REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE
Abstract INTRODUCTION For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease stat...
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| Veröffentlicht in: | Inflammatory bowel diseases 2023-01, Vol.29 (Supplement_1), p.S51-S52 |
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| creator | Guisado, Daniela Talware, Sayali Singh, Shishir Gold, Stephanie Mansi, Moutasem Fozilov, Elbek Etra, Aaron Cho, Judy Cohen, Louis |
| description | Abstract
INTRODUCTION
For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells. As such, the study of how the immune system responds to auto-SCT will provide unique insight into CD pathogenesis and treatment. To date, no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT. Here we report initial studies of high dimensional immune phenotyping of patients with CD during auto-SCT.
METHODS
Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359). 14 patients were transplanted (2018-2022). Paired blood and intestinal samples were taken prior to transplant and 6 months post-transplant. Fresh leukocytes were isolated and analyzed by mass cytometry (CyTOF). Supervised clustering of immune cell populations using canonical markers was performed in parallel with unsupervised clustering by FlowSOM.(3)
RESULTS
After 6 months post-transplant,12/13 patients had an endoscopic response (↓SES-CD by 50%) and 10/13 patients were in endoscopic remission (SES-CD |
| doi_str_mv | 10.1093/ibd/izac247.101 |
| format | Article |
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INTRODUCTION
For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells. As such, the study of how the immune system responds to auto-SCT will provide unique insight into CD pathogenesis and treatment. To date, no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT. Here we report initial studies of high dimensional immune phenotyping of patients with CD during auto-SCT.
METHODS
Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359). 14 patients were transplanted (2018-2022). Paired blood and intestinal samples were taken prior to transplant and 6 months post-transplant. Fresh leukocytes were isolated and analyzed by mass cytometry (CyTOF). Supervised clustering of immune cell populations using canonical markers was performed in parallel with unsupervised clustering by FlowSOM.(3)
RESULTS
After 6 months post-transplant,12/13 patients had an endoscopic response (↓SES-CD by 50%) and 10/13 patients were in endoscopic remission (SES-CD<4). Supervised clustering of major immune cell subsets demonstrated distinct site-specific responses to transplant in myeloid and lymphoid cell populations (Fig 1). Naïve CD4+ and CD8+ T cells universally decrease in number at 6 months post-transplant whereas all other B and T cell populations have discordant changes in the blood and intestine, especially naïve and transitional CD27- B cell populations which significantly increase in blood and decrease in the intestine. CD14+ populations are universally increased in number post-transplant with a specific increase in CD14+ CD206+ macrophages in the intestine. Unsupervised clustering of blood and intestinal immune cells resolve 100 cell clusters that correlate with canonical immune cell markers (Fig 2). Unsupervised analysis further highlights a significant increase in multiple intestinal CD14+CD206+ immune cell populations reflecting newly arrived and/or differentiating and mature monocyte derived macrophages. Principal component and hierarchical clustering analyses of immune cell clusters suggest a reprograming of the intestinal immune compartment post-transplant whereas changes in circulating immune cells populations fail to separate the pre and post-transplant states.
Fig 1.
Supervised clustering of immune cell populations demonstrates site specific responses. Whole blood and intestinal leukocytes were phenotyped before and 6 months after auto-SCT by CyTOF using a panel of 38 cell surface markers. Live singlets underwent supervised clustering of populations using canonical surface markers.(4) The ratio of immune cell populations from pre-transplant to 6 months post-transplant were calculated and log normalized (all populations calculated as percent of live singlets). Mann-Whitney test with Holm-Sidak correction for multiple comparisons was used to compare pre-transplant to 6 months post-transplant immune populations.
Fig 2.
Unsupervised clustering of immune cell populations demonstrates reprograming of the intestinal immune compartment. Unsupervised clustering (FlowSOM) of live singlets resolved into 100 cell clusters grouped into 15 metaclusters. a, PCA analysis of FlowSOM predicted immune cell clusters resolves patient samples pre- vs post-transplant from the intestine but not blood. b, Hierarchical clustering (Pearson correlation) of Z score normalized intestinal cell clusters (FlowSOM). Cell networks increased post-transplant or pre-transplant anchored by significantly changed clusters are highlighted (significant cluster thick box, network shaded box). Significantly increased clusters post-transplant are CD14+ CD206+, significantly increased clusters at baseline, pre-transplant, are CD66b+.
CONCLUSION
We demonstrate for the first time differences in the intestinal and peripheral immune response to auto-SCT. These studies highlight the changes in intestinal immune cell networks that define the transplant response perhaps through CD14+ cells.</description><identifier>ISSN: 1078-0998</identifier><identifier>EISSN: 1536-4844</identifier><identifier>DOI: 10.1093/ibd/izac247.101</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><ispartof>Inflammatory bowel diseases, 2023-01, Vol.29 (Supplement_1), p.S51-S52</ispartof><rights>2023 by the Crohn’s & Colitis Foundation and the AGA Institute. This article is being published jointly in Inflammatory Bowel Diseases and Gastroenterology . 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1621-60254f1feb9c8a90006e7a4fb03d0db196d1ceec01ee599112c04cf5bef499af3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids></links><search><creatorcontrib>Guisado, Daniela</creatorcontrib><creatorcontrib>Talware, Sayali</creatorcontrib><creatorcontrib>Singh, Shishir</creatorcontrib><creatorcontrib>Gold, Stephanie</creatorcontrib><creatorcontrib>Mansi, Moutasem</creatorcontrib><creatorcontrib>Fozilov, Elbek</creatorcontrib><creatorcontrib>Etra, Aaron</creatorcontrib><creatorcontrib>Cho, Judy</creatorcontrib><creatorcontrib>Cohen, Louis</creatorcontrib><title>REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE</title><title>Inflammatory bowel diseases</title><description>Abstract
INTRODUCTION
For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells. As such, the study of how the immune system responds to auto-SCT will provide unique insight into CD pathogenesis and treatment. To date, no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT. Here we report initial studies of high dimensional immune phenotyping of patients with CD during auto-SCT.
METHODS
Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359). 14 patients were transplanted (2018-2022). Paired blood and intestinal samples were taken prior to transplant and 6 months post-transplant. Fresh leukocytes were isolated and analyzed by mass cytometry (CyTOF). Supervised clustering of immune cell populations using canonical markers was performed in parallel with unsupervised clustering by FlowSOM.(3)
RESULTS
After 6 months post-transplant,12/13 patients had an endoscopic response (↓SES-CD by 50%) and 10/13 patients were in endoscopic remission (SES-CD<4). Supervised clustering of major immune cell subsets demonstrated distinct site-specific responses to transplant in myeloid and lymphoid cell populations (Fig 1). Naïve CD4+ and CD8+ T cells universally decrease in number at 6 months post-transplant whereas all other B and T cell populations have discordant changes in the blood and intestine, especially naïve and transitional CD27- B cell populations which significantly increase in blood and decrease in the intestine. CD14+ populations are universally increased in number post-transplant with a specific increase in CD14+ CD206+ macrophages in the intestine. Unsupervised clustering of blood and intestinal immune cells resolve 100 cell clusters that correlate with canonical immune cell markers (Fig 2). Unsupervised analysis further highlights a significant increase in multiple intestinal CD14+CD206+ immune cell populations reflecting newly arrived and/or differentiating and mature monocyte derived macrophages. Principal component and hierarchical clustering analyses of immune cell clusters suggest a reprograming of the intestinal immune compartment post-transplant whereas changes in circulating immune cells populations fail to separate the pre and post-transplant states.
Fig 1.
Supervised clustering of immune cell populations demonstrates site specific responses. Whole blood and intestinal leukocytes were phenotyped before and 6 months after auto-SCT by CyTOF using a panel of 38 cell surface markers. Live singlets underwent supervised clustering of populations using canonical surface markers.(4) The ratio of immune cell populations from pre-transplant to 6 months post-transplant were calculated and log normalized (all populations calculated as percent of live singlets). Mann-Whitney test with Holm-Sidak correction for multiple comparisons was used to compare pre-transplant to 6 months post-transplant immune populations.
Fig 2.
Unsupervised clustering of immune cell populations demonstrates reprograming of the intestinal immune compartment. Unsupervised clustering (FlowSOM) of live singlets resolved into 100 cell clusters grouped into 15 metaclusters. a, PCA analysis of FlowSOM predicted immune cell clusters resolves patient samples pre- vs post-transplant from the intestine but not blood. b, Hierarchical clustering (Pearson correlation) of Z score normalized intestinal cell clusters (FlowSOM). Cell networks increased post-transplant or pre-transplant anchored by significantly changed clusters are highlighted (significant cluster thick box, network shaded box). Significantly increased clusters post-transplant are CD14+ CD206+, significantly increased clusters at baseline, pre-transplant, are CD66b+.
CONCLUSION
We demonstrate for the first time differences in the intestinal and peripheral immune response to auto-SCT. These studies highlight the changes in intestinal immune cell networks that define the transplant response perhaps through CD14+ cells.</description><issn>1078-0998</issn><issn>1536-4844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkMFLwzAYxYMoOKdnrzkLdUmbds0xdNkWaJPSpOfSpglMlI0WD3r2Dzdzu8t3eB-P936HB8AzRq8Y0WR1GMbV4bu3MVkHA9-ABU6TLCI5IbfhR-s8QpTm9-Bhnt8QisPRBfhpeK12DauE3EG1hWbPoZCGayMkK6GoqlZyWPCyhIWqataYiksDN3wrJNd_8YbrWknNoVGQtUaVaqdaDbXh1aVoGiZ1XTJpmBFKBj4sGrWXGm6E5kzzR3Dn-_fZPV11CdotN8U-CihRsDKyOItxlKE4JR57N1Cb9xQhlLl1T_yAkhGNA6bZiK1zFmHnUkoxji0i1qeD84TS3idLsLpw7XSc58n57jQdPvrpq8OoO4_YhRG764jBwKHxcmkcP0__hn8Byr1rDw</recordid><startdate>20230126</startdate><enddate>20230126</enddate><creator>Guisado, Daniela</creator><creator>Talware, Sayali</creator><creator>Singh, Shishir</creator><creator>Gold, Stephanie</creator><creator>Mansi, Moutasem</creator><creator>Fozilov, Elbek</creator><creator>Etra, Aaron</creator><creator>Cho, Judy</creator><creator>Cohen, Louis</creator><general>Oxford University Press</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20230126</creationdate><title>REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE</title><author>Guisado, Daniela ; Talware, Sayali ; Singh, Shishir ; Gold, Stephanie ; Mansi, Moutasem ; Fozilov, Elbek ; Etra, Aaron ; Cho, Judy ; Cohen, Louis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1621-60254f1feb9c8a90006e7a4fb03d0db196d1ceec01ee599112c04cf5bef499af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guisado, Daniela</creatorcontrib><creatorcontrib>Talware, Sayali</creatorcontrib><creatorcontrib>Singh, Shishir</creatorcontrib><creatorcontrib>Gold, Stephanie</creatorcontrib><creatorcontrib>Mansi, Moutasem</creatorcontrib><creatorcontrib>Fozilov, Elbek</creatorcontrib><creatorcontrib>Etra, Aaron</creatorcontrib><creatorcontrib>Cho, Judy</creatorcontrib><creatorcontrib>Cohen, Louis</creatorcontrib><collection>CrossRef</collection><jtitle>Inflammatory bowel diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guisado, Daniela</au><au>Talware, Sayali</au><au>Singh, Shishir</au><au>Gold, Stephanie</au><au>Mansi, Moutasem</au><au>Fozilov, Elbek</au><au>Etra, Aaron</au><au>Cho, Judy</au><au>Cohen, Louis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE</atitle><jtitle>Inflammatory bowel diseases</jtitle><date>2023-01-26</date><risdate>2023</risdate><volume>29</volume><issue>Supplement_1</issue><spage>S51</spage><epage>S52</epage><pages>S51-S52</pages><issn>1078-0998</issn><eissn>1536-4844</eissn><abstract>Abstract
INTRODUCTION
For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells. As such, the study of how the immune system responds to auto-SCT will provide unique insight into CD pathogenesis and treatment. To date, no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT. Here we report initial studies of high dimensional immune phenotyping of patients with CD during auto-SCT.
METHODS
Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359). 14 patients were transplanted (2018-2022). Paired blood and intestinal samples were taken prior to transplant and 6 months post-transplant. Fresh leukocytes were isolated and analyzed by mass cytometry (CyTOF). Supervised clustering of immune cell populations using canonical markers was performed in parallel with unsupervised clustering by FlowSOM.(3)
RESULTS
After 6 months post-transplant,12/13 patients had an endoscopic response (↓SES-CD by 50%) and 10/13 patients were in endoscopic remission (SES-CD<4). Supervised clustering of major immune cell subsets demonstrated distinct site-specific responses to transplant in myeloid and lymphoid cell populations (Fig 1). Naïve CD4+ and CD8+ T cells universally decrease in number at 6 months post-transplant whereas all other B and T cell populations have discordant changes in the blood and intestine, especially naïve and transitional CD27- B cell populations which significantly increase in blood and decrease in the intestine. CD14+ populations are universally increased in number post-transplant with a specific increase in CD14+ CD206+ macrophages in the intestine. Unsupervised clustering of blood and intestinal immune cells resolve 100 cell clusters that correlate with canonical immune cell markers (Fig 2). Unsupervised analysis further highlights a significant increase in multiple intestinal CD14+CD206+ immune cell populations reflecting newly arrived and/or differentiating and mature monocyte derived macrophages. Principal component and hierarchical clustering analyses of immune cell clusters suggest a reprograming of the intestinal immune compartment post-transplant whereas changes in circulating immune cells populations fail to separate the pre and post-transplant states.
Fig 1.
Supervised clustering of immune cell populations demonstrates site specific responses. Whole blood and intestinal leukocytes were phenotyped before and 6 months after auto-SCT by CyTOF using a panel of 38 cell surface markers. Live singlets underwent supervised clustering of populations using canonical surface markers.(4) The ratio of immune cell populations from pre-transplant to 6 months post-transplant were calculated and log normalized (all populations calculated as percent of live singlets). Mann-Whitney test with Holm-Sidak correction for multiple comparisons was used to compare pre-transplant to 6 months post-transplant immune populations.
Fig 2.
Unsupervised clustering of immune cell populations demonstrates reprograming of the intestinal immune compartment. Unsupervised clustering (FlowSOM) of live singlets resolved into 100 cell clusters grouped into 15 metaclusters. a, PCA analysis of FlowSOM predicted immune cell clusters resolves patient samples pre- vs post-transplant from the intestine but not blood. b, Hierarchical clustering (Pearson correlation) of Z score normalized intestinal cell clusters (FlowSOM). Cell networks increased post-transplant or pre-transplant anchored by significantly changed clusters are highlighted (significant cluster thick box, network shaded box). Significantly increased clusters post-transplant are CD14+ CD206+, significantly increased clusters at baseline, pre-transplant, are CD66b+.
CONCLUSION
We demonstrate for the first time differences in the intestinal and peripheral immune response to auto-SCT. These studies highlight the changes in intestinal immune cell networks that define the transplant response perhaps through CD14+ cells.</abstract><cop>US</cop><pub>Oxford University Press</pub><doi>10.1093/ibd/izac247.101</doi><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current) |
| title | REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE |
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