Contributions
Abstract: EP717
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Chronic graft-vs-host disease (cGVHD) is an immune related disease condition that is incompletely understood. It coincides with transplantation of non-purified Hematopoietic Stem Cells (HSCs) in up to 70% of patients and represents a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HCT). Sclerodermatous GVHD (Scl GVHD) is a more severe form of cGVHD and is associated with poor prognosis and low sensitivity to immune suppression which is the current first line therapy.
Aims
We hypothesized that there exist a range of inflammatory cells delivering profibrotic signals. Such signals while initially performing tissue repair following transplant-related injury of the skin, can eventually perpetuate uncontrolled pathologic fibrosis. Therefore, we aimed at identifying downstream fibrotic gene expression signatures in fibroblasts associated with chronic inflammation.
Methods
In skin biopsies, we show that JUN and CD47 are key regulatory molecules overexpressed and activated in Scl cGVHD patients. Mechanistically, using ChIP-seq and ATAC-seq we describe JUNs role in altering the transcriptional landscape of IL6 and CD47. Finally, using novel and conventional mouse models that recapitulate clinical Scl cGVHD we show the effect of anti-CD47 and anti-IL6 antibodies as promising therapeutics for the treatment of inflammation and fibrosis in Scl cGVHD patients.
Results
1. Our combined expression and signaling data confirm that JUN activation is tightly linked to a profibrotic and immune dampening signature in Scl cGVHD.
2. JUN deletion alters chromatin accessibility and nucleosome positioning of immune regulatory and fibrosis genes in human Scl cGVHD.
3. We demonstrate that JUN, CD47 and IL6 are upregulated in a novel mouse model of Scl cGVHD demonstrating progressive disease.
4. Finally we show that CD47 and IL6 blockade are an effective therapeutic strategy for the treatment of sclerosis in the skin related to Scl cGVHD in mice.
Conclusion
In summary, we describe a novel mechanism through which chronic inflammation perpetuates fibrosis via activation of JUN, CD47, IL6, which result in a profibrotic signature in Scl cGVHD. Our findings are of particular interest, as these pathways have been implicated in tissue sclerosis in other contexts and indicate potential targets for therapeutic intervention using anti-CD47 and IL6R antibodies.
Keyword(s): Chronic graft-versus-host, Immune response, Immune therapy
Abstract: EP717
Type: E-Poster Presentation
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
Chronic graft-vs-host disease (cGVHD) is an immune related disease condition that is incompletely understood. It coincides with transplantation of non-purified Hematopoietic Stem Cells (HSCs) in up to 70% of patients and represents a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HCT). Sclerodermatous GVHD (Scl GVHD) is a more severe form of cGVHD and is associated with poor prognosis and low sensitivity to immune suppression which is the current first line therapy.
Aims
We hypothesized that there exist a range of inflammatory cells delivering profibrotic signals. Such signals while initially performing tissue repair following transplant-related injury of the skin, can eventually perpetuate uncontrolled pathologic fibrosis. Therefore, we aimed at identifying downstream fibrotic gene expression signatures in fibroblasts associated with chronic inflammation.
Methods
In skin biopsies, we show that JUN and CD47 are key regulatory molecules overexpressed and activated in Scl cGVHD patients. Mechanistically, using ChIP-seq and ATAC-seq we describe JUNs role in altering the transcriptional landscape of IL6 and CD47. Finally, using novel and conventional mouse models that recapitulate clinical Scl cGVHD we show the effect of anti-CD47 and anti-IL6 antibodies as promising therapeutics for the treatment of inflammation and fibrosis in Scl cGVHD patients.
Results
1. Our combined expression and signaling data confirm that JUN activation is tightly linked to a profibrotic and immune dampening signature in Scl cGVHD.
2. JUN deletion alters chromatin accessibility and nucleosome positioning of immune regulatory and fibrosis genes in human Scl cGVHD.
3. We demonstrate that JUN, CD47 and IL6 are upregulated in a novel mouse model of Scl cGVHD demonstrating progressive disease.
4. Finally we show that CD47 and IL6 blockade are an effective therapeutic strategy for the treatment of sclerosis in the skin related to Scl cGVHD in mice.
Conclusion
In summary, we describe a novel mechanism through which chronic inflammation perpetuates fibrosis via activation of JUN, CD47, IL6, which result in a profibrotic signature in Scl cGVHD. Our findings are of particular interest, as these pathways have been implicated in tissue sclerosis in other contexts and indicate potential targets for therapeutic intervention using anti-CD47 and IL6R antibodies.
Keyword(s): Chronic graft-versus-host, Immune response, Immune therapy