twice a day for two days (500 mg/kg for pip-tazo and 100 mg/kg for others) and stool samples were collected, followed by 16S rRNA gene amplification and sequence analysis. We found that treatment with pip-tazo and imipenem significantly reduced the abundance of anaerobic Clostridial species and increased that of Enterococcus, while treatment with cefepime and aztreonam spared Clostridiales (Figure 1A). We next investigated the effects of antibiotic treatment in a clinically relevant MHC matched, minor antigen mismatched murine allogeneic BMT model. Lethally irradiated 129S1 recipients were transplanted with C57BL/6 T cell depleted bone marrow cells and 2 × 106 C57BL/6 T cells. Recipients were either treated with imipenem or aztreonam subcutaneously beginning on day +10 after BMT. We observed significantly worsened GVHD survival in imipenem-treated recipients (Figure 1B, P We have also retrospectively evaluated the impact of antibiotic spectrum of activity on clinical GVHD-related mortality. We examined a cohort of 546 adult patients transplanted at MSKCC from 1992 to 2013 who received conventional (non-T cell depleted) grafts and received treatment for peri-transplant fever with empiric ABX classified as either including anaerobic coverage or with reduced anaerobic activity. Of these, 156 patients who received ABX from both classifications were excluded, as were 99 patients exposed to other ABX with anaerobic coverage not routinely used to treat peri-transplant fever. We examined the impact of anaerobic coverage in the remaining 291 patients. Therapies for peri-transplant fever were divided into those that included significant activity against anaerobic bacteria (pip-tazo, ticarcillin-clavulanate, imipenem, meropenem), and those with reduced activity (ceftriaxone, ceftazidime, cefepime, aztreonam). Additional ABX that have anaerobic activity but were not routinely used to treat peri-transplant fever included metronidazole, oral vancomycin and clindamycin. We found that 60 patients that received ABX without anaerobic coverage had a significantly reduced incidence of GVHD-related mortality, compared to 231 patients treated with anaerobe-active ABX (Figure 2, P Taken together, our results suggest that a population of anaerobic commensals may mediate protection against life-threatening GVHD and that selecting ABX with a more limited spectrum of activity can prevent microbiota injury and reduce GVHD. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
- Full Text
- View/download PDF
50. Intrathymic Innate Lymphoid Cells: Long-Lived Mediators Of Immune Regeneration
- Author
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Emily R Levy, Jarrod A Dudakov, Fabiana M Kreines, Marcel R.M. van den Brink, Enrico Velardi, Denzel Cole, Lauren F. Young, Odette M. Smith, and Alan M. Hanash
- Subjects
education.field_of_study ,medicine.medical_treatment ,T cell ,Immunology ,Innate lymphoid cell ,Population ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Interleukin 22 ,Cytokine ,medicine.anatomical_structure ,Immune system ,Cancer research ,medicine ,Thymic Damage ,education ,CD8 - Abstract
Innate lymphoid cells (ILCs) are a newly described heterogeneous population of immune cells that can be defined by their expression of specific transcription factors (Tbet, GATA3 or RORgt) and their production of cytokines (IFNg, IL-13, or IL-22). Group 3 ILCs (which can be identified by expression of RORgt and production of IL-22) have been implicated in the maintenance and function of tissues as diverse as liver, gut, lung, spleen and lymph nodes. We have recently described a central role for intrathymic group 3 ILCs (tILC3) in a complex network of endogenous thymic regeneration (Dudakov et al. 2012 Science 336:91-95); a crucial function that allows for renewal of immune competence following infection or immune depletion caused by cytoreductive chemotherapy or radiation injury. In this model, 1) loss of thymic cellularity (and in particular the depletion of CD4+CD8+ double positive, DP, thymocytes) triggers, 2) upregulation of IL-23 by dendritic cells (DCs) which induces, 3) the production of IL-22 by tILC3. Given that IL-22 promotes the survival and proliferation of thymic epithelial cells (TECs), this cascade of events leads to regeneration of the supporting epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis. In our previous studies we had demonstrated that, unlike other lymphoid cells, tILC3 were extremely radio-resistant with little if any depletion of cells after even lethal doses of total body irradiation (TBI). Consistent with these findings, here we show that a considerable proportion of tILC3 were non-cycling in steady-state conditions and expressed high endogenous levels of the anti-apoptotic protein Bcl-2 (Fig. 1a). Perhaps unsurprising given their resistance to proliferation-targeted damage, a residual population of host-derived tILC3s could be identified for up to 12 months after syngeneic hematopoietic stem cell transplantation (HSCT). Although at this stage it is unclear if this is because they are very long-lived or if they have the capacity for self-renewal, residual host tILC3 were almost exclusively non-proliferating and expressed high levels of Bcl-2, indicating a quiescent state. Transcriptome analysis of IL-22 target cells revealed two mechanisms by which IL-22 mediates its effects on TECs; 1) by directly promoting the upregulation of proliferation-associated molecules such as E2f2; and 2) by reducing expression of negative signalling regulators such as Socs3 (an inhibitor of cytokine signalling) and Tnfrsf11b (Osteoprotegerin, a RANKL decoy receptor). This suggests a possible secondary role for IL-22 in promoting enhanced responsiveness to other regenerative factors, such as KGF, BMP4 and RANKL, all of which are increased in the thymus as part of the regenerative response after TBI (Fig. 1b). In our previous studies we found that increased production of IL-22 by tILC3 in response to immune injury was strikingly consistent across several mouse models with lesions in T cell development, including TBI, exposure to corticosteroids, and in mice with genetic mutations. However, one model where this increase in IL-22 does not occur is in the setting of graft versus host disease (GVHD), where tILC3s are profoundly depleted in the thymus (Fig. 1c), likely contributing towards reduced rejuvenation of thymic cellularity and failure to recover during GVHD. Intriguingly, although IL-22 appears to play a considerable role in the regenerative capacity of tILC3, preliminary studies suggest that depletion of tILC3 in IL-22 deficient mice leads to significantly worse recovery compared to Il22-/- mice replete with tILC3 (Fig. 1d). Consistent with this hypothesis of an alternate role in regeneration beyond IL-22 production, production of RANKL is also increased by tILC3 after thymic damage. Thus, we have identified that tILC3 are highly radio-resistant and long-lived owing largely to their quiescent nature and resistance to apoptosis. These pre-clinical studies focusing on tILC3 biology not only help to identify the mechanisms that allow this nascent cell population to mediate its regenerative effects, but also offer a tantalising glimpse into an alternate pathway mediating their regeneration in the thymus. Taken together, these studies could have the potential to result in novel clinical approaches to enhance T cell immunity in individuals with T cell deficiencies due to aging, infectious disease, chemotherapy or radiation injury. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
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