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1
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Karmi N, Oelen R, Bigaeva E, de Jong S, Haveman JW, van der Heide F, Hermoso MA, van der Wijst MGP, Kats-Ugurlu G, Weersma RK, Festen EAM, Uniken Venema WTC, Dijkstra G. Insights in Cellular and Molecular Signatures of the Small Intestinal Graft Posttransplantation: Successful, Recovered, and Rejected-A Case Series. Transplantation 2025:00007890-990000000-01069. [PMID: 40280178 DOI: 10.1097/tp.0000000000005411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
BACKGROUND Intestinal transplantation is the treatment for patients with irreversible intestinal failure and complications of parenteral nutrition. Five-year graft survival is only 56%, possibly due to an imbalance in immunosuppression, aiming to prevent rejection while maintaining protection against pathogens. Studying the graft's mucosal cell populations and regulation of donor and recipient cells posttransplantation offers a unique opportunity to address this (im)balance leading to rejection. METHODS We performed single-cell mRNA sequencing of longitudinally sampled ileal graft biopsies from surgery up to 6 mo after transplantation, althrough the TransplantLines Biobank and Cohort Study to characterize the composition and function of donor and recipient cell populations. RESULTS A rapid influx of recipient immune cells was observed in the rejected transplant. Induction therapy using anti-thymocyte globulin did not achieve complete T-cell depletion. Instead, during moderate rejection, apoptotic pathways in epithelial cells preceded pathology-defined severe rejection, indicating potential prognostic information in the transcriptomic profiles. CONCLUSIONS This first longitudinal cellular-molecular study of the total ileal graft mucosa and recipient cells within, shows a variable clinical course and response to medication, which align with heterogeneous signatures before intestinal transplantation rejection.
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Affiliation(s)
- Naomi Karmi
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Roy Oelen
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Emilia Bigaeva
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Sofie de Jong
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jan Willem Haveman
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Frans van der Heide
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Marcela A Hermoso
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Laboratory of Innate Immunity, Immunology Program, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | - Monique G P van der Wijst
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Gursah Kats-Ugurlu
- Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Werna T C Uniken Venema
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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2
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Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 2025; 31:552-562. [PMID: 38582044 PMCID: PMC11808579 DOI: 10.1093/ibd/izae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 04/08/2024]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.
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Affiliation(s)
- Stefano Kayali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Stefano Fantasia
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy
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3
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Cui Y, Hackett RG, Ascue J, Muralidaran V, Patil D, Kang J, Kaufman SS, Khan K, Kroemer A. Innate and Adaptive Immune Responses in Intestinal Transplant Rejection: Through the Lens of Inflammatory Bowel and Intestinal Graft-Versus-Host Diseases. Gastroenterol Clin North Am 2024; 53:359-382. [PMID: 39068000 DOI: 10.1016/j.gtc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Intestinal transplantation is a life-saving procedure utilized for patients failing total parenteral nutrition. However, intestinal transplantattion remains plagued with low survival rates and high risk of allograft rejection. The authors explore roles of innate (macrophages, natural killer cells, innate lymphoid cells) and adaptive immune cells (Th1, Th2, Th17, Tregs) in inflammatory responses, particularly inflammatory bowel disease and graft versus host disease, and correlate these findings to intestinal allograft rejection, highlighting which effectors exacerbate or suppress intestinal rejection. Better understanding of this immunology can open further investigation into potential biomolecular targets to develop improved therapeutic treatment options and immunomonitoring techniques to combat allograft rejection and enhance patient lives.
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Affiliation(s)
- Yuki Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Ryan G Hackett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jhalen Ascue
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Vinona Muralidaran
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA
| | - Stuart S Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA.
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4
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Suek N, Young T, Fu J. Immune cell profiling in intestinal transplantation. Hum Immunol 2024; 85:110808. [PMID: 38762429 PMCID: PMC11283363 DOI: 10.1016/j.humimm.2024.110808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 05/20/2024]
Abstract
Since the first published case study of human intestinal transplantation in 1967, there have been significant studies of intestinal transplant immunology in both animal models and humans. An improved understanding of the profiles of different immune cell subsets is critical for understanding their contributions to graft outcomes. While different studies have focused on the contribution of one or a few subsets to intestinal transplant, no study has integrated these data for a comprehensive overview of immune dynamics after intestinal transplant. Here, we provide a systematic review of the literature on different immune subsets and discuss their roles in intestinal transplant outcomes on multiple levels, focusing on chimerism and graft immune reconstitution, clonal alloreactivity, and cell phenotype. In Sections 1, 2 and 3, we lay out a shared framework for understanding intestinal transplant, focusing on the mechanisms of rejection or tolerance in the context of mucosal immunology and illustrate the unique role of the bidirectional graft-versus-host (GvH) and host-versus-graft (HvG) alloresponse. In Sections 4, 5 and 6, we further expand upon these concepts as we discuss the contribution of different cell subsets to intestinal transplant. An improved understanding of intestinal transplantation immunology will bring us closer to maximizing the potential of this important treatment.
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Affiliation(s)
- Nathan Suek
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Tyla Young
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Jianing Fu
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
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5
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Paulo Guzman J, Maklad M, Osman M, Elsherif A, Fujiki M. Updates in induction immunosuppression regimens for intestinal transplantation. Hum Immunol 2024; 85:110800. [PMID: 38599892 DOI: 10.1016/j.humimm.2024.110800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/08/2024] [Accepted: 04/04/2024] [Indexed: 04/12/2024]
Abstract
Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex immunosuppressive management. We evaluated the latest information regarding induction immunosuppression, with an emphasis on established, novel, and emergent therapies. We also reviewed classic and novel induction immunosuppression strategies for highly sensitized recipients. Comparable progress has been made in intestinal transplantation clinical outcomes since the implementation of induction strategies. This review shows a clear diversity of induction protocols can be observed across different centers. The field of intestinal transplantation is still in its early stages, which is further complicated by the limited number of institutions capable of intestinal transplantation and their geographical variation, which further hinders the development of adequately powered studies in comparison to other organs. As the implementation of institution-specific induction protocols becomes more refined and results are disseminated, future research efforts should be directed towards the development of efficacious induction strategies.
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Affiliation(s)
- Johann Paulo Guzman
- Center for Gut Rehabilitation and Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mohamed Maklad
- Center for Gut Rehabilitation and Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mohammed Osman
- Center for Gut Rehabilitation and Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ayat Elsherif
- Center for Gut Rehabilitation and Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Masato Fujiki
- Center for Gut Rehabilitation and Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.
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6
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Garcia J, Oltean M, Rumbo C, Sharkey L, Kaufman SS, Ramos Boluda E, Gupte G, Martinez M, Moon J, Raghu V, Segovia MC, Sudan D, Talbotec C, Varkey J, Gondolesi GE, Mazariegos G, Venick R. Endoscopic Surveillance of the Intestinal Allograft: Recommendations From the Intestinal Rehabilitation and Transplant Association Working Group. Transplantation 2024; 108:827-835. [PMID: 37723639 DOI: 10.1097/tp.0000000000004785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Abstract
Intestinal transplant (ITx) rejection lacks a reliable noninvasive biomarker and rejection surveillance relies on serial endoscopies and mucosal biopsies followed by histologic assessment. Endoscopic biopsies are also essential for identifying other ITx-related complications such as infectious, allergic, and inflammatory graft enteritis as well as post-transplant lymphoproliferative disease or graft versus host disease. In spite of its central role in ITx, published guidelines on endoscopy and biopsy are lacking and significant variability between centers in terms of timing and technical performance exists. Therefore, an international expert group convened and discussed several aspects related to the surveillance endoscopy after ITx with the aim to summarize and standardize its practice. This article summarizes these considerations on endoscopic ITx monitoring and highlights practices of surveillance and for-cause endoscopy, biopsy techniques, pathologic evaluation, potential risks and complications, outsourcing, and less-invasive monitoring techniques.
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Affiliation(s)
- Jennifer Garcia
- Miami Transplant Institute, University of Miami/Jackson Memorial Hospital, Miami, FL
| | - Mihai Oltean
- Sahlgrenska Intestinal Failure and Transplant Center, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Carolina Rumbo
- Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Lisa Sharkey
- Department of Gastroenterology, Intestinal Failure and Intestinal/Multivisceral Transplant, Cambridge University Hospital, Cambridge, United Kingdom
| | | | | | - Girish Gupte
- Birmingham Children's Hospital, Birmingham, United Kingdom
| | - Mercedes Martinez
- Center for Liver Disease and Abdominal Organ Transplantation, Columbia University Medical Center, New York, NY
| | - Jang Moon
- Recanati Miller Transplantation Institute, New York, NY
| | - Vikram Raghu
- Children's Hospital of Pittsburgh, Hillman Center for Pediatric Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA
| | | | | | - Cécile Talbotec
- Pediatric Gastroenterology-Hepatology-Nutrition, Hôpital Necker-Enfants Malades, Paris, France
| | - Jonas Varkey
- Sahlgrenska Intestinal Failure and Transplant Center, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - George Mazariegos
- Children's Hospital of Pittsburgh, Hillman Center for Pediatric Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA
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7
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Yu CH, Chen Y, Tsai CC, Lee TH, Tsai YH, Chung CS. Magnifying Endoscopy With Narrow Band Imaging for Graft Failure and Disease Recurrence in Patients With Crohn Disease After Intestinal Transplantation: 2 Case Reports. Transplant Proc 2024; 56:422-426. [PMID: 38336485 DOI: 10.1016/j.transproceed.2024.01.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/16/2024] [Indexed: 02/12/2024]
Abstract
Crohn disease (CD) is one of the most common causes of short bowel syndrome and intestinal failure. Intestinal transplantation (IT) is sometimes needed for patients with CD who develop intestinal failure after multiple intestinal resections resulting from CD-related complications, such as uncontrollable bleeding and penetrating diseases. However, there have been few case reports concerning the endoscopic surveillance of patients with CD after IT. In this article, we present 2 patients with CD who underwent IT because of short bowel syndrome with intestinal failure. We administered posttransplantation immunosuppressants and conducted regular follow-up magnifying endoscopy with narrow-band imaging (ME-NBI). Both cases demonstrated favorable outcomes after surveillance with ME-NBI. In this report, we outline our post-IT follow-up strategies applying the VENCH scoring system, which is based on endoscopic features using ME-NBI to predict graft rejection. Our approach could effectively distinguish between acute cellular rejection and non-rejection, particularly disease recurrence of underlying CD. This study was approved by the institutional review board of Far Eastern Memorial Hospital (FEMH-105023-F). The patients provided written informed consent for publication.
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Affiliation(s)
- Chen-Huan Yu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Yun Chen
- Taiwan Association for the Study of Small Intestinal Diseases (TASSID), Taoyuan City, Taiwan; Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan
| | - Chien-Chen Tsai
- Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Tzong-Hsi Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Ya-Hui Tsai
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan
| | - Chen-Shuan Chung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Taiwan Association for the Study of Small Intestinal Diseases (TASSID), Taoyuan City, Taiwan; College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan..
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8
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Hong JS, Shamim A, Atta H, Nonnecke EB, Merl S, Patwardhan S, Manell E, Gunes E, Jordache P, Chen B, Lu W, Shen B, Dionigi B, Kiran RP, Sykes M, Zorn E, Bevins CL, Weiner J. Application of enzyme-linked immunosorbent assay to detect antimicrobial peptides in human intestinal lumen. J Immunol Methods 2024; 525:113599. [PMID: 38081407 PMCID: PMC10956375 DOI: 10.1016/j.jim.2023.113599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
Intestinal transplantation is the definitive treatment for intestinal failure. However, tissue rejection and graft-versus-host disease are relatively common complications, necessitating aggressive immunosuppression that can itself pose further complications. Tracking intraluminal markers in ileal effluent from standard ileostomies may present a noninvasive and sensitive way to detect developing pathology within the intestinal graft. This would be an improvement compared to current assessments, which are limited by poor sensitivity and specificity, contributing to under or over-immunosuppression, respectively, and by the need for invasive biopsies. Herein, we report an approach to reproducibly analyze ileal fluid obtained through stoma sampling for antimicrobial peptide/protein concentrations, reasoning that these molecules may provide an assessment of intestinal homeostasis and levels of intestinal inflammation over time. Concentrations of lysozyme (LYZ), myeloperoxidase (MPO), calprotectin (S100A8/A9) and β-defensin 2 (DEFB2) were assessed using adaptations of commercially available enzyme-linked immunosorbent assays (ELISAs). The concentration of α-defensin 5 (DEFA5) was assessed using a newly developed sandwich ELISA. Our data support that with proper preparation of ileal effluent specimens, precise and replicable determination of antimicrobial peptide/protein concentrations can be achieved for each of these target molecules via ELISA. This approach may prove to be reliable as a clinically useful assessment of intestinal homeostasis over time for patients with ileostomies.
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Affiliation(s)
- Julie S Hong
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America.
| | - Abrar Shamim
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America; College of Dental Medicine, Columbia University, New York, NY, United States of America
| | - Hussein Atta
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Eric B Nonnecke
- Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, United States of America
| | - Sarah Merl
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States of America
| | - Satyajit Patwardhan
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Elin Manell
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America; Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Esad Gunes
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Philip Jordache
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Bryan Chen
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Wuyuan Lu
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Bo Shen
- Department of Surgery, Columbia University/New York-Presbyterian Hospital, New York, NY, United States of America
| | - Beatrice Dionigi
- Department of Surgery, Columbia University/New York-Presbyterian Hospital, New York, NY, United States of America
| | - Ravi P Kiran
- Department of Surgery, Columbia University/New York-Presbyterian Hospital, New York, NY, United States of America
| | - Megan Sykes
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America; Department of Surgery, Columbia University/New York-Presbyterian Hospital, New York, NY, United States of America
| | - Emmanuel Zorn
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America
| | - Charles L Bevins
- Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, United States of America
| | - Joshua Weiner
- Columbia Center of Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States of America; Department of Surgery, Columbia University/New York-Presbyterian Hospital, New York, NY, United States of America
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9
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Balasubramanian I, Bandyopadhyay S, Flores J, Bianchi‐Smak J, Lin X, Liu H, Sun S, Golovchenko NB, Liu Y, Wang D, Patel R, Joseph I, Suntornsaratoon P, Vargas J, Green PHR, Bhagat G, Lagana SM, Ying W, Zhang Y, Wang Z, Li WV, Singh S, Zhou Z, Kollias G, Farr LA, Moonah SN, Yu S, Wei Z, Bonder EM, Zhang L, Kiela PR, Edelblum KL, Ferraris R, Liu T, Gao N. Infection and inflammation stimulate expansion of a CD74 + Paneth cell subset to regulate disease progression. EMBO J 2023; 42:e113975. [PMID: 37718683 PMCID: PMC10620768 DOI: 10.15252/embj.2023113975] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.
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Affiliation(s)
| | | | - Juan Flores
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | | | - Xiang Lin
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Haoran Liu
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Shengxiang Sun
- Department of Pathology and ImmunologyWashington University School of MedicineSaint LouisMOUSA
| | | | - Yue Liu
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Dahui Wang
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Radha Patel
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Ivor Joseph
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Panan Suntornsaratoon
- Department of Pharmacology, Physiology & NeuroscienceRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Justin Vargas
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Peter HR Green
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Govind Bhagat
- Department of Medicine, Celiac Disease CenterColumbia University Irving Medical CenterNew YorkNYUSA
- Department of Pathology and Cell BiologyColumbia University Irving Medical CenterNew YorkNYUSA
| | - Stephen M Lagana
- Department of Pathology and Cell BiologyColumbia University Irving Medical CenterNew YorkNYUSA
| | - Wang Ying
- Hackensack Meridian Health Center for Discovery and InnovationNutleyNJUSA
| | - Yi Zhang
- Hackensack Meridian Health Center for Discovery and InnovationNutleyNJUSA
| | - Zhihan Wang
- Department of StatisticsRutgers UniversityNew BrunswickNJUSA
| | - Wei Vivian Li
- Department of Biostatistics and EpidemiologyRutgers UniversityNew BrunswickNJUSA
| | - Sukhwinder Singh
- Department of PathologyRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Zhongren Zhou
- Department of Pathology & Laboratory Medicine, Robert Wood Johnson Medical SchoolRutgers UniversityNew BrunswickNJUSA
| | - George Kollias
- Biomedical Sciences Research Centre, “Alexander Fleming”VariGreece
| | - Laura A Farr
- Division of Infectious Diseases and International HealthUniversity of VirginiaCharlottesvilleVAUSA
| | - Shannon N Moonah
- Division of Infectious Diseases and International HealthUniversity of VirginiaCharlottesvilleVAUSA
| | - Shiyan Yu
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Zhi Wei
- Department of Computer ScienceNew Jersey Institute of TechnologyNewarkNJUSA
| | - Edward M Bonder
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Lanjing Zhang
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
- Department of PathologyPenn Medicine Princeton Medical CenterPlainsboroNJUSA
| | - Pawel R Kiela
- Departments of Pediatrics and Immunology, and Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research CenterThe University of Arizona Health SciencesTucsonAZUSA
| | - Karen L Edelblum
- Center for Immunity and InflammationRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Ronaldo Ferraris
- Department of Pharmacology, Physiology & NeuroscienceRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Ta‐Chiang Liu
- Department of Pathology and ImmunologyWashington University School of MedicineSaint LouisMOUSA
| | - Nan Gao
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
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10
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Abstract
PURPOSE OF REVIEW The role of intestinal transplant has expanded in recent years and is no longer only considered for patients with no other options remaining. 5 year survival in high-volume centres is over 80% for certain graft types. The aim of this review is to update the audience on the current state of intestinal transplant, with a focus on recent medical and surgical advances. RECENT FINDINGS There has been a greater understanding of the interplay and balance of host and graft immune responses, which may facilitate individualized immunosuppression. Some centres are now performing 'no-stoma' transplants, with preliminary data showing no adverse effects from this strategy and other surgical advances have lessened the physiological insult of the transplant operation. Earlier referrals are encouraged by transplant centres, such that vascular access or liver disease has not progressed too much to increase the technical and physiological challenge of the procedure. SUMMARY Clinicians should consider intestinal transplant as a viable option for patients with intestinal failure, benign unresectable abdominal tumours or acute abdominal catastrophes.
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Affiliation(s)
| | - Neil K Russell
- Department of Transplant Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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11
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Girlanda R, Liggett JR, Jayatilake M, Kroemer A, Guerra JF, Hawksworth JS, Radkani P, Matsumoto CS, Zasloff M, Fishbein TM. The Microbiome and Metabolomic Profile of the Transplanted Intestine with Long-Term Function. Biomedicines 2022; 10:biomedicines10092079. [PMID: 36140180 PMCID: PMC9495872 DOI: 10.3390/biomedicines10092079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/14/2022] [Accepted: 08/16/2022] [Indexed: 11/25/2022] Open
Abstract
We analyzed the fecal microbiome by deep sequencing of the 16S ribosomal genes and the metabolomic profiles of 43 intestinal transplant recipients to identify biomarkers of graft function. Stool samples were collected from 23 patients with stable graft function five years or longer after transplant, 15 stable recipients one-year post-transplant and four recipients with refractory rejection and graft loss within one-year post-transplant. Lactobacillus and Streptococcus species were predominant in patients with stable graft function both in the short and long term, with a microbiome profile consistent with the general population. Conversely, Enterococcus species were predominant in patients with refractory rejection as compared to the general population, indicating profound dysbiosis in the context of graft dysfunction. Metabolomic analysis demonstrated significant differences between the three groups, with several metabolites in rejecting recipients clustering as a distinct set. Our study suggests that the bacterial microbiome profile of stable intestinal transplants is similar to the general population, supporting further application of this non-invasive approach to identify biomarkers of intestinal graft function.
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Affiliation(s)
- Raffaelle Girlanda
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
- Correspondence:
| | - Jedson R. Liggett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
- Department of Surgery, Naval Medical Center Portsmouth, Portsmouth, VA 23704, USA
| | - Meth Jayatilake
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
| | - Juan Francisco Guerra
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
| | - Jason Solomon Hawksworth
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
- Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD 20812, USA
| | - Pejman Radkani
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
| | - Cal S. Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
| | - Michael Zasloff
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Center for Translational Transplant Medicine, Georgetown University, Washington, DC 20007, USA
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12
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Fujimura T, Yamada Y, Umeyama T, Kudo Y, Kanamori H, Mori T, Shimizu T, Kato M, Kawaida M, Hosoe N, Hasegawa Y, Matsubara K, Shimojima N, Shinoda M, Obara H, Naganuma M, Kitagawa Y, Hoshino K, Kuroda T. Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report. World J Clin Cases 2021; 9:5270-5279. [PMID: 34307578 PMCID: PMC8283613 DOI: 10.12998/wjcc.v9.i19.5270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/18/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE SUMMARY The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab. CONCLUSION Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.
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Affiliation(s)
- Takumi Fujimura
- Department of Pediatric Surgery, National Saitama Hospital, Wako Shi, Saitama 351-0102, Japan
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yohei Yamada
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoshige Umeyama
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yumi Kudo
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroki Kanamori
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Teizaburo Mori
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takahiro Shimizu
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Mototoshi Kato
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Miho Kawaida
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Naoki Hosoe
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yasushi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kentaro Matsubara
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Naoki Shimojima
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
- Digestive Diseases Center, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329, Japan
| | - Hideaki Obara
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ken Hoshino
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tatsuo Kuroda
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
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13
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Weiner J, Svetlicky N, Kang J, Sadat M, Khan K, Duttargi A, Stovroff M, Moturi S, Kara Balla A, Hyang Kwon D, Kallakury B, Hawksworth J, Subramanian S, Yazigi N, Kaufman S, Pasieka HB, Matsumoto CS, Robson SC, Pavletic S, Zasloff M, Fishbein TM, Kroemer A. CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation. Am J Transplant 2021; 21:1878-1892. [PMID: 33226726 PMCID: PMC10364625 DOI: 10.1111/ajt.16405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 09/30/2020] [Accepted: 11/13/2020] [Indexed: 01/25/2023]
Abstract
Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (TRM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (TEM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+TRM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+TRM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+TRM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in TEM at the time of GvHD, possibly of donor derivation; (2) donor TRM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.
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Affiliation(s)
- Joshua Weiner
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Nina Svetlicky
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Mohammed Sadat
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Anju Duttargi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Merrill Stovroff
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Sangeetha Moturi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Abdalla Kara Balla
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Dong Hyang Kwon
- Department of Pathology, MedStar Georgetown University Hospital, Washington, District of Columbia
| | - Bhaskar Kallakury
- Department of Pathology, MedStar Georgetown University Hospital, Washington, District of Columbia
| | - Jason Hawksworth
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia.,Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Sukanya Subramanian
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Nada Yazigi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Stuart Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Helena B Pasieka
- Division of Dermatology, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia
| | - Cal S Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Simon C Robson
- Departments of Anesthesiology and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Steven Pavletic
- National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | - Michael Zasloff
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Thomas M Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
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14
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Kroemer A, Belyayev L, Khan K, Loh K, Kang J, Duttargi A, Dhani H, Sadat M, Aguirre O, Gusev Y, Bhuvaneshwar K, Kallakury B, Cosentino C, Houlihan B, Diaz J, Moturi S, Yazigi N, Kaufman S, Subramanian S, Hawksworth J, Girlanda R, Robson SC, Matsumoto CS, Zasloff M, Fishbein TM. Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab. Am J Transplant 2021; 21:1238-1254. [PMID: 32882110 PMCID: PMC8049508 DOI: 10.1111/ajt.16283] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
Intestinal transplantation (ITx) can be life-saving for patients with advanced intestinal failure experiencing complications of parenteral nutrition. New surgical techniques and conventional immunosuppression have enabled some success, but outcomes post-ITx remain disappointing. Refractory cellular immune responses, immunosuppression-linked infections, and posttransplant malignancies have precluded widespread ITx application. To shed light on the dynamics of ITx allograft rejection and treatment resistance, peripheral blood samples and intestinal allograft biopsies from 51 ITx patients with severe rejection, alongside 37 stable controls, were analyzed using immunohistochemistry, polychromatic flow cytometry, and reverse transcription-PCR. Our findings inform both immunomonitoring and treatment. In terms of immunomonitoring, we found that while ITx rejection is associated with proinflammatory and activated effector memory T cells in the blood, evidence of treatment efficacy can only be found in the allograft itself, meaning that blood-based monitoring may be insufficient. In terms of treatment, we found that the prominence of intra-graft memory TNF-α and IL-17 double-positive T helper type 17 (Th17) cells is a leading feature of refractory rejection. Anti-TNF-α therapies appear to provide novel and safer treatment strategies for refractory ITx rejection; with responses in 14 of 14 patients. Clinical protocols targeting TNF-α, IL-17, and Th17 warrant further testing.
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Affiliation(s)
- Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Leonid Belyayev
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC,Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Katrina Loh
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC,Department of Gastroenterology, Hepatology and Nutrition, Children’s National Medical Center, Washington, DC
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Anju Duttargi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Harmeet Dhani
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Mohammed Sadat
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Oswaldo Aguirre
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Yuriy Gusev
- Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC
| | - Krithika Bhuvaneshwar
- Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, Washington, DC
| | - Bhaskar Kallakury
- Department of Pathology, MedStar Georgetown University Hospital, Washington, DC
| | - Christopher Cosentino
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Brenna Houlihan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Jamie Diaz
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC,Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD
| | - Sangeetha Moturi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Nada Yazigi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Stuart Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Sukanya Subramanian
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Jason Hawksworth
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC,Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD
| | - Raffaele Girlanda
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Simon C. Robson
- Departments of Anesthesiology and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Cal S. Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Michael Zasloff
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
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15
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Kang J, Loh K, Belyayev L, Cha P, Sadat M, Khan K, Gusev Y, Bhuvaneshwar K, Ressom H, Moturi S, Kaiser J, Hawksworth J, Robson SC, Matsumoto CS, Zasloff M, Fishbein TM, Kroemer A. Type 3 innate lymphoid cells are associated with a successful intestinal transplant. Am J Transplant 2021; 21:787-797. [PMID: 32594614 PMCID: PMC8049507 DOI: 10.1111/ajt.16163] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 06/19/2020] [Accepted: 06/19/2020] [Indexed: 01/25/2023]
Abstract
Although innate lymphoid cells (ILCs) play fundamental roles in mucosal barrier functionality and tissue homeostasis, ILC-related mechanisms underlying intestinal barrier function, homeostatic regulation, and graft rejection in intestinal transplantation (ITx) patients have yet to be thoroughly defined. We found protective type 3 NKp44+ ILCs (ILC3s) to be significantly diminished in newly transplanted allografts, compared to allografts at 6 months, whereas proinflammatory type 1 NKp44- ILCs (ILC1s) were higher. Moreover, serial immunomonitoring revealed that in healthy allografts, protective ILC3s repopulate by 2-4 weeks postoperatively, but in rejecting allografts they remain diminished. Intracellular cytokine staining confirmed that NKp44+ ILC3 produced protective interleukin-22 (IL-22), whereas ILC1s produced proinflammatory interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Our findings about the paucity of protective ILC3s immediately following transplant and their repopulation in healthy allografts during the first month following transplant were confirmed by RNA-sequencing analyses of serial ITx biopsies. Overall, our findings show that ILCs may play a key role in regulating ITx graft homeostasis and could serve as sentinels for early recognition of allograft rejection and be targets for future therapies.
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Affiliation(s)
- Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Katrina Loh
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007,Children’s National Medical Center, 111 Michigan Avenue NW, Washington DC, 20010
| | - Leonid Belyayev
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007,Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda MD, 20814
| | - Priscilla Cha
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007,Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda MD, 20814
| | - Mohammed Sadat
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Yuriy Gusev
- Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, 2115 Wisconsin Ave NW, Suite 110, Washington DC, 20007
| | - Krithika Bhuvaneshwar
- Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, 2115 Wisconsin Ave NW, Suite 110, Washington DC, 20007
| | - Habtom Ressom
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 4000 Reservoir Road NW, Washington DC, 20007
| | - Sangeetha Moturi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Jason Kaiser
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007,Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda MD, 20814
| | - Jason Hawksworth
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007,Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda MD, 20814
| | - Simon C. Robson
- Departments of Anesthesiology and Medicine, CLS 612, 330 Brookline Avenue, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, 02115
| | - Cal S. Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Michael Zasloff
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington DC, 20007
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16
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Abstract
PURPOSE OF REVIEW Despite three decades of clinical experience, this article is the first to comprehensively address disease recurrence after gut transplantation. Pertinent scientific literature is reviewed and management strategies are discussed with new insights into advances in gut pathobiology and human genetics. RECENT FINDINGS With growing experience and new perspectives in the field of gut transplantation, the topic of disease recurrence continues to evolve. The clinicopathologic spectrum and diagnostic criteria are better defined in milieu of the nature of the primary disease. In addition to neoplastic disorders, disease recurrence is suspected in patients with pretransplant Crohn's disease, gut dysmotility, hypercoagulability and metabolic syndrome. There has also been an increased awareness of the potential de-novo development of various disorders in the transplanted organs. For conventionally unresectable gastrointestinal and abdominal malignancies, ex-vivo excision and autotransplantation are advocated, particularly for the nonallotransplant candidates. SUMMARY Similar to other solid organ and cell transplantations, disease recurrence has been suspected following gut transplantation. Despite current lack of conclusive diagnostic criteria, recurrence of certain mucosal and neuromuscular disorders has been recently described in a large single-centre series with an overall incidence of 7%. Disease recurrence was also observed in recipients with pretransplant hypercoagulability and morbid obesity with respective incidences of 4 and 24%. As expected, tumour recurrence is largely determined by type, extent and biologic behaviour of the primary neoplasm. With the exception of high-grade aggressive malignancy, disease recurrence is still of academic interest with no significant impact on overall short and long-term outcome.
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17
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Late graft loss after intestinal transplantation. Curr Opin Organ Transplant 2021; 26:220-228. [PMID: 33528223 DOI: 10.1097/mot.0000000000000851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Despite improvement in short-term outcomes after intestinal transplantation in the last 20 years, long-term rates of graft attrition and patient survival remain unchanged, with worse outcomes compared with other solid organ transplants. This review investigates the multiple causes of late graft loss, including chronic rejection, infection, graft-versus-host disease, posttransplant lymphoproliferative disorder and postsurgical complications. RECENT FINDINGS New insights into immunology of the intestine and evolution of immunosuppression, as well as review of current persistent causes of late graft loss, shed light on findings that may help improve long-term intestinal allograft survival. SUMMARY Although intestinal transplantation remains a life-saving intervention with significant advancements since its inception, further understanding of mechanisms of injury is needed to improve long-term outcomes and prevent late intestinal graft loss.
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18
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Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children. J Pediatr Gastroenterol Nutr 2020; 71:617-623. [PMID: 33093368 DOI: 10.1097/mpg.0000000000002849] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Intestinal transplantation is an option for permanent intestinal failure with parenteral nutrition intolerance. We sought to determine long-term intestinal graft survival in pediatric patients at our center and to identify factors influencing survival. METHODS Retrospective chart review of 86 patients transplanted between 2003 and 2013, targeting potential explanatory variables related to demographics, perioperative factors, and postoperative complications. RESULTS Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively. Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure compared with 45% with functional intestinal failure (P = 0.0055). Compared with nonsurvival, 5-year graft survival was also associated with reduced incidences of graft-versus-host disease (2% vs 16%, P = 0.0237), post-transplant lymphoproliferative disorder (3% vs 24%, P = 0.0067), and de novo donor-specific antibodies (19% vs 57%, P = 0.0451) plus a lower donor-recipient weight ratio (median 0.727 vs 0.923, P = 0.0316). Factors not associated with 5-year intestinal graft survival included graft rejection of any severity and inclusion of a liver graft. Factors associated with graft survival at 10 years were similar to those at 5 years. CONCLUSIONS In our experience, outcomes in pediatric intestinal transplantation have improved substantially for anatomic but not functional intestinal failure. Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit. Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.
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19
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Paneth Cell Alterations During Ischemia-reperfusion, Follow-up, and Graft Rejection After Intestinal Transplantation. Transplantation 2020; 104:1952-1958. [PMID: 32265415 DOI: 10.1097/tp.0000000000003257] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Ischemia-reperfusion injury is inevitable during intestinal transplantation (ITx) and executes a key role in the evolution towards rejection. Paneth cells (PCs) are crucial for epithelial immune defense and highly vulnerable to ischemia-reperfusion injury. We investigated the effect of ITx on PC after reperfusion (T0), during follow-up, and rejection. Moreover, we investigated whether PC loss was associated with impaired graft homeostasis. METHODS Endoscopic biopsies, collected according to center protocol and at rejection episodes, were retrospectively included (n = 28 ITx, n = 119 biopsies) Biopsies were immunohistochemically co-stained for PC (lysozyme) and apoptosis, and PC/crypt and lysozyme intensity were scored. RESULTS We observed a decrease in PC/crypt and lysozyme intensity in the first week after ITx (W1) compared with T0. There was a tendency towards a larger decline in PC/crypt (P = 0.08) and lysozyme intensity (P = 0.08) in W1 in patients who later developed rejection compared with patients without rejection. Follow-up biopsies showed that the PC number recovered, whereas lysozyme intensity remained reduced. This persisting innate immune defect may contribute to the well-known vulnerability of the intestine to infection. There was no clear evidence that PCs were affected throughout rejection. CONCLUSIONS This study revealed a transient fall in PC numbers in the early post-ITx period but a permanent reduction in lysozyme intensity following ITx. Further research is needed to determine the potential clinical impact of PC impairment after ITx.
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20
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Immunologic Complications and Graft Survival in Crohn's Disease and NOD2 Mutant Non-Crohn's Disease Adult Recipients Following Intestine Transplantation. Transplant Direct 2020; 6:e556. [PMID: 32607422 PMCID: PMC7266359 DOI: 10.1097/txd.0000000000001006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 11/26/2022] Open
Abstract
Despite improved outcomes in the modern era of targeted immunotherapy, intestinal failure and chronic parenteral nutrition remains a significant burden for patients with Crohn’s disease (CD) worldwide. Transplantation is a key component of management when a patient with CD suffers from life-threatening complications of parenteral nutrition. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is a risk factor for both development of CD and intestinal allograft rejection.
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21
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Wehkamp J, Stange EF. An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease. Front Immunol 2020; 11:646. [PMID: 32351509 PMCID: PMC7174711 DOI: 10.3389/fimmu.2020.00646] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022] Open
Abstract
The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, life-style risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.
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Affiliation(s)
- Jan Wehkamp
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
| | - Eduard F Stange
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
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22
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Tang XY, Gao MX, Xiao HH, Yun WJ, Dai Y, Yao ZH, Wong MS, Yao XS. Simultaneous Quantitative Analysis of Multiple Biotransformation Products of Xian-Ling-Gu-Bao, a Traditional Chinese Medicine Prescription, with Rat Intestinal Microflora by Ultra-Performance Liquid Chromatography Tandem Triple Quadrupole Mass Spectrometry. J Chromatogr Sci 2020; 58:494-503. [PMID: 32236407 DOI: 10.1093/chromsci/bmaa012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 12/11/2019] [Accepted: 02/25/2020] [Indexed: 11/15/2022]
Abstract
Abstract
Xian-Ling-Gu-Bao (XLGB), a famous traditional Chinese medicine prescription consisted of six herbal medicines, was used for prevention and treatment of osteoporosis in China. As an oral formulation, the multiple components contained in XLGB were inevitably biotransformed by the intestinal microflora before absorption via the gastrointestinal tract. However, the dynamic profiles of biotransformation products of XLGB remain unknown. In this paper, a rapid and sensitive ultra-performance liquid chromatography tandem triple quadrupole mass spectrometry method was developed for the simultaneous quantitative analysis of multiple biotransformation products of XLGB with rat intestinal microflora. For 10 selected quantitative compounds, all calibration curves revealed good linearity (r2 > 0.99) within the sampling ranges considered. The whole intra- and inter-day precisions (as relative standard deviation) of all analytes were <13.5%, and the accuracies (as relative error) were in the range from −11.3 to 11.2%. The lower limits of quantification were 20, 10, 5, 20, 2, 2, 2, 5, 2 and 2 ng/mL for sweroside, timosaponin BII, epimedin C, asperosaponin VI, psoralen, isobavachin, icariside II, timosaponin AIII, isobavachalcone and icaritin, respectively. The matrix effects, extraction recoveries and stabilities were all satisfactory. Meanwhile, dynamic profiles of 21 additional biotransformation products were also monitored by their area-time curves. The analytical method was successfully applied to describe dynamic profiles of 31 biotransformation products of XLGB and the recipes with removal of a definite composed herbal medicine (Anemarrhenae Rhizoma or Rehmanniae Radix).
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Affiliation(s)
- Xi-Yang Tang
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou 510632, China
| | - Meng-Xue Gao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou 510632, China
| | - Hui-Hui Xiao
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Nanshan District, Shenzhen 518057, China
| | - Wei-Jing Yun
- College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road No. 103, Shenhe District, Shenyang 110016, China
| | - Yi Dai
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou 510632, China
| | - Zhi-Hong Yao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou 510632, China
| | - Man-Sau Wong
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Nanshan District, Shenzhen 518057, China
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, 999077, China
| | - Xin-Sheng Yao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou 510632, China
- College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road No. 103, Shenhe District, Shenyang 110016, China
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23
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Singh R, Balasubramanian I, Zhang L, Gao N. Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation. Front Physiol 2020; 11:280. [PMID: 32296343 PMCID: PMC7138011 DOI: 10.3389/fphys.2020.00280] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/12/2020] [Indexed: 12/12/2022] Open
Abstract
Paneth cells are residents of the intestinal epithelium. Abnormal appearance of Paneth cells has been widely documented in non-intestinal tissues within the digestive tract and even observed in non-gastrointestinal organs. Although metaplastic Paneth cells are part of the overarching pathology of intestinal metaplasia (IM), only a fraction of intestinal metaplastic lesions contain Paneth cells. We survey literature documenting metaplastic Paneth cells to gain insights into mechanism underlying their etiologic development as well as their potential relevance to human health. A synthesized view from this study suggests that the emergence of metaplastic Paneth cells at extra-intestinal mucosal sites likely represents a protective, anti-bacterial, and inflammatory response evoked by an altered microbial activity.
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Affiliation(s)
- Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States
| | | | - Lanjing Zhang
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.,Department of Pathology, Princeton Medical Center, Plainsboro, NJ, United States
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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24
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Berlin P, Reiner J, Witte M, Wobar J, Lindemann S, Barrantes I, Kreikemeyer B, Bastian M, Schäffler H, Bannert K, Jaster R, Lamprecht G. Nod2 deficiency functionally impairs adaptation to short bowel syndrome via alterations of the epithelial barrier function. Am J Physiol Gastrointest Liver Physiol 2019; 317:G727-G738. [PMID: 31509436 DOI: 10.1152/ajpgi.00117.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene mutations are a risk factor for Crohn's disease and also associated with worse outcome in short bowel syndrome (SBS) patients independent of the underlying disease. The aim of this study was to analyze the effect of Nod2 deficiency on barrier function and stool microbiome after extensive ileocecal resection in mice. Male C57BL6/J wild-type (WT) and Nod2-knockout (KO) mice underwent 40% ileocecal resection. Sham control mice received simple transection of the ileum. Clinical outcome was monitored daily. Barrier function was measured with Ussing chambers using FITC-4-kDa-Dextran flux, transmucosal electrical resistance, and dilution potentials. Immunofluorescence of claudin-2 was studied. Composition of the stool microbiome was assessed by 16S rRNA gene sequencing. Resected Nod2-KO mice had impaired clinical outcome compared with resected WT mice. This was accompanied by increased stool water contents and increased plasma aldosterone. Histomorphological adaptation was independent of Nod2. Barrier function studies revealed impaired sodium to chloride permeability and altered claudin-2 localization in the absence of Nod2. Resection induced decreases of bacterial diversity and a shift of bacteriodetes-to-firmicutes ratios. Ileum and cecum resection-induced increase in proteobacteria was absent in Nod2-deficient mice. Verrucomicrobia were temporarily increased in Nod2-KO mice. Nod2 deficiency functionally impairs adaptation to short bowel syndrome via a lesser increase of epithelial sodium pore permeability, altered epithelial barrier function, and the microbiome.NEW & NOTEWORTHYNOD2 gene mutations are associated with the development of severe short bowel syndrome and intestinal failure. The influence of Nod2 mutations on intestinal adaptation in experimental short bowel syndrome has not been studied yet. Here, we provide data that Nod2 deficiency worsens clinical outcome and functional adaptation under SBS conditions in mice, indicating that NOD2 is required for successful adaptation after ileocecal resection.
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Affiliation(s)
- Peggy Berlin
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Johannes Reiner
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Maria Witte
- Department of General, Thoracic, Vascular, and Transplantation Surgery, Rostock University Medical Center, Rostock, Germany
| | - Jakob Wobar
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Sabeth Lindemann
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Israel Barrantes
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Bernd Kreikemeyer
- Institute for Microbiology, Virology, and Hygiene, University of Medicine Rostock, Rostock, Germany
| | - Manuela Bastian
- Institute for Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Rostock, Germany
| | - Holger Schäffler
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Karen Bannert
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Robert Jaster
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Georg Lamprecht
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
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25
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Elsabbagh AM, Hawksworth J, Khan KM, Kaufman SS, Yazigi NA, Kroemer A, Smith C, Fishbein TM, Matsumoto CS. Long-term survival in visceral transplant recipients in the new era: A single-center experience. Am J Transplant 2019; 19:2077-2091. [PMID: 30672105 PMCID: PMC6591067 DOI: 10.1111/ajt.15269] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 12/31/2018] [Accepted: 01/14/2019] [Indexed: 02/06/2023]
Abstract
There is a paucity of data on long-term outcomes following visceral transplantation in the contemporary era. This is a single-center retrospective analysis of all visceral allograft recipients who underwent transplant between November 2003 and December 2013 with at least 3-year follow-up data. Clinical data from a prospectively maintained database were used to assess outcomes including patient and graft survival. Of 174 recipients, 90 were adults and 84 were pediatric patients. Types of visceral transplants were isolated intestinal transplant (56.3%), combined liver-intestinal transplant (25.3%), multivisceral transplant (16.1%), and modified multivisceral transplant (2.3%). Three-, 5-, and 10-year overall patient survival was 69.5%, 66%, and 63%, respectively, while 3-, 5-, and 10-year overall graft survival was 67%, 62%, and 61%, respectively. In multivariable analysis, significant predictors of survival included pediatric recipient (P = .001), donor/recipient weight ratio <0.9 (P = .008), no episodes of severe acute rejection (P = .021), cold ischemia time <8 hours (P = .014), and shorter hospital stay (P = .0001). In conclusion, visceral transplantation remains a good option for treatment of end-stage intestinal failure with parenteral nutritional complications. Proper graft selection, shorter cold ischemia time, and improvement of immunosuppression regimens could significantly improve the long-term survival.
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Affiliation(s)
- Ahmed M. Elsabbagh
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC,Gastroenterology Surgical Center, Department of Surgery, Mansoura University, Mansoura, Egypt,St. Vincent Abdominal Transplant Center, St. Vincent Hospital, Indianapolis, Indiana
| | - Jason Hawksworth
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC,Department of Surgery, Organ Transplant Service, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Khalid M. Khan
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Stuart S. Kaufman
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Nada A. Yazigi
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Coleman Smith
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
| | - Cal S. Matsumoto
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC
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26
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Belyayev L, Loh K, Fishbein TM, Kroemer A. The parallel paradigm between intestinal transplant inflammation and inflammatory bowel disease. Curr Opin Organ Transplant 2019; 24:207-211. [PMID: 30694990 PMCID: PMC6408947 DOI: 10.1097/mot.0000000000000615] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW A significant shift in our understanding of the molecular and cellular basis for inflammatory bowel disease (IBD) mirrors research that has been ongoing in intestinal transplantation. The blurring of lines between these two disease states creates an avenue into potential therapeutic interventions which take advantage of these molecular similarities. RECENT FINDINGS Traditional knowledge of T-cell involvement in IBD has expanded to highlight the role of T helper 17 (Th17) cells as key effector cells. A similar role has been demonstrated in cellular rejection of intestinal allografts. Genetic polymorphism related to the propagation and function of Th17 cells has been found to confer significant risk of developing autoimmune conditions. Interleukin-23, a cytokine identified as crucial to the expansion of Th17 cells, has become a validated molecular target in psoriatic arthritis and IBD, and could become a target for intestinal transplant therapies. SUMMARY Intestinal transplant rejection and IBD share a similar phenotype, especially as it relates to key effector cells and gene polymorphisms. Improvements in our understanding of the immune-pathogenesis of IBD, as well as molecular targeting exploiting that knowledge, provide a potential route to improve outcomes for intestinal transplant patients.
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Affiliation(s)
- Leonid Belyayev
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Northwest, Washington, DC
- Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Katrina Loh
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Northwest, Washington, DC
- Department of Gastroenterology, Hepatology and Nutrition, Children’s National Medical Center, Northwest, Washington, DC, USA
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Northwest, Washington, DC
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Northwest, Washington, DC
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27
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Barbut D, Stolzenberg E, Zasloff M. Gastrointestinal Immunity and Alpha-Synuclein. JOURNAL OF PARKINSON'S DISEASE 2019; 9:S313-S322. [PMID: 31594249 PMCID: PMC6839499 DOI: 10.3233/jpd-191702] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 09/09/2019] [Indexed: 12/20/2022]
Abstract
The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease.
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Affiliation(s)
| | | | - Michael Zasloff
- Enterin, Inc., Philadelphia, PA, USA
- MedStar Georgetown Transplant Institute, Georgetown University Medical Center, Washington, DC, USA
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28
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Abstract
Adult intestinal transplantation differs significantly from pediatric intestinal transplantation. While indications have remained largely consistent since 2000, indications for adults have expanded over the last two decades to include motility disorders and desmoid tumors. Graft type in adult recipients depends on the distinct anatomic characteristics of the adult recipient. Colonic inclusion, while initially speculated to portend unfavorable outcomes due to complex host-bacterial interactions has increased over the past two decades with superior graft survival and improved patient quality of life. Overall, outcomes have steadily improved. For adult intestinal transplant candidates, intestinal transplantation remains a mainstay therapy for complicated intestinal failure and is a promising option for other life threatening and debilitating conditions.
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29
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Hawksworth JS, Desai CS, Khan KM, Kaufman SS, Yazigi N, Girlanda R, Kroemer A, Fishbein TM, Matsumoto CS. Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes. Am J Transplant 2018; 18:1312-1320. [PMID: 29498797 PMCID: PMC5992069 DOI: 10.1111/ajt.14715] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/11/2017] [Accepted: 02/04/2018] [Indexed: 01/25/2023]
Abstract
Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver-intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD.
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Affiliation(s)
- Jason S. Hawksworth
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA,Walter Reed National Military Medical Center, Department of Surgery, Organ Transplant Service, Bethesda, MD USA
| | - Chirag S. Desai
- University of North Carolina, Department of Surgery, Division of Abdominal Transplant, Chapel Hill, NC USA
| | - Khalid M. Khan
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Stuart S. Kaufman
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Nada Yazigi
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Raffaele Girlanda
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Alexander Kroemer
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Thomas M. Fishbein
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
| | - Cal S. Matsumoto
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC USA
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30
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Howell K, de Leeuw E. Cell adhesion properties of human defensins. Biochem Biophys Res Commun 2018; 502:238-242. [PMID: 29800568 DOI: 10.1016/j.bbrc.2018.05.150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 05/20/2018] [Indexed: 10/16/2022]
Abstract
Effector peptides of innate immunity play an important role in host defense. They act directly by inactivating microbes but also link innate to adaptive immunity. A variety of innate immune functions has been described for these peptides, including chemoattraction and cytokine release. In this study, we describe the effect on cell morphology and cell adhesion of human defensins. We find that Human Defensin 5, the major product of specialized gut epithelial cells, causes changes in cell morphology. HD-5 induces cell adhesion, binds to fibronectin and facilitates binding of T cells to intestinal epithelial cells. These effects were found also for a second prominent defensing, termed Human Neutrophil peptide-1, but not for other human defensins.
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Affiliation(s)
- Katie Howell
- Integrated Biotherapeutics, Inc., Rockville, MD 20850, USA
| | - Erik de Leeuw
- Institute of Human Virology of the University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
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31
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Lauro A, Oltean M, Marino IR. Chronic Rejection After Intestinal Transplant: Where Are We in Order to Avert It? Dig Dis Sci 2018; 63:551-562. [PMID: 29327261 DOI: 10.1007/s10620-018-4909-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/02/2018] [Indexed: 12/18/2022]
Abstract
Chronic rejection affects the long-term survival of all solid organ transplants and, among intestinal allografts, occurs in up to 10% of the recipients. The insidious clinical evolution of the chronic allograft enteropathy, the absence of noninvasive biomarkers, and the late endoscopic findings delay its diagnosis. No pharmacological approach has been proven effective, and allograft removal nowadays still represents the only available therapy. The inclusion of the liver in the visceral allograft appears to be the only intervention affecting the development of chronic rejection, as revealed by large-center studies and registry reports. A significant body of evidence emerged from the experimental setting and provided essential knowledge on the complex mechanisms behind the development of chronic allograft enteropathy. More recently, donor-specific antibodies have been suggested as an early, key element in the natural history of chronic allograft enteropathy and several novel approaches, tackling the antibody-mediated graft injury, have gained acceptance in clinical settings and are believed to impact on chronic rejection. The inclusion of a liver allograft is advocated when re-transplanting a sensitized recipient, due to its protective effect against humoral immunity. Multicenter trials are required to understand and tackle chronic rejection, and find the therapeutic answer to this clinical dilemma.
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Affiliation(s)
- Augusto Lauro
- Liver and Multiorgan Transplant Unit, St. Orsola University Hospital, Alma Mater Studiorum, Bologna, Italy.
| | - Mihai Oltean
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ignazio R Marino
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
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Lauro A, D'Amico F, Gondolesi G. The current therapeutic options for Crohn's disease: from medical therapy to intestinal transplantation. Expert Rev Gastroenterol Hepatol 2017; 11:1105-1117. [PMID: 28805088 DOI: 10.1080/17474124.2017.1367665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn's disease (CD) has an annual incidence per 100.000 person-year of 20.2 in North America and 12.7 in Europe, and the purpose of this review is to evaluate its medical management, from diagnosis to transplant. Pharmacologic manipulation with nutritional care aims to achieve and maintain remission, but more than half of patients will undergo an intestinal resection, very often repeated over time. They could experience short bowel syndrome (SBS) requiring total parenteral nutrition (TPN). Intestinal transplantation (ITx) represents an alternative in case of irreversible intestinal failure (IF) with life-threatening TPN complications. Patient survival after ITx is 79%, 53% and 43% at 1, 3 and 5 years respectively, with no differences among ITx for other disorders. Areas covered: The research discussed medical therapy with nutritional support, evaluating the role of endoscopy, surgery and transplant in CD. A systematic literature review was conducted using the PubMed search engine up to May 31th, 2017 without restriction of the language. The decision on paper's eligibility was reached by consensus between the 3 screening authors. Expert commentary: CD treatment is mainly medical, leaving endoscopy and surgery for a complex course. ITx represents a therapeutic option if TPN complications with IF arise.
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Affiliation(s)
- Augusto Lauro
- a Liver and Multiorgan Transplant Unit , St. Orsola University Hospital , Bologna , Italy
| | - Francesco D'Amico
- b Hepatobiliary Surgery and Liver Transplant Unit , University Hospital of Padua , Padua , Italy
| | - Gabriel Gondolesi
- c Intestinal Failure, Rehabilitation and Transplantation Unit , Fundación Favaloro University Hospitals , Buenos Aires , Argentina
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Gassler N. Paneth cells in intestinal physiology and pathophysiology. World J Gastrointest Pathophysiol 2017; 8:150-160. [PMID: 29184701 PMCID: PMC5696613 DOI: 10.4291/wjgp.v8.i4.150] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 07/28/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
Small intestinal mucosa is characterised by villus forming connective tissues with highly specialised surface lining epithelial cells essentially contributing to the establishment of the intestinal border. In order to perform these diverse functions, spatially distinct compartments of epithelial differentiation are found along the crypt-villus axis, including Paneth cells as a highly specialised cell type. Paneth cells locate in crypts and assist undifferentiated columnar cells, called crypt base columnar cells, and rapidly amplifying cells in the regeneration of absorptive and secretory cell types. There is some evidence that Paneth cells are involved in the configuration and function of the stem cell zone as well as intestinal morphogenesis and crypt fission. However, the flow of Paneth cells to crypt bottoms requires strong Wnt signalling guided by EphB3 and partially antagonised by Notch. In addition, mature Paneth cells are essential for the production and secretion of antimicrobial peptides including α-defensins/cryptdins. These antimicrobials are physiologically involved in shaping the composition of the microbiome. The autophagy related 16-like 1 (ATG16L1) is a genetic risk factor and is involved in the exocytosis pathway of Paneth cells as well as a linker molecule to PPAR signalling and lipid metabolism. There is evidence that injuries of Paneth cells are involved in the etiopathogenesis of different intestinal diseases. The review provides an overview of the key points of Paneth cell activities in intestinal physiology and pathophysiology.
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Affiliation(s)
- Nikolaus Gassler
- Institute of Pathology, RWTH Aachen University, Braunschweig 38114, Germany
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Stolzenberg E, Berry D, Yang D, Lee EY, Kroemer A, Kaufman S, Wong GCL, Oppenheim JJ, Sen S, Fishbein T, Bax A, Harris B, Barbut D, Zasloff MA. A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. J Innate Immun 2017. [PMID: 28651250 DOI: 10.1159/000477990] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. METHODS We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation. FINDINGS We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation. INTERPRETATION These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
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Affiliation(s)
- Ethan Stolzenberg
- Department of Pathology, Section of Neuropathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Lacaille F, Irtan S, Dupic L, Talbotec C, Lesage F, Colomb V, Salvi N, Moulin F, Sauvat F, Aigrain Y, Revillon Y, Goulet O, Chardot C. Twenty-eight years of intestinal transplantation in Paris: experience of the oldest European center. Transpl Int 2017; 30:178-186. [DOI: 10.1111/tri.12894] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 10/31/2016] [Accepted: 11/20/2016] [Indexed: 01/19/2023]
Affiliation(s)
- Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition; Necker-Enfants malades Hospital; Paris France
| | - Sabine Irtan
- Pediatric Surgery; Necker-Enfants malades Hospital; Paris France
| | - Laurent Dupic
- Pediatric Intensive Care; Necker-Enfants malades Hospital; Paris France
| | - Cécile Talbotec
- Pediatric Gastroenterology-Hepatology-Nutrition; Necker-Enfants malades Hospital; Paris France
| | - Fabrice Lesage
- Pediatric Intensive Care; Necker-Enfants malades Hospital; Paris France
| | - Virinie Colomb
- Pediatric Gastroenterology-Hepatology-Nutrition; Necker-Enfants malades Hospital; Paris France
| | - Nadège Salvi
- Anesthesiology; Necker-Enfants malades Hospital; Paris France
| | - Florence Moulin
- Pediatric Intensive Care; Necker-Enfants malades Hospital; Paris France
| | | | - Yves Aigrain
- Pediatric Surgery; Necker-Enfants malades Hospital; Paris France
| | - Yann Revillon
- Pediatric Surgery; Necker-Enfants malades Hospital; Paris France
| | - Olivier Goulet
- Pediatric Gastroenterology-Hepatology-Nutrition; Necker-Enfants malades Hospital; Paris France
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Hashimoto K, Costa G, Khanna A, Fujiki M, Quintini C, Abu-Elmagd K. Recent Advances in Intestinal and Multivisceral Transplantation. Adv Surg 2016; 49:31-63. [PMID: 26299489 DOI: 10.1016/j.yasu.2015.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Koji Hashimoto
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Guilherme Costa
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Ajai Khanna
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Masato Fujiki
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Cristiano Quintini
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Kareem Abu-Elmagd
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Kroemer A, Cosentino C, Kaiser J, Matsumoto CS, Fishbein TM. Intestinal Transplant Inflammation: the Third Inflammatory Bowel Disease. Curr Gastroenterol Rep 2016; 18:56. [PMID: 27645751 DOI: 10.1007/s11894-016-0530-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Intestinal transplantation is the most immunologically complex of all abdominal organ transplants. Understanding the role both humoral and innate and adaptive cellular immunity play in intestinal transplantation is critical to improving outcomes and increasing indications for patients suffering from intestinal failure. Recent findings highlighting the impact of donor-specific antibodies on intestinal allografts, the role of NOD2 as a key regulator of intestinal immunity, the protective effects of innate lymphoid cells, and the role of Th17 in acute cellular rejection are reviewed here.
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Affiliation(s)
- Alexander Kroemer
- MedStar Georgetown Transplant Institute, 2PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA.
| | - Christopher Cosentino
- MedStar Georgetown Transplant Institute, 2PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA
| | - Jason Kaiser
- MedStar Georgetown Transplant Institute, 2PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA
| | - Cal S Matsumoto
- MedStar Georgetown Transplant Institute, 2PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA
| | - Thomas M Fishbein
- MedStar Georgetown Transplant Institute, 2PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA
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Limketkai BN, Orandi BJ, Luo X, Segev DL, Colombel JF. Mortality and Rates of Graft Rejection or Failure Following Intestinal Transplantation in Patients With vs Without Crohn's Disease. Clin Gastroenterol Hepatol 2016; 14:1574-1581. [PMID: 27374004 DOI: 10.1016/j.cgh.2016.06.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 06/04/2016] [Accepted: 06/14/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Treatment of Crohn's disease (CD) may require multiple bowel resections that lead to short bowel syndrome. Intestinal transplantation is an effective treatment for short bowel syndrome, but limited data are available on long-term outcomes in CD. We aimed to characterize the long-term risk of rejection, graft failure, and death among patients with CD after intestinal transplantation, and compare their outcomes with those of patients without CD. METHODS We performed a retrospective study of adults in the Scientific Registry of Transplant Recipients who received intestinal transplants in the United States from May 1990 through June 2014. Outcomes data were collected at 3 months, 6 months, 1 year, and every year after the procedure. We compared risks of rejection at 1 year after transplantation between patients with and without CD using the chi-square test and logistic regression. Longitudinal risks of graft failure and death were compared between patients with and without CD using the Kaplan-Meier method and Cox proportional hazards. Multivariable analyses adjusted for recipient, donor, and institutional characteristics. RESULTS Of 1115 cases of intestinal transplantation, 142 were performed for CD and 973 for non-CD indications. One year after the procedure, the transplant was rejected in 36.9% of patients with CD and 33.3% of patients without CD (P = .48). For patients with CD, the actuarial risk of graft failure at 1, 5, and 10 years after intestinal transplantation was 18.6%, 38.7%, and 49.2%; the risk of death was 22.5%, 50.3%, and 59.7%, respectively. The risk of graft failure was greater for patients with CD (adjusted hazard ratio [aHR], 1.48; 95% CI, 1.03-2.13; P = .04), but patients with versus without CD had similar risks of death (aHR, 0.88; 95% CI, 0.64-1.20; P = .41). In subgroup analyses, the risk of graft failure was increased among patients with CD undergoing transplantation between 1990 and 2000 (aHR, 3.49; 95% CI, 1.23-9.92; P = .02), but not after 2000 (aHR, 1.37; 95% CI, 0.92-2.04; P = .12). CONCLUSIONS In an analysis of patients who received intestinal transplants, the risks of graft rejection or death were similar between patients with versus without CD. Before year 2000, patients with CD had an increased risk of graft failure, but not thereafter. Changes in posttransplant immunosuppression around the same time might be analyzed to learn more about the mechanisms and management strategies to reduce graft failure in CD.
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Affiliation(s)
- Berkeley N Limketkai
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
| | - Babak J Orandi
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Xun Luo
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dorry L Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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Abstract
PURPOSE OF REVIEW This article summarizes the complex interplay between the microbiota and host immune responses, and its impact on intestinal transplantation and allograft rejection. RECENT FINDINGS Recent findings highlight the importance of Paneth cells as crucial producers of antimicrobial peptides that control the intestinal host-microbial interface as well as the essential role of NOD2 as a master regulator of antimicrobial host defenses. Moreover, complex interactions between innate and adaptive immune responses have been shown to critically shape host antimicrobial Th17 responses, which may be key for the pathogenesis of inflammatory bowel diseases and intestinal allograft rejection. SUMMARY A growing body of evidence indicates that crosstalk between the microbiome and innate and adaptive host immunity determines alloimmune responses and outcomes in intestinal transplantation. Elaboration of this emerging field might lead to novel mechanistic insight into these complex interactions and allow for new therapeutic approaches.
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Abstract
PURPOSE OF REVIEW This article summarizes the current and potential future nutritional approaches to stimulate adaptation in intestinal failure. Adaptation in this context usually refers to intestinal adaptation but also involves changes in whole body physiology as well as in eating/drinking behavior. RECENT FINDINGS Adaptation largely depends on residual functional anatomy. Luminal exposure to complex nutrients is the most important trigger for intestinal adaptation. Enteral fat as well as enteral or parenteral short chain fatty acids have a specific stimulatory effect. Zinc and vitamin A status need to be optimized for adaptation to proceed and be maintained. In the context of maintaining sodium and water homeostasis, flushing the remnant intestine because of uncontrolled thirst/drinking must be avoided. Complications of nutritional care such as malnutrition, intestinal failure-associated liver disease, and recurrent line sepsis also need optimal management. SUMMARY Stimulation by luminal nutrients as well as prophylaxis against and treatment of (nutritional) complications are the cornerstones of adaptation to the short bowel situation. Based on ample data from animal studies but only limited evidence in humans specific nutritional stimulators need to be studied more rigorously. As long as such data are missing they can be tried on an individual basis.
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Abstract
Despite recent therapeutic advances, patients with Crohn's disease (CD) continue to experience high recurrence with cumulative structural damage and ultimate loss of nutritional autonomy. With short bowel syndrome, strictures, and enteric fistulae being the underlying pathology, CD is the second common indication for home parenteral nutrition (HPN). With development of intestinal failure, nutritional management including HPN is required as a rescue therapy. Unfortunately, some patients do not escape the HPN-associated complications. Therefore, the concept of gut rehabilitation has evolved as part of the algorithmic management of these patients, with transplantation being the ultimate life-saving therapy. With type 2 intestinal failure, comprehensive rehabilitative measures including nutritional care, pharmacologic manipulation, autologous reconstruction, and bowel lengthening is often successful, particularly in patients with quiescent disease. With type 3 intestinal failure, transplantation is the only life-saving treatment for patients with HPN failure and intractable disease. With CD being the second common indication for transplantation in adults, survival outcome continues to improve because of surgical innovation, novel immunosuppression, and better postoperative care. Despite being a rescue therapy, the procedure has achieved survival rates similar to other solid organs, and comparable to those who continue to receive HPN therapy. With similar technical, immunologic, and infectious complications, survival is similar in the CD and non-CD recipients. Full nutritional autonomy is achievable in most survivors with better quality of life and long-term cost-effectiveness. CD recurrence is rare with no impact on graft function. Further progress is anticipated with new insights into the pathogenesis of CD and mechanisms of transplant tolerance.
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Schäffler H, Kaschitzki A, Alberts C, Bodammer P, Bannert K, Köller T, Warnke P, Kreikemeyer B, Lamprecht G. Alterations in the mucosa-associated bacterial composition in Crohn's disease: a pilot study. Int J Colorectal Dis 2016; 31:961-971. [PMID: 26951181 DOI: 10.1007/s00384-016-2548-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2016] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Changes in the intestinal bacterial composition seem to play a major role in the pathogenesis and in the clinical course of inflammatory bowel diseases (IBD), which consist of Crohn's disease (CD), and ulcerative colitis (UC). Mutations in the NOD2 gene are the most important genetic risk factors for the development of CD. In this study, the association between mucosal biopsies and the mucosa-associated bacterial composition from CD and UC patients regarding their genetic risk factors (mutations in the NOD2 gene), their endoscopic activity, and their medical therapy (TNF-α blocking therapy) was examined. MATERIAL AND METHODS Seventy biopsies from routine colonoscopies from 33 IBD patients (26 CD and 7 UC) were obtained. Disease activity and clinical characteristics were assessed. Seven different bacterial strains (Bacteroides fragilis, Escherichia coli, Prevotella melaninogenica, Clostridium coccoides, Clostridium difficile, Bifidobacterium bifidum, and Faecalibacterium prausnitzii) were quantified using real-time PCR. NOD2 genotyping from patients with CD was performed. RESULTS Five of the 24 patients were positive for at least one mutation in the NOD2 gene. The bacterial composition was different in CD compared to UC, in macroscopic healthy compared to macroscopic inflamed biopsies, in NOD2 mutated compared to NOD2 wildtype patients, and in patients receiving TNF-α blocking therapy compared to patients without this treatment. CONCLUSION This study further characterizes the mucosa-associated bacteria in IBD patients. Different clinical situations lead to an altered mucosa-associated bacterial composition. The analyzed bacteria could be promising targets for cost-effective surveillance or therapies in IBD patients.
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Affiliation(s)
- Holger Schäffler
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.
| | - Annika Kaschitzki
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Christian Alberts
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Peggy Bodammer
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Karen Bannert
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Thomas Köller
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Philipp Warnke
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Georg Lamprecht
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
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Remi Treasa E, B. AM, K.G. T, G. DR, S.M.K. K, R. R. Sequence characterization and screening for polymorphism in the caspase recruitment domain 15 gene of goat (Capra hircus). Small Rumin Res 2016. [DOI: 10.1016/j.smallrumres.2016.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Rege A, Sudan D. Intestinal transplantation. Best Pract Res Clin Gastroenterol 2016; 30:319-35. [PMID: 27086894 DOI: 10.1016/j.bpg.2016.02.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/08/2016] [Accepted: 02/11/2016] [Indexed: 01/31/2023]
Abstract
Intestinal transplantation has now emerged as a lifesaving therapeutic option and standard of care for patients with irreversible intestinal failure. Improvement in survival over the years has justified expansion of the indications for intestinal transplantation beyond the original indications approved by Center for Medicare and Medicaid services. Management of patients with intestinal failure is complex and requires a multidisciplinary approach to accurately select candidates who would benefit from rehabilitation versus transplantation. Significant strides have been made in patient and graft survival with several advancements in the perioperative management through timely referral, improved patient selection, refinement in the surgical techniques and better understanding of the immunopathology of intestinal transplantation. The therapeutic efficacy of the procedure is well evident from continuous improvements in functional status, quality of life and cost-effectiveness of the procedure. This current review summarizes various aspects including current practices and evidence based recommendations of intestinal transplantation.
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Affiliation(s)
- Aparna Rege
- Department of Surgery, Division of Abdominal Transplantation, Duke University Medical Center, Durham, NC, USA.
| | - Debra Sudan
- Department of Surgery, Division of Abdominal Transplantation, Duke University Medical Center, Durham, NC, USA
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Zhao A, Lu W, de Leeuw E. Functional synergism of Human Defensin 5 and Human Defensin 6. Biochem Biophys Res Commun 2015; 467:967-72. [DOI: 10.1016/j.bbrc.2015.10.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 10/07/2015] [Indexed: 12/18/2022]
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Abstract
Crohn's disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell α-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease.
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Abstract
PURPOSE OF REVIEW This review focuses on the known mechanisms of alloimmunity that occur after transplantation and what is being done in order to improve graft and patient survival, particularly in the long term. RECENT FINDINGS The presence of mismatched antigens and epitopes might relate directly to the development of de-novo donor-specific antibodies (DSA), and thus, rejection. In an abdominal wall transplant, the skin graft could be the first to show signs of rejection. The epithelial or endothelial cells are the main targets in acute and chronic rejection, respectively. Possible therapeutical targets are gut homing T cells and cells of the innate immune system. Chimerism development might mostly occur in isolated lymph nodes, but also in the epithelium, particularly after transplantation of bone marrow mesenchymal stromal cells. SUMMARY Ischemia-reperfusion, surgical injury, and bacterial translocation trigger the innate immune system, starting acute rejection. Interaction between donor and recipient immune cells generate injury and tolerance, which occur mostly in secondary lymphoid organs, lamina propria, and epithelium. Chronic rejection mostly affects the endothelial cells, generating graft dysfunction. DSA increase the risk of graft rejection both acutely and chronically, and the liver protects against their effects. Induction therapies deplete lymphocytes prior to implantation, and maintenance therapies inhibit T-cell expansion. Rejection rates are the lowest when depleting drugs and a combination of interleukin 2 receptor blockade, inhibition of T-cell expansion, and steroids are used as maintenance therapy. Chimerism and tolerogenic regiments that induce Tregs and prevent the development of DSA are important treatment goals for the future.
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Role of Innate and Acquired Immune Mechanisms in Clinical Intestinal Transplant Rejection. Transplantation 2015; 99:1273-81. [DOI: 10.1097/tp.0000000000000491] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abu-Elmagd K. The concept of gut rehabilitation and the future of visceral transplantation. Nat Rev Gastroenterol Hepatol 2015; 12:108-20. [PMID: 25601664 DOI: 10.1038/nrgastro.2014.216] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the 1990s, the introduction of visceral transplantation fuelled interest in other innovative therapeutic modalities for gut rehabilitation. Ethanol lock and omega-3 lipid formulations were introduced to reduce the risks associated with total parenteral nutrition (TPN). Autologous surgical reconstruction and bowel lengthening have been increasingly utilized for patients with complex abdominal pathology and short-bowel syndrome. Glucagon-like peptide 2 analogue, along with growth hormone, are available to enhance gut adaptation and achieve nutritional autonomy. Intestinal transplantation continues to be limited to a rescue therapy for patients with TPN failure. Nonetheless, survival outcomes have substantially improved with advances in surgical techniques, immunosuppressive strategies and postoperative management. Furthermore, both nutritional autonomy and quality of life can be restored for more than two decades in most survivors, with social support and inclusion of the liver being favourable predictors of long-term outcome. One of the current challenges is the discovery of biomarkers to diagnose early rejection and further improve liver-free allograft survival. Currently, chronic rejection with persistence of preformed and development of de novo donor-specific antibodies is a major barrier to long-term graft function; this issue might be overcome with innovative immunological and tolerogenic strategies. This Review discusses advances in the field of gut rehabilitation, including intestinal transplantation, and highlights future challenges. With the growing interest in individualized medicine and the value of health care, a novel management algorithm is proposed to optimize patient care through an integrated multidisciplinary team approach.
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Affiliation(s)
- Kareem Abu-Elmagd
- Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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