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CYTOSOLIC NUCLEIC ACID SENSORS PROMOTE INTESTINAL EPITHELIALINTEGRITY DURING ACUTE TISSUE DAMAGE AND PROTECT FROM GRAFT-VERSUS-HOST DISEASE
Author(s):
Julius C. Fischer
,
Julius C. Fischer
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Gabriel Eisenkolb
,
Gabriel Eisenkolb
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Michael Bscheider
,
Michael Bscheider
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Alexander Wintges
,
Alexander Wintges
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Christian Peschel
,
Christian Peschel
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Caroline A. Lindemans
,
Caroline A. Lindemans
Affiliations:
Pediatric Blood and Bone marrow Transplant Program,University Medical 20 Center Utrecht,Utrecht,Netherlands
Alan M. Hanash
,
Alan M. Hanash
Affiliations:
Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,United States
Robert Jenq
,
Robert Jenq
Affiliations:
Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,United States
Jarrod Dudakov
,
Jarrod Dudakov
Affiliations:
Clinical Research Division,Fred Hutchinson 44 Cancer Center,Seattle,United States
Tobias Haas
,
Tobias Haas
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
Marcel R.M. van den Brink
,
Marcel R.M. van den Brink
Affiliations:
Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,United States
Hendrik Poeck
Hendrik Poeck
Affiliations:
3. Medizinische Klinik; Klinikum Rechts der Isar,Technische Universität München,München,Germany
(Abstract release date: 05/18/17) EHA Library. Poeck H. 06/24/17; 181733; S446
Dr. Hendrik Poeck
Dr. Hendrik Poeck
Contributions
PDF Abstract
Abstract

Abstract: S446

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45

Location: Room N104

Background

The epithelial lining of the gastrointestinal (GI) tract represents the first line of defense mediating protection from microbial challenge. Next to producing antimicrobial molecules, Paneth cells contribute to this defense by providing a supportive niche for intestinal stem cells (ISCs) maintaining the epithelium. Loss of intestinal barrier function by total body irradiation (TBI) or chemotherapy (CTx) is an essential step in enhancing the development of inflammatory disease associated with epithelial surface such as graft versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our current limited ability to protect epithelium and promote regeneration in GVHD is at least in part due a limited understanding of ISC function and epithelial regeneration in the allo-HSCT setting. Recent work suggests a protective function of Type I Interferons (IFN-I) at epithelial surfaces and in the preventon of GVHD. Yet, the molecular pathways that trigger those functions during acute tissue damage are poorly understood. Given that the RIG-I-MAVS and STING pathways are important regulators of IFN-I production and IFN-Is can initiate epithelial repair, we hypothesized that activation of these pathways during conditioning therapy may protect epithelial integrity and could be exploited interventionally to promote intestinal barrier function and prevent GVHD. 

Aims
We aimed at characterizing the role of of RIG-I/MAVS and STING during allo-HSCT, and at understanding mechanisms by which activation of these pathways can promote barrier function to enhance healing after genotoxic tissue damage. 

Methods
We used an integrated approach with pathophysiologic mechanistic studies on IECs in experimental mouse models (MHC-mismatched and minor histocompatibility antigen (miHA)-mismatched transplants to model highly aggressive GVHD; genotoxic stress induced by TBI and CTx) and evaluation of immune-mediated regenerative strategies to promote epithelial barrier function (organoid cultures, barrier function test)

Results

Mice lacking MAVS were more sensitive to total body irradiation (TBI)- and chemotherapy induced intestinal barrier damage, and, like RIG-I-deficient mice, developed worse graft transplantation (allo-HSCT). This phenotype was not associated with changes in the intestinal microbiota, but with reduced epithelial integrity and regeneration. Conversely, targeted activation of the RIG-I pathway during damage promoted these processes and ameliorated GVHD. Mechanistically, IFN-I (RIG-I-induced or recombinant) could promote growth of intestinal organoid cultures and production of RegIIIγ. Importantly,our findings were not confined to RIG-I/MAVS signaling, as interventional engagement of the STING pathway also protected from loss of barrier function and GVHD and led to IFN-I-dependent intestinal organoid growth. Consistent with this, STING-deficient animals suffered from worse GVHD.

Conclusion
Our studies may have the potential to develop novel targeted therapies (i) to promote intestinal barrier integrity, (ii) to prevent the development of GVHD, and (iii) for the regenerative response of other tissues. 

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Innate Immunity, Graft-versus-host disease (GVHD), Stem cell niche, Regeneration

Abstract: S446

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45

Location: Room N104

Background

The epithelial lining of the gastrointestinal (GI) tract represents the first line of defense mediating protection from microbial challenge. Next to producing antimicrobial molecules, Paneth cells contribute to this defense by providing a supportive niche for intestinal stem cells (ISCs) maintaining the epithelium. Loss of intestinal barrier function by total body irradiation (TBI) or chemotherapy (CTx) is an essential step in enhancing the development of inflammatory disease associated with epithelial surface such as graft versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our current limited ability to protect epithelium and promote regeneration in GVHD is at least in part due a limited understanding of ISC function and epithelial regeneration in the allo-HSCT setting. Recent work suggests a protective function of Type I Interferons (IFN-I) at epithelial surfaces and in the preventon of GVHD. Yet, the molecular pathways that trigger those functions during acute tissue damage are poorly understood. Given that the RIG-I-MAVS and STING pathways are important regulators of IFN-I production and IFN-Is can initiate epithelial repair, we hypothesized that activation of these pathways during conditioning therapy may protect epithelial integrity and could be exploited interventionally to promote intestinal barrier function and prevent GVHD. 

Aims
We aimed at characterizing the role of of RIG-I/MAVS and STING during allo-HSCT, and at understanding mechanisms by which activation of these pathways can promote barrier function to enhance healing after genotoxic tissue damage. 

Methods
We used an integrated approach with pathophysiologic mechanistic studies on IECs in experimental mouse models (MHC-mismatched and minor histocompatibility antigen (miHA)-mismatched transplants to model highly aggressive GVHD; genotoxic stress induced by TBI and CTx) and evaluation of immune-mediated regenerative strategies to promote epithelial barrier function (organoid cultures, barrier function test)

Results

Mice lacking MAVS were more sensitive to total body irradiation (TBI)- and chemotherapy induced intestinal barrier damage, and, like RIG-I-deficient mice, developed worse graft transplantation (allo-HSCT). This phenotype was not associated with changes in the intestinal microbiota, but with reduced epithelial integrity and regeneration. Conversely, targeted activation of the RIG-I pathway during damage promoted these processes and ameliorated GVHD. Mechanistically, IFN-I (RIG-I-induced or recombinant) could promote growth of intestinal organoid cultures and production of RegIIIγ. Importantly,our findings were not confined to RIG-I/MAVS signaling, as interventional engagement of the STING pathway also protected from loss of barrier function and GVHD and led to IFN-I-dependent intestinal organoid growth. Consistent with this, STING-deficient animals suffered from worse GVHD.

Conclusion
Our studies may have the potential to develop novel targeted therapies (i) to promote intestinal barrier integrity, (ii) to prevent the development of GVHD, and (iii) for the regenerative response of other tissues. 

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Innate Immunity, Graft-versus-host disease (GVHD), Stem cell niche, Regeneration

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