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Book ; Online ; E-Book: Immune biology of allogeneic hematopoietic stem cell transplantation

Socié, Gérard / Zeiser, Robert / Blazar, Bruce R.

models in discovery and translation

2019

Author's details	edited by Gérard Socié, Robert Zeiser, Bruce R. Blazar
Keywords	Hematopoietic stem cells / Transplantation ; Blood / Diseases ; Immunology ; Graft versus host disease
Language	English
Size	1 Online-Ressource (xv, 431 Seiten), Illustrationen
Edition	Second edition
Publisher	Elsevier AP Academic Press
Publishing place	London
Publishing country	Great Britain
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
HBZ-ID	HT020194964
ISBN	978-0-12-813439-9 ; 9780128126301 ; 0-12-813439-9 ; 0128126302
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation.

Kean, Leslie S / Blazar, Bruce R

The Journal of clinical investigation

2024 Volume 134, Issue 8

MeSH term(s)	Hematopoietic Stem Cell Transplantation ; Humans
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI179944
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book: Immune biology of allogeneic hematopoietic stem cell transplantation

Socié, Gérard / Blazar, Bruce R.

models in discovery and translation

2013

Title variant	Allogeneic heamatopoietic stem cell transplantation
Author's details	ed. by Gérard Socié and Bruce R. Blazar
Keywords	Hematopoietic stem cells--Transplantation ; Immunology ; Graft versus host disease
Language	English
Size	XVIII, 518 S. : Ill., graph. Darst., 28 cm
Publisher	Elsevier Acad. Press
Publishing place	Amsterdam u.a.
Publishing country	Netherlands
Document type	Book
HBZ-ID	HT017594003
ISBN	978-0-12-416004-0 ; 0-12-416004-2
Database	Catalogue ZB MED Medicine, Health

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Shelf mark	Loan status	Location
2013 A 258	available for loan (reading room)	Lesesaal EG

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Article ; Online: Antibody based conditioning for allogeneic hematopoietic stem cell transplantation.

Saha, Asim / Blazar, Bruce R

Frontiers in immunology

2022 Volume 13, Page(s) 1031334

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells ( ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.
MeSH term(s)	Mice ; Animals ; Neoplasm Recurrence, Local ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Transplantation Conditioning/methods ; Graft vs Host Disease/etiology ; Graft vs Host Disease/prevention & control ; Hematologic Neoplasms/therapy
Language	English
Publishing date	2022-10-20
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; 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.2022.1031334
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Acute Graft-versus-Host Disease.

Zeiser, Robert / Blazar, Bruce R

The New England journal of medicine

2018 Volume 378, Issue 6, Page(s) 586

MeSH term(s)	Bone Marrow Transplantation ; Graft vs Host Disease ; Humans
Language	English
Publishing date	2018-02-07
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc1716969
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Article ; Online: Cytolytic CD4

Bolivar-Wagers, Sara / Larson, Jemma H / Jin, Sujeong / Blazar, Bruce R

Frontiers in immunology

2022 Volume 13, Page(s) 864748

Abstract: Regulatory T-cells (Treg) are critical for the maintenance of immune homeostasis and tolerance induction. While the immunosuppressive mechanisms of Treg have been extensively investigated for decades, the mechanisms responsible for Treg cytotoxicity and ... ...

Abstract	Regulatory T-cells (Treg) are critical for the maintenance of immune homeostasis and tolerance induction. While the immunosuppressive mechanisms of Treg have been extensively investigated for decades, the mechanisms responsible for Treg cytotoxicity and their therapeutic potential in regulating immune responses have been incompletely explored and exploited. Conventional cytotoxic T effector cells (Teffs) are known to be important for adaptive immune responses, particularly in the settings of viral infections and cancer. CD4+ and CD8+ Treg subsets may also share similar cytotoxic properties with conventional Teffs. Cytotoxic effector Treg (cyTreg) are a heterogeneous population in the periphery that retain the capacity to suppress T-cell proliferation and activation, induce cellular apoptosis, and migrate to tissues to ensure immune homeostasis. The latter can occur through several cytolytic mechanisms, including the Granzyme/Perforin and Fas/FasL signaling pathways. This review focuses on the current knowledge and recent advances in our understanding of cyTreg and their potential application in the treatment of human disease, particularly Graft-versus-Host Disease (GVHD).
MeSH term(s)	Graft vs Host Disease ; Humans ; Immunotherapy ; Perforin/metabolism ; T-Lymphocytes, Cytotoxic ; T-Lymphocytes, Regulatory
Chemical Substances	Perforin (126465-35-8)
Language	English
Publishing date	2022-04-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.864748
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease.

Thangavelu, Govindarajan / Blazar, Bruce R

Frontiers in immunology

2019 Volume 10, Page(s) 309

Abstract: Acute graft-vs.-host disease (GVHD) limits the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), a main therapy to treat various hematological disorders. Despite rapid progress in understanding GVHD pathogenesis, broad ... ...

Abstract	Acute graft-vs.-host disease (GVHD) limits the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), a main therapy to treat various hematological disorders. Despite rapid progress in understanding GVHD pathogenesis, broad immunosuppressive agents are most often used to prevent and remain the first line of therapy to treat GVHD. Strategies enhancing immune tolerance in allo-HSCT would permit reductions in immunosuppressant use and their associated undesirable side effects. In this review, we discuss the mechanisms responsible for GVHD and advancement in strategies to achieve immune balance and tolerance thereby avoiding GVHD and its complications.
MeSH term(s)	Acute Disease ; Animals ; Cell Movement ; Cell- and Tissue-Based Therapy ; Graft vs Host Disease/prevention & control ; Humans ; Immune Tolerance ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chemokine/immunology ; T-Lymphocytes/physiology
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Chemokine
Language	English
Publishing date	2019-03-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00309
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease.

Hippen, Keli L / Hefazi, Mehrdad / Larson, Jemma H / Blazar, Bruce R

Frontiers in immunology

2022 Volume 13, Page(s) 926550

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure. Adoptive cell therapy (ACT) with Treg has demonstrated, first in murine models and now in patients, that prophylactic Treg infusion can also suppress GVHD. While clinical trials have demonstrated Treg reduce severe GVHD occurrence, several impediments remain, including Treg variability and practical need for individualized Treg production for each patient. Additionally, there are challenges in the use of in vitro expansion techniques and in achieving in vivo Treg persistence in context of both immune suppressive drugs and in lymphoreplete patients being treated for GVHD. This review will focus on 3 main translational approaches taken to improve the efficacy of tTreg ACT in GVHD prophylaxis and development of treatment options, following HSCT: genetic modification, manipulating TCR and cytokine signaling, and Treg production protocols. In vitro expansion for Treg ACT presents a multitude of approaches for gene modification to improve efficacy, including: antigen specificity, tissue targeting, deletion of negative regulators/exhaustion markers, resistance to immunosuppressive drugs common in GVHD treatment. Such expansion is particularly important in patients without significant lymphopenia that can drive Treg expansion, enabling a favorable Treg:Teff ratio in vivo. Several potential therapeutics have also been identified that enhance tTreg stability or persistence/expansion following ACT that target specific pathways, including: DNA/histone methylation status, TCR/co-stimulation signaling, and IL-2/STAT5 signaling. Finally, this review will discuss improvements in Treg production related to tissue source, Treg subsets, therapeutic approaches to increase Treg suppression and stability during tTreg expansion, and potential for storing large numbers of Treg from a single production run to be used as an off-the-shelf infusion product capable of treating multiple recipients.
MeSH term(s)	Animals ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Mice ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes, Regulatory
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-07-28
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.926550
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges.

Hefazi, Mehrdad / Bolivar-Wagers, Sara / Blazar, Bruce R

International journal of molecular sciences

2021 Volume 22, Issue 18

Abstract: Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat ... ...

Abstract	Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs. Functional enhancement through genetic engineering offers the possibility of improved potency, specificity, and persistence. In this review, we provide the most up to date preclinical and clinical data on Treg cell therapy with a particular focus on GVHD. We discuss the different Treg subtypes and highlight the pharmacological and genetic approaches under investigation to enhance the application of Tregs in allo-HSCT. Lastly, we discuss the remaining challenges for optimal clinical translation and provide insights as to future directions of the field.
MeSH term(s)	Animals ; Biomarkers ; Cytokines/metabolism ; Energy Metabolism ; Genetic Engineering ; Graft vs Host Disease/etiology ; Graft vs Host Disease/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immunomodulation ; Immunophenotyping ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Translational Research, Biomedical
Chemical Substances	Biomarkers ; Cytokines
Language	English
Publishing date	2021-09-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22189676
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease.

Zanin-Zhorov, Alexandra / Blazar, Bruce R

Clinical immunology (Orlando, Fla.)

2021 Volume 230, Page(s) 108823

Abstract: Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating ... ...

Abstract	Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-β signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.
MeSH term(s)	Acetamides/pharmacology ; Animals ; Chronic Disease ; Disease Models, Animal ; Fibrosis ; Graft vs Host Disease/enzymology ; Graft vs Host Disease/immunology ; Graft vs Host Disease/therapy ; Humans ; Immunomodulation ; Models, Immunological ; Protein Kinase Inhibitors/pharmacology ; T-Lymphocytes, Regulatory/immunology ; rho-Associated Kinases/antagonists & inhibitors ; rho-Associated Kinases/immunology
Chemical Substances	Acetamides ; Protein Kinase Inhibitors ; belumosudil ; ROCK1 protein, human (EC 2.7.11.1) ; ROCK2 protein, human (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2021.108823
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