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1
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Zimmerer JM, Chaudhari S, Koneru K, Han JL, Abdel-Rasoul M, Uwase H, Yi T, Breuer CK, Bumgardner GL. Germinal Center B Cells are Uniquely Targeted by Antibody-Suppressor CXCR5 +CD8 + T Cells. Transplant Direct 2025; 11:e1742. [PMID: 39802197 PMCID: PMC11723704 DOI: 10.1097/txd.0000000000001742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/16/2024] [Accepted: 10/31/2024] [Indexed: 01/16/2025] Open
Abstract
Background Alloprimed antibody-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp cells) downregulate alloantibody production, mediate cytotoxicity of IgG+ B cells, and prolong allograft survival. The purpose of this investigation was to determine which immune-cell subsets are susceptible to CD8+ TAb-supp cell-mediated cytotoxicity or noncytotoxic suppression. Methods Alloprimed immune-cell subsets were evaluated for susceptibility to CD8+ TAb-supp cell-mediated in vitro cytotoxicity and/or suppression of intracellular cytokine expression. In vivo CD8-mediated cytotoxicity to wild-type germinal center (GC) B cells or wild-type CD4+ T follicular helper cells (TFH cells) was assessed in RAG1 knockout mice. The impact of in vivo adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients on the quantity of lymphoid immune-cell subsets was assessed. Results CD8+ TAb-supp cells mediated allospecific cytotoxicity to alloprimed GC B cells but not alloprimed extrafollicular plasmablasts, marginal zone B cells, follicular B cells, or plasma cells. CD8+ TAb-supp cells did not mediate cytotoxicity to alloprimed dendritic cells, macrophages, CD4+ TFH cells, CD4+ T follicular regulatory cells, or CD4+ regulatory T cell. CD8+ TAb-supp cells did not suppress CD4+ TFH cell, T follicular regulatory cell, or regulatory T-cell cytokine expression. Adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients reduced alloantibody production and the quantity of GC B cells, TFH cells, and plasma cells (but not other B-cell, T-cell, or antigen-presenting cell subsets). The reduction of TFH-cell quantity was dependent on CD8+ TAb-supp cell-mediated major histocompatibility complex-I-dependent cytotoxic killing of GC B cells. Conclusions The primary targets of CD8+ TAb-supp cells are GC B cells with downstream reduction of TFH and plasma cells.
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Affiliation(s)
- Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Sachi Chaudhari
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Kavya Koneru
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Jing L. Han
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
- Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Mahmoud Abdel-Rasoul
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH
| | - Hope Uwase
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Tai Yi
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Christopher K. Breuer
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
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2
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Assadiasl S, Nicknam MH. Intestinal transplantation: Significance of immune responses. Arab J Gastroenterol 2024; 25:330-337. [PMID: 39289083 DOI: 10.1016/j.ajg.2024.08.001] [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: 03/05/2024] [Revised: 07/06/2024] [Accepted: 08/02/2024] [Indexed: 09/19/2024]
Abstract
Intestinal allografts, with many resident immune cells and as a destination for circulating lymphocytes of the recipient, appear to be the most challenging solid organ transplants. The high incidence of acute rejection and frequent reports of fatal graft-versus-host disease (GvHD) after intestinal transplantation call for more research to describe the molecular mechanisms involved in the immunopathogenesis of post-transplant complications to define new therapeutic targets. In addition, according to the rapid development of immunosuppressive agents, it is time to consider novel therapeutic approaches in managing treatment-refractory patients with rejection or severe GvHD. Herein, the main immunological challenges before and after intestinal transplant including, brain-dead donor inflammation, acute rejection, antibody-mediated, and chronic rejections, as well as GvHD have been described. Besides, the new immune-based therapies used in experimental and clinical settings to improve tolerance toward intestinal allograft, and cases of operational tolerance have been reviewed.
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Affiliation(s)
- Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Tissue Bank and Research Center, Tehran University of Medical Science, Tehran, Iran.
| | - Mohammad Hossein Nicknam
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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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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Garcia J, Vianna R. B-Cell Induction Therapies in Intestinal Transplantation. Gastroenterol Clin North Am 2024; 53:343-357. [PMID: 39067999 DOI: 10.1016/j.gtc.2024.01.001] [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
Despite advancements in short-term outcomes since the inception of intestinal transplant, significant long-term graft failure persists. Early successes are attributed to the utilization of tacrolimus for maintenance therapy, coupled with T-cell modulating induction regimens, which effectively reduce the incidence of acute cellular rejection. However, the challenge of chronic allograft injury remains unresolved. There is increasing evidence indicating a correlation between donor-specific antibodies and the survival of visceral allografts. Strategies aimed at reducing the presence or load of these antibodies may potentially enhance long-term outcomes. Consequently, our focus is now turning toward B-cell induction therapies as a possible solution.
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Affiliation(s)
- Jennifer Garcia
- Adult and Pediatric Intestinal Transplant, Miami Transplant Institute, University of Miami-Jackson Memorial Hospital, 1801 Northwest 9th Avenue, MTI 7th Floor, Jackson Professional Building, Miami, FL 33136, USA.
| | - Rodrigo Vianna
- Adult and Pediatric Intestinal Transplant, Miami Transplant Institute, University of Miami-Jackson Memorial Hospital, 1801 Northwest 9th Avenue, MTI 7th Floor, Jackson Professional Building, Miami, FL 33136, USA
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5
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McArdle R, Cope R, Chaudhry A, Sharkey L, Peacock S. Exploring the immunological relevance of pre-transplant donor-specific antibody in intestinal transplantation, with special consideration to the liver. Int J Immunogenet 2024; 51:217-227. [PMID: 38637869 DOI: 10.1111/iji.12670] [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: 11/15/2023] [Revised: 02/19/2024] [Accepted: 03/15/2024] [Indexed: 04/20/2024]
Abstract
Despite recent advances that have improved outcomes following intestinal transplantation (ITx), achieving long-term patient survival and rejection-free survival is still challenging. Understanding the relevance of pre-transplant human leukocyte antigen (HLA) donor-specific antibody (DSA) in ITx and the immunomodulatory potential of the liver within the allograft is crucial to providing an accurate assessment of pre-transplant immunological risk, which could influence and improve post-transplant outcomes further. This was the primary objective of this retrospective study of 95 adult ITx transplants which took place at Cambridge University Hospitals (United Kingdom) between 2007 and 2019. Two novel programs were developed and validated to identify DSA (tested by Luminex single antigen beads) in this dataset. Data analysis utilised Kaplan-Meier survival methods, and statistical analysis was performed using log-rank tests and adjusted Cox models. Fifty-four (57%) ITx cases contained a liver, and 36 (38%) were sensitised to HLA. Pre-transplant DSA > 500 mean fluorescent intensity appeared to negatively affect post-ITx patient survival and rejection outcomes. Additionally, liver-inclusive allografts seemed to show particular resistance to HLA class I DSA. Our data hints towards consistency with other ITx studies where deleterious effects of DSA have been demonstrated, and where liver inclusion is protective from HLA class I DSA. This is in line with current national guidelines for immunological risk. Our publicly available research programs could support future large or multicentre studies where statistically relevant data might be gained.
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Affiliation(s)
- Rhea McArdle
- Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
- Faculty of Biology, Medicine and Health, Division of Medical Education, School of Medical Sciences, University of Manchester, Manchester, UK
- Transplant Laboratory, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Gwendolen Road, Leicester, UK
| | - Rebecca Cope
- Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
- Faculty of Biology, Medicine and Health, Division of Medical Education, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Afzal Chaudhry
- Department of Nephrology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
| | - Lisa Sharkey
- Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
| | - Sarah Peacock
- Tissue Typing Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
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6
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Xu Q, Zeevi A, Ganoza A, Cruz RJ, Mazariegos GV. Current approaches for risk assessment of intestinal transplant patients: A view from the histocompatibility laboratory. Hum Immunol 2024; 85:110768. [PMID: 38433035 DOI: 10.1016/j.humimm.2024.110768] [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: 01/25/2024] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2024]
Abstract
Despite its recent decline in volumes, intestinal transplantation remains an important option for patients with irreversible intestinal failures. The long-term outcome of an intestinal transplant has stagnated. The major cause of graft loss is rejection, resulting from mismatches in human leukocyte antigens (HLA) and the presence of antibodies to mismatched donor-specific HLA antigens (DSA). Literature has reported that DSAs, either preformed before transplantation or developed de novo after transplantation, are harmful to intestinal grafts, especially for those without combined liver grafts. A comprehensive assessment of DSA by the histocompatibility laboratory is critical for successful intestinal transplantation and its long-term survival. This paper briefly reviews the history and current status of different methods for detecting DSA and their clinical applications in intestinal transplantation. The focus is on applying different antibody assays to manage immunologically challenging intestinal transplant patients before and after transplantation. A clinical case is presented to illustrate the complexity of HLA tests and the necessity of multiple assays. The review of risk assessment by the histocompatibility laboratory also highlights the need for close interaction between the laboratory and the intestinal transplant program.
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Affiliation(s)
- Qingyong Xu
- Department of Pathology, University of Pittsburgh, USA.
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh, USA
| | | | - Ruy J Cruz
- Department of Surgery, University of Pittsburgh, USA; Gastrointestinal Rehabilitation and Transplant Center, Starzl Transplantation Institute, USA
| | - George V Mazariegos
- Department of Surgery, University of Pittsburgh, USA; Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, USA
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7
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Klein K, Keck M, Langewisch E, Merani S, Hitchman K, Leick M. Evaluation of serial monitoring of donor-specific antibodies in pediatric and adult intestinal/multivisceral transplant recipients. Pediatr Transplant 2024; 28:e14638. [PMID: 37942670 DOI: 10.1111/petr.14638] [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: 06/15/2023] [Revised: 08/23/2023] [Accepted: 10/24/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring. METHODS This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed. RESULTS Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II. CONCLUSION Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients.
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Affiliation(s)
- Kelsey Klein
- University Health Transplant Institute, San Antonio, Texas, USA
- The University of Texas at Austin, College of Pharmacy, Pharmacotherapy Division, Austin TX, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Megan Keck
- Nebraska Medicine, Omaha, NE, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Eric Langewisch
- Nebraska Medicine, Omaha, NE, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Shaheed Merani
- Nebraska Medicine, Omaha, NE, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Kelley Hitchman
- University Health Transplant Institute, San Antonio, Texas, USA
- Department of Pathology and Laboratory Medicine, UT Health San Antonio, San Antonio, Texas, USA
| | - Mary Leick
- Nebraska Medicine, Omaha, NE, University of Nebraska Medical Center, Omaha, Nebraska, USA
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8
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Abreu P, Manzi J, Vianna R. Innovative surgical techniques in the intestine and multivisceral transplant. Curr Opin Organ Transplant 2024; 29:88-96. [PMID: 37902277 DOI: 10.1097/mot.0000000000001098] [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: 10/31/2023]
Abstract
PURPOSE OF REVIEW This timely review delves into the evolution of multivisceral transplantation (MVT) over the past six decades underscoring how advancements in surgical techniques and immunosuppression have driven transformation, to provide insight into the historical development of MVT, shedding light on its journey from experimentation to a valuable clinical approach. RECENT FINDINGS The review presents contemporary enhancements in surgical methods within the context of intestinal transplantation. The versatility of MVT is emphasized, accommodating diverse organ combinations and techniques. Both isolated intestinal transplantation (IIT) and MVT have seen expanded indications, driven by improved parenteral nutrition, transplantation outcomes, and surgical innovations. Surgical techniques are tailored based on graft type, with various approaches for isolated transplantation. Preservation strategies and ostomy techniques are also covered, along with graft assessment advancements involving donor-specific antibodies. SUMMARY This review's findings underscore the remarkable evolution of MVT from experimental origins to a comprehensive clinical practice. The progress in surgical techniques and immunosuppression has broadened the spectrum of patients who can benefit from intestinal transplant, including both IIT and MVT. The expansion of indications offers hope to patients with complex gastrointestinal disorders. The detection of donor-specific antibodies in graft assessment advances diagnostic accuracy, ultimately improving patient outcomes.
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Affiliation(s)
- Phillipe Abreu
- Department of Surgery, University of Miami, Jackson Memorial Hospital, Miami Transplant Institute, Florida, USA
| | - Joao Manzi
- Department of Surgery, University of Miami, Jackson Memorial Hospital, Miami Transplant Institute, Florida, USA
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Rodrigo Vianna
- Department of Surgery, University of Miami, Jackson Memorial Hospital, Miami Transplant Institute, Florida, USA
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9
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Battle R, Pritchard D, Peacock S, Hastie C, Worthington J, Jordan S, McCaughlan JA, Barnardo M, Cope R, Collins C, Diaz-Burlinson N, Rosser C, Foster L, Kallon D, Shaw O, Briggs D, Turner D, Anand A, Akbarzad-Yousefi A, Sage D. BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation. Int J Immunogenet 2023; 50 Suppl 2:3-63. [PMID: 37919251 DOI: 10.1111/iji.12641] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023]
Abstract
Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.
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Affiliation(s)
- Richard Battle
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | | | - Sarah Peacock
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | - Sue Jordan
- National Blood Service Tooting, London, UK
| | | | - Martin Barnardo
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rebecca Cope
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | | | - Luke Foster
- Birmingham Blood Donor Centre, Birmingham, UK
| | | | - Olivia Shaw
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - David Turner
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | - Arthi Anand
- Imperial College Healthcare NHS Trust, London, UK
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10
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Hussan E, Kroemer A, Elsabbagh AM, Khan KM, Yazigi NA, Ekong UD, Subramanian S, Ghobrial SS, Guerra JF, Fishbein TM, Matsumoto CS, Kaufman SS. Idiopathic Ileal Ulceration After Intestinal Transplantation. Transplant Direct 2023; 9:e1529. [PMID: 37899780 PMCID: PMC10602531 DOI: 10.1097/txd.0000000000001529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 10/31/2023] Open
Abstract
Background Idiopathic ileal ulceration after intestinal transplantation (ITx) has been discussed infrequently and has an uncertain natural history and relation to graft rejection. Herein, we review our experience with this pathology. Methods We retrospectively reviewed 225 ITx in 217 patients with minimum 1 y graft survival. Routine graft endoscopy was conducted up to twice weekly within the first 90 d after ITx, gradually decreasing to once yearly. Risks for ulceration over time were evaluated using Cox regression. Results Of 93 (41%) patients with ulcers, 50 were found within 90 d after ITx mostly via ileoscopy; delayed healing after biopsy appeared causal in the majority. Of the remaining 43 patients with ulcers found >90 d after ITx, 36 were after ileostomy closure. Multivariable modeling demonstrated within 90-d ulcer associations with increasing patient age (hazard ratio [HR], 1.027; P < 0.001) and loop ileostomy (versus Santulli ileostomy; HR, 0.271; P < 0.001). For ulcers appearing after ileostomy closure, their sole association was with absence of graft colon (HR, 7.232; P < 0.001). For ulcers requiring extended anti-microbial and anti-inflammatory therapy, associations included de novo donor-specific antibodies (HR, 3.222; P < 0.007) and nucleotide oligomerization domain mutations (HR, 2.772; P < 0.016). Whole-cohort post-ITx ulceration was not associated with either graft rejection (P = 0.161) or graft failure (P = 0.410). Conclusions Idiopathic ulceration after ITx is relatively common but has little independent influence on outcome; risks include ileostomy construction, colon-free ITx, immunologic mutation, and donor sensitization.
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Affiliation(s)
- Elsadig Hussan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Ahmed M. Elsabbagh
- Gastroenterology Surgical Center, Department of Surgery, Mansoura University, Mansoura, Egypt
| | - Khalid M. Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Nada A. Yazigi
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Udeme D. Ekong
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Sukanya Subramanian
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | | | - Juan-Francisco Guerra
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Thomas M. Fishbein
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Cal S. Matsumoto
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
| | - Stuart S. Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC
- Georgetown University School of Medicine, Washington, DC
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11
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Raghu VK, Vetterly CG, Horslen SP. Immunosuppression Regimens for Intestinal Transplantation in Children. Paediatr Drugs 2022; 24:365-376. [PMID: 35604536 DOI: 10.1007/s40272-022-00512-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 10/18/2022]
Abstract
Pediatric intestinal transplant serves as the only definitive treatment for children with irreversible intestinal failure. Successful intestinal transplant hinges upon appropriate management of immunosuppression. The indications for intestinal transplant have changed over time. Immunosuppression regimens can be divided into induction and maintenance phases along with treatment of acute rejection. Intestinal transplant induction now often includes antithymocyte globulin or basiliximab in addition to corticosteroids. Maintenance regimens continue to be dominated by tacrolimus, with additional agents used to either decrease goal tacrolimus levels to limit toxicity or as an adjunct in sensitized patients. Careful monitoring can help to limit serious complications, such as rejection, infection, and malignancy. Future work will aim to decrease variation in practice and identify methods to determine optimal immunosuppression for a particular patient. Furthermore, there is a need for non-invasive monitoring of the intestinal graft and functional assessments of immunosuppression.
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Affiliation(s)
- Vikram Kalathur Raghu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh, School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Carol G Vetterly
- Department of Pharmacy, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Simon Peter Horslen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh, School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
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12
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Moon JI, Ko HM, Iyer KR. Enhanced virtual crossmatch in intestinal transplantation: association with outcomes and application in practice. KOREAN JOURNAL OF TRANSPLANTATION 2021; 35:230-237. [PMID: 35769851 PMCID: PMC9235456 DOI: 10.4285/kjt.21.0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/19/2021] [Accepted: 12/06/2021] [Indexed: 11/04/2022] Open
Affiliation(s)
- Jang Il Moon
- Recanati Miller Transplantation Institute and Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Huaibin M Ko
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kishore R Iyer
- Recanati Miller Transplantation Institute and Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Spaggiari M, Lichvar A, Tzvetanov I, Carroll R, Gaitonde S, Setty S, Cocco PD, Alvarez JAA, Benedetti E. Temporary Deceased Donor Splenic Transplant Prior to Intestinal Transplantation: A New Strategy for Desensitization? Transplant Proc 2021; 53:2602-2608. [PMID: 34503818 DOI: 10.1016/j.transproceed.2021.08.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/07/2021] [Indexed: 11/24/2022]
Abstract
Intestinal transplantation is a therapeutic treatment option for patients with irreversible intestinal failure. The presence of donor-specific antibodies (DSAs) has been associated with increased antibody-mediated rejection and allograft loss for recipients of all the solid organ transplants. This case report describes the posttransplant course in the first year of a patient who received a T-cell and B-cell flow cross-match (FXM) and complement-dependent cytotoxicity cross-match positive intestinal transplant in the presence of several class I and class II DSAs who underwent a "temporary desensitization" using the donor spleen. The temporary donor splenic transplant removed several class I and II DSAs as demonstrated by the negative subsequent T-cell FXM, the decreased mean channel shift of the positive B-cell FXM with a significant decrease in DSA mean florescence intensity post temporary splenic transplant. The patient experienced an isolated incidence of acute rejection, which responded to therapy. He had no infectious or cancerous sequelae from the immunosuppression modalities. He was able to discontinue total parenteral nutrition and gained weight after the procedure. Long-term effects are not able to be determined from this approach; hence, further research is warranted to better evaluate the real efficacy of this strategy.
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Affiliation(s)
- Mario Spaggiari
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois.
| | - Alicia Lichvar
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois
| | - Ivo Tzvetanov
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois
| | - Robert Carroll
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Sujata Gaitonde
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Suman Setty
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Pierpaolo Di Cocco
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois
| | - Jorge A Almario Alvarez
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois
| | - Enrico Benedetti
- Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois
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14
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Vo HD, Radio SJ, Reyes-Santiago EM, Mauch TJ. Post-transplant hepatic fibrosis in pediatric liver-small bowel transplant recipients: A single-center, retrospective, observational study. Pediatr Transplant 2021; 25:e13965. [PMID: 33378567 DOI: 10.1111/petr.13965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/02/2020] [Accepted: 12/15/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Little is known about the prevalence of hepatic graft fibrosis in combined LSBT children. We aimed to determine the prevalence of and identify potential predictors for hepatic graft fibrosis in LSBT children and to compare them with those in LT children. METHODS We retrospectively included children younger than 19 years who had received a primary LT/LSBT between 2000 and 2018 and had a liver biopsy performed at least 6 months post-transplant. A Cox proportional hazards regression model was used to determine predictors associated with significant hepatic graft fibrosis (≥F2) in LSBT vs LT children. RESULTS Ninety-six children (47 LSBT, 54 females) were included. The median post-transplant follow-up (years) was 12.8 in LT vs 10.5 in LSBT patients (P = .06). Hepatic graft fibrosis was found in 81.6% of LT vs 70.2% of LSBT children (P = .19), after a median time of 2.5 years and 2.6 years, respectively. On multivariate analyses, having post-transplant biliary complications was found to be associated with significant graft fibrosis in LT children, whereas AST/ALT ratio was found to predict significant hepatic graft fibrosis in LSBT children. The use of parenteral nutrition after transplant was not associated with significant hepatic graft fibrosis. CONCLUSIONS The prevalence of hepatic graft fibrosis in LSBT children did not significantly differ from that in LT children, but the predictors may differ. Future studies should investigate the role of post-transplant autoimmune antibodies and donor-specific antibodies in the development and progression of hepatic graft fibrosis in LSBT children.
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Affiliation(s)
- Hanh D Vo
- Pediatric Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA
| | - Stanley J Radio
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Emille M Reyes-Santiago
- Pediatric Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA
| | - Teri J Mauch
- Pediatric Nephrology, University of Nebraska Medical Center, Omaha, NE, USA
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15
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Abstract
PURPOSE OF REVIEW The current review aims to describe in detail the most common practices utilized to monitor graft function in intestinal transplant (ITx) recipients. In addition, to discussing the role of endoscopy and stool studies it will examine the use of other potential biomarkers which have been utilized. Data will be discussed from contemporary publications in the field, the Intestinal Transplant Registry as well as detailed data from a large, ITx single-center. RECENT FINDINGS Significant improvements have been made in early outcomes following ITx, yet long-term survival remains challenged by infection and rejection, both of which can present with diarrhea. While endoscopy and stool studies are the gold-standard for graft monitoring, calprotectin, citrulline, measurements of immunoreactivity and donor-specific antibodies have been investigated in the field and are herein reviewed. SUMMARY Despite a number of tests which are currently available for monitoring ITx recipients, a strong need exists for improved noninvasive, timely and accurate biomarkers to help improve ITx graft and patient survival.
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16
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Varkey J. Graft assessment for acute rejection after intestinal transplantation: current status and future perspective. Scand J Gastroenterol 2021; 56:13-19. [PMID: 33202155 DOI: 10.1080/00365521.2020.1847318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal transplantation has since its inception evolved as a lifesaving treatment option for patients with irreversible intestinal failure who can no longer be sustained on parenteral nutrition. Improvement in short-term survival after transplantation has also justified the expansion of treatment indications. Unfortunately, success is somewhat limited by a plateau observed in long-term survival. The reason for this sub-optimal long-term result experienced in this cohort may in part be attributed to the intestinal graft with the lymphoid content it carries inflicting the host with multiple complications where acute cellular rejection is one of the most common causes for graft loss. Graft monitoring is for this reason of paramount importance and detection of rejection at an early stage essential to enable early instigation of treatment and successful reversal of the pathology. Due to the challenges in diagnosing acute rejection with a noninvasive marker we are still limited to a surveillance protocol using endoscopy and biopsies for the diagnosis of rejection. The purpose of our paper is to review the adequacy of different methods in monitoring the graft for acute rejection using biomarkers, endoscopy and imaging. In conclusion, the evidence base continues to support the use of histology for the diagnosis of acute rejection. The role of biomarkers are still debatable, although markers such as calprotectin might be beneficial in excluding an ongoing process.
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Affiliation(s)
- Jonas Varkey
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Sahlgrenska Intestinal Failure and Transplant Centre, Gothenburg, Sweden
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17
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Inverse Association Between the Quantity of Human Peripheral Blood CXCR5+IFN-γ+CD8+ T Cells With De Novo DSA Production in the First Year After Kidney Transplant. Transplantation 2020; 104:2424-2434. [PMID: 32032292 DOI: 10.1097/tp.0000000000003151] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND We recently reported that a novel CXCR5IFN-γCD8 T-cell subset significantly inhibits posttransplant alloantibody production in a murine transplant model. These findings prompted the current study to investigate the association of human CD8 T cells with the same phenotype with the development of de novo donor-specific antibody (DSA) after kidney transplantation. METHODS In the current studies, we prospectively and serially analyzed peripheral blood CD8 and CD4 T-cell subsets and monitored for the development of de novo DSA in kidney transplant recipients during the first-year posttransplant. We report results on 95 first-time human kidney transplant recipients with 1-year follow-up. RESULTS Twenty-three recipients (24.2%) developed de novo DSA within 1-year posttransplant. Recipients who developed DSA had significantly lower quantities of peripheral CXCR5IFN-γCD8 T cells (P = 0.01) and significantly lower ratios of CXCR5IFN-γCD8 T cell to combined CD4 Th1/Th2 cell subsets (IFN-γCD4 and IL-4CD4 cells; P = 0.0001) compared to recipients who remained DSA-negative over the first-year posttransplant. CONCLUSIONS Our data raise the possibility that human CXCR5IFN-γCD8 T cells are a homolog to murine CXCR5IFN-γCD8 T cells (termed antibody-suppressor CD8 T cells) and that the quantity of CXCR5IFN-γCD8 T cells (or the ratio of CXCR5IFN-γCD8 T cells to Th1/Th2 CD4 T cells) may identify recipients at risk for development of DSA.
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18
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Wozniak LJ, Venick RS. Donor-specific antibodies following liver and intestinal transplantation: Clinical significance, pathogenesis and recommendations. Int Rev Immunol 2019; 38:106-117. [DOI: 10.1080/08830185.2019.1630404] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Laura J. Wozniak
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Robert S. Venick
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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19
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Donor-specific antibody management in intestine transplantation: hope for improving the long-term durability of the intestine allograft? Curr Opin Organ Transplant 2019; 24:212-218. [DOI: 10.1097/mot.0000000000000619] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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20
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Talayero P, Ramos Boluda E, Gómez Massa E, Castro Panete MJ, Prieto Bozano G, Hernández Oliveros F, López Santamaría M, Calvo Pulido J, Paz-Artal E, Mancebo E. Donor-Specific Antibodies in Pediatric Intestinal and Multivisceral Transplantation: The Role of Liver and Human Leukocyte Antigen Mismatching. Liver Transpl 2018; 24:1726-1735. [PMID: 30112820 DOI: 10.1002/lt.25323] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/07/2018] [Indexed: 01/13/2023]
Abstract
Rejection is one of the most important drawbacks for graft and patient survival in intestinal and multivisceral transplantation. However, there is no consensus on the diagnostic criteria for humoral rejection, and the literature about the role of donor-specific antibodies (DSA) on allograft outcome and the risk factors that contribute to their development is scant with contradictory results. The present study analyzes the role of DSA exclusively in a pediatric cohort of 43 transplants. Among our patients, 11.6% showed preformed DSA, but they did not correlate with more rejection or less allograft survival. Having previous transplants was the main sensitization factor with an odds ratio (OR) = 44.85 (P = 0.001). In total, 16.3% of recipients developed de novo donor-specific antibodies (dnDSA), mostly directed against human leukocyte antigen (HLA) class II, polyspecific and complement fixing. Additionally, the presence of dnDSA had a deleterious effect on graft rejection (hazard ratio [HR] = 11.00; P = 0.01) and survival (HR = 66.52; P < 0.001) in an observational period of 5 years after transplantation. The inclusion of the liver emerged as the main protective factor against dnDSA development with an OR = 0.07 (P = 0.007). The analysis of HLA compatibility at the serological and epitope level with the computational tools HLAMatchmaker and PIRCHE revealed no association between HLA mismatching and dnDSA. In conclusion, this study performed in pediatric recipients shows the deleterious effect of dnDSA on intestinal transplantation supported by the complement-fixing activity observed. Additionally, the liver inclusion in the allografts showed to be a protective factor against dnDSA generation.
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Affiliation(s)
- Paloma Talayero
- Department of Immunology, University Hospital 12 de Octubre, Madrid, Spain.,I+12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain
| | - Esther Ramos Boluda
- Pediatric Gastroenterology Intestinal Rehabilitation Unit, University Hospital La Paz, Madrid, Spain
| | - Elena Gómez Massa
- Department of Immunology, University Hospital 12 de Octubre, Madrid, Spain.,I+12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain
| | | | - Gerardo Prieto Bozano
- Pediatric Gastroenterology Intestinal Rehabilitation Unit, University Hospital La Paz, Madrid, Spain
| | - Francisco Hernández Oliveros
- Department of Pediatric Surgery, University Hospital La Paz, Madrid, Spain.,EOC of ERN-Transplantchild, University Hospital La Paz, Madrid, Spain
| | | | - Jorge Calvo Pulido
- General and Digestive Surgery and Abdominal Organ Transplantation, University Hospital 12 de Octubre, Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain
| | - Estela Paz-Artal
- Department of Immunology, University Hospital 12 de Octubre, Madrid, Spain.,I+12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain.,Section of Immunology, San Pablo CEU University, Madrid, Spain
| | - Esther Mancebo
- Department of Immunology, University Hospital 12 de Octubre, Madrid, Spain.,I+12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain
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21
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Lacaille F. Intestinal Transplantation and Donor-Specific Antibodies: Another Brick in the Wall. Liver Transpl 2018; 24:1651-1652. [PMID: 30369014 DOI: 10.1002/lt.25369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 10/22/2018] [Indexed: 01/13/2023]
Affiliation(s)
- Florence Lacaille
- Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France
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22
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Rabant M, Racapé M, Petit LM, Taupin JL, Aubert O, Bruneau J, Barbet P, Goulet O, Chardot C, Suberbielle C, Lacaille F, Canioni D, Duong Van Huyen JP. Antibody-mediated rejection in pediatric small bowel transplantation: Capillaritis is a major determinant of C4d positivity in intestinal transplant biopsies. Am J Transplant 2018; 18:2250-2260. [PMID: 29397036 DOI: 10.1111/ajt.14685] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/21/2017] [Accepted: 01/24/2018] [Indexed: 01/25/2023]
Abstract
The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor-specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy-eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome.
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Affiliation(s)
- Marion Rabant
- Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.,INSERM U1151, Hôpital Necker, Paris, France.,Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France
| | - Maud Racapé
- Paris Translational Research for Organ Transplant INSERM U 970, PARCC, HEGP, Paris, France
| | - Laetitia-Marie Petit
- Pediatric Gastroenterology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jean Luc Taupin
- Immunology and histocompatibility laboratory, Saint Louis Hospital, Paris, France
| | - Olivier Aubert
- Paris Translational Research for Organ Transplant INSERM U 970, PARCC, HEGP, Paris, France
| | - Julie Bruneau
- Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.,Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France
| | - Patrick Barbet
- Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.,Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France
| | - Olivier Goulet
- Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France.,Pediatric Gastroenterology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christophe Chardot
- Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France.,Pediatric Surgery Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Caroline Suberbielle
- Immunology and histocompatibility laboratory, Saint Louis Hospital, Paris, France
| | - Florence Lacaille
- Pediatric Gastroenterology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Danielle Canioni
- Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.,Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France
| | - Jean-Paul Duong Van Huyen
- Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.,Paris V Descartes University, Sorbonne-Paris-Cité, Paris, France.,Paris Translational Research for Organ Transplant INSERM U 970, PARCC, HEGP, Paris, France
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23
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Celik N, Stanley K, Rudolph J, Al-Issa F, Kosmach B, Ashokkumar C, Sun Q, Brown-Bakewell R, Zecca D, Soltys K, Khanna A, Bond G, Ganoza A, Mazariegos G, Sindhi R. Improvements in intestine transplantation. Semin Pediatr Surg 2018; 27:267-272. [PMID: 30342602 DOI: 10.1053/j.sempedsurg.2018.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Transplantation of the intestine in children has presented significant challenges even as it has become a standard to treat nutritional failure due to short gut syndrome. These challenges have been addressed in part by significant improvements in short and long-term care. Noteworthy enhancements include reduced need for intestine transplantation, drug-sparing immunosuppressive regimens, immune monitoring, and improved surveillance and management of PTLD and non-adherence.
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Affiliation(s)
- Neslihan Celik
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Kaitlin Stanley
- Division of Pediatric Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, USA
| | - Jeff Rudolph
- Intestinal Care and Rehabilitation Center, Children's Hospital of Pittsburgh of UPMC, USA
| | - Feras Al-Issa
- Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, USA
| | - Beverly Kosmach
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Chethan Ashokkumar
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Qing Sun
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Renee Brown-Bakewell
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Dale Zecca
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Kyle Soltys
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Ajai Khanna
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Geoffrey Bond
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Armando Ganoza
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - George Mazariegos
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Rakesh Sindhi
- Thomas E Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
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24
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Weissenbacher A, Vrakas G, Chen M, Reddy S, Allan P, Giele H, Barnardo MC, Vaidya A, Friend PJ, Fuggle SV. De novo
donor-specific HLA antibodies after combined intestinal and vascularized composite allotransplantation - a retrospective study. Transpl Int 2017; 31:398-407. [DOI: 10.1111/tri.13096] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 07/24/2017] [Accepted: 11/12/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Annemarie Weissenbacher
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
- Department of Visceral; Transplant and Thoracic Surgery; Innsbruck Medical University Innsbruck, Austria
| | - Georgios Vrakas
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
| | - Mian Chen
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
| | - Srikanth Reddy
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
| | - Philip Allan
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
- Translational Gastroenterology Unit; John Radcliffe Hospital; Oxford UK
| | - Henk Giele
- Department of Plastic and Reconstructive Surgery; John Radcliffe Hospital; Oxford UK
| | - Martin C.N.M Barnardo
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
| | - Anil Vaidya
- Transplant Department; Apollo Hospitals Enterprise; Chennai India
| | - Peter J. Friend
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
| | - Susan V. Fuggle
- Oxford Transplant Centre; Nuffield Department of Surgical Sciences; Oxford University Hospitals; Churchill Hospital Oxford, UK
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25
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Gürkan A. Advances in small bowel transplantation. Turk J Surg 2017; 33:135-141. [PMID: 28944322 DOI: 10.5152/turkjsurg.2017.3544] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
Small bowel transplantation is a life-saving surgery for patients with intestinal failure. The biggest problem in intestinal transplantation is graft rejection. Graft rejection is the main reason for morbidity and mortality. Rejection has a negative effect on the survival of the graft. While 50%-75% of small bowel transplantation patients experience acute rejection, chronic rejection occurs in approximately 15% of patients. Immune monitoring is crucial after small bowel transplantation. Unlike other types of transplantation, there are no non-invasive or reliable markers to predict rejection in small bowel transplantation. The diagnosis of AR is confirmed by clinical symptoms, endoscopic appearance, and pathological specimens taken by endoscopy. Thus, histopathological examinations obtained by protocol biopsies remain as the gold standard for intestinal graft monitoring; however, biopsies have some complications, especially in small grafts. In addition to the high complication rate, biopsies are non-diagnostic; thus, multiple biopsies should be performed to exclude rejection. Therefore, auxiliary assays, such as measurements of citrulline and calprotectin in the blood, cytofluorographic examination of peripheral blood immune cells, cytokine profiling, and distinct gene-set-change measurements, are increasingly being used in small bowel transplantation. Developments in the understanding of genes seem to be promising that limited gene sets, taken from blood or from intestinal biopsies, will enhance pathological diagnosis. Bone marrow mesenchymal stem cell transplantation with SBT and tissue engineering are also promising procedures.
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Affiliation(s)
- Alp Gürkan
- Department of General Surgery, Çamlıca Medicana Hospital, İstanbul, Turkey.,Department of General Surgery, İstanbul Aydın University School of Medicine, İstanbul, Turkey
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26
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Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients. Transplantation 2017; 101:873-882. [PMID: 27490417 DOI: 10.1097/tp.0000000000001391] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Rejection remains the leading cause of allograft loss, and a major barrier to improving long-term outcomes after intestinal transplantation. Our aim is to define the prevalence and investigate the role of donor-specific antibody (DSA) on intestinal graft outcomes. METHODS The study includes 109 transplants performed in 95 recipients at a single center. Patients were screened for DSA pretransplant, monitored regularly posttransplant and when clinically indicated using the single-antigen bead Luminex assay. Standard induction immunosuppression was with interleukin-2 receptor antagonists, and antithymocyte globulin in high-risk recipients. Maintenance regimens were tacrolimus-based. RESULTS Pretransplant DSA was detected in 12 (11%) recipients with 50% continuing to have circulating antibodies posttransplant. An additional 24 (25%) patients developed de novo DSA, and of these, 71% had persistent antibodies. Recipients with preformed DSA demonstrated elevated risks of early graft failure, whereas those with de novo DSA experienced accelerated graft loss once DSA was detected, reaching a 28% failure rate within 2 years. HLA-DQ mismatch is a significant risk factor for de novo DSA emergence, whereas the persistence of antibodies is predicted by DSA strength and specificity. Although inclusion of the liver in the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect was lost among recipients with persistent DSA. CONCLUSIONS The presence of DSA is associated with inferior graft outcomes among intestinal transplant recipients. An enhanced understanding of the mechanisms by which DSA causes allograft injury, and effective strategies targeting humoral immune reactivity are needed to improve long-term intestinal graft outcomes.
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27
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The impact of antibodies and virtual crossmatching on intestinal transplant outcomes. Curr Opin Organ Transplant 2017; 22:149-154. [DOI: 10.1097/mot.0000000000000393] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Petit LM, Rabant M, Canioni D, Suberbielle-Boissel C, Goulet O, Chardot C, Lacaille F. Impacts of donor-specific anti-HLA antibodies and antibody-mediated rejection on outcomes after intestinal transplantation in children. Pediatr Transplant 2017; 21. [PMID: 28084679 DOI: 10.1111/petr.12847] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2016] [Indexed: 11/28/2022]
Abstract
AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre-Tx period and de novo post-Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow-up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx.
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Affiliation(s)
- L-M Petit
- Unité d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpitaux Universitaires de Genève, Geneve, Switzerland
| | - M Rabant
- Service d'Anatomopathologie, Hôpital Necker Enfants Malades, Paris, France
| | - D Canioni
- Service d'Anatomopathologie, Hôpital Necker Enfants Malades, Paris, France
| | | | - O Goulet
- Service d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpital Necker Enfants Malades, Paris, France
| | - C Chardot
- Service de Chirurgie Viscérale Pédiatrique, Hôpital Necker Enfants Malades, Paris, France
| | - F Lacaille
- Service d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpital Necker Enfants Malades, Paris, France
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Successful Rescue of Late-onset Antibody-mediated Rejection 12 Years After Living-donor Intestinal Transplantation: A Case Report. Transplant Proc 2017; 49:232-236. [PMID: 28104146 DOI: 10.1016/j.transproceed.2016.10.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 10/27/2016] [Indexed: 11/21/2022]
Abstract
BACKGROUND Antibody-mediated rejection (ABMR) has recently surfaced as a potential form of graft dysfunction after intestinal transplantation. METHODS We present a case of an intestinal transplant recipient who developed late-onset ABMR 12 years after living-donor transplantation. An 18-year-old male recipient with a history of extensive intestinal resection secondary to acute bowel volvulus exhibited an excellent baseline immune profile for transplantation, including ABO-identical and HLA-haploidentical to the donor; a negative cross-match with a panel reactive antibody of 3.0%. RESULTS Post-transplantation immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and prednisone within the first year, followed by tacrolimus and MMF in the second year, and maintenance with tacrolimus monotherapy thereafter. The recipient experienced a single episode of indetermined acute cellular rejection 3 months after transplantation. Since then, he did not require any parenteral nutrition and had completely reintegrated with society. Twelve years later, the patient developed persistent diarrhea associated with transplant biopsy diffuse C4d deposition and circulating donor-specific antibodies. After the use of rituximab and intravenous immunoglobulin, the recipient stabilized 17 years after transplantation with complete recovery of intestinal mucosal damage. CONCLUSION Late-onset ABMR can emerge after transplantation and must be considered a possible cause of graft dysfunction in long-term intestinal transplantation survivors.
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Parekh R, Kazimi M, Skorupski S, Fagoaga O, Jafri S, Segovia MC. Intestine Transplantation Across a Positive Crossmatch With Preformed Donor-Specific Antibodies. Transplant Proc 2017; 48:489-91. [PMID: 27109984 DOI: 10.1016/j.transproceed.2015.10.084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 10/21/2015] [Indexed: 01/11/2023]
Abstract
BACKGROUND We describe our experience using a modified protocol for immunosuppression for intestine transplantation across a positive crossmatch. Patients who underwent transplantation in 2013 were evaluated over a 12-month period for rejection and infectious events with comparison to procedure-matched controls on our standard protocol of immunosuppression. PATIENTS AND METHODS We used a modified protocol for intestine and multivisceral transplantation for patients with a positive flow crossmatch. In addition to our standard protocol, patients with positive crossmatch were given rituximab and intravenous immunoglobulin (IVIg) preoperatively. DSA was sent for clinical evaluation at monthly intervals. Patients were screened for rejection by endoscopic evaluation. RESULTS Four patients underwent transplantation within a single year across a positive crossmatch. Two received isolated intestine transplants and 2 had multivisceral transplantation (MVT). During the 12-month follow-up, 1 patients had an episode of severe acute cellular rejection, which was managed with increased immunosuppression. None of the patients had episodes of cytomegalovirus infection. One patient developed major infection and 3 patients developed minor bacterial infections. Among procedure-matched controls with negative final crossmatch on standard management (no preoperative rituximab or IVIg), 2 developed mild acute cellular rejection and 2 developed minor infections. One developed cytomegalovirus viremia with invasion to the colonic mucosa. CONCLUSIONS We report our protocol for immunosuppression for IT and MVT across a positive crossmatch. This allowed transplantation despite the presence of a positive crossmatch, with low rejection rates but potentially increased risk for major infections compared to the negative crossmatch controls on our standard protocol.
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Affiliation(s)
- R Parekh
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan
| | - M Kazimi
- Department of Transplant Surgery, Henry Ford Hospital, Detroit, Michigan
| | - S Skorupski
- Department of Pathology, Henry Ford Hospital, Detroit, Michigan
| | - O Fagoaga
- Department of Pathology, Henry Ford Hospital, Detroit, Michigan
| | - S Jafri
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan
| | - M C Segovia
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan.
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Wu GS, Cruz Jr RJ, Cai JC. Acute antibody-mediated rejection after intestinal transplantation. World J Transplant 2016; 6:719-728. [PMID: 28058223 PMCID: PMC5175231 DOI: 10.5500/wjt.v6.i4.719] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 10/02/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx).
METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction.
RESULTS Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died.
CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.
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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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Matsuda Y, Sarwal MM. Unraveling the Role of Allo-Antibodies and Transplant Injury. Front Immunol 2016; 7:432. [PMID: 27818660 PMCID: PMC5073555 DOI: 10.3389/fimmu.2016.00432] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 10/03/2016] [Indexed: 12/25/2022] Open
Abstract
Alloimmunity driving rejection in the context of solid organ transplantation can be grossly divided into mechanisms predominantly driven by either T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), though the co-existence of both types of rejections can be seen in a variable number of sampled grafts. Acute TCMR can generally be well controlled by the establishment of effective immunosuppression (1, 2). Acute ABMR is a low frequency finding in the current era of blood group and HLA donor/recipient matching and the avoidance of engraftment in the context of high-titer, preformed donor-specific antibodies. However, chronic ABMR remains a major complication resulting in the untimely loss of transplanted organs (3-10). The close relationship between donor-specific antibodies and ABMR has been revealed by the highly sensitive detection of human leukocyte antigen (HLA) antibodies (7, 11-15). Injury to transplanted organs by activation of humoral immune reaction in the context of HLA identical transplants and the absence of donor specific antibodies (17-24), strongly suggest the participation of non-HLA (nHLA) antibodies in ABMR (25). In this review, we discuss the genesis of ABMR in the context of HLA and nHLA antibodies and summarize strategies for ABMR management.
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Affiliation(s)
- Yoshiko Matsuda
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Minnie M. Sarwal
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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34
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Wu GS. Updates on antibody-mediated rejection in intestinal transplantation. World J Transplant 2016; 6:564-572. [PMID: 27683635 PMCID: PMC5036126 DOI: 10.5500/wjt.v6.i3.564] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/26/2016] [Accepted: 08/18/2016] [Indexed: 02/05/2023] Open
Abstract
Antibody-mediated rejection (ABMR) has increasingly emerged as an important cause of allograft loss after intestinal transplantation (ITx). Compelling evidence indicates that donor-specific antibodies can mediate and promote acute and chronic rejection after ITx. However, diagnostic criteria for ABMR after ITx have not been established yet and the mechanisms of antibody-mediated graft injury are not well-known. Effective approaches to prevent and treat ABMR are required to improve long-term outcomes of intestine recipients. Clearly, ABMR after ITx has become an important area for research and clinical investigation.
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Effectiveness of Bortezomib in a Patient With Acute Rejection Associated With an Elevation of Donor-Specific HLA Antibodies After Small-Bowel Transplantation: Case Report. Transplant Proc 2016; 48:525-7. [DOI: 10.1016/j.transproceed.2015.09.073] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 09/15/2015] [Indexed: 01/20/2023]
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Garcia-Roca R, Tzvetanov IG, Jeon H, Hetterman E, Oberholzer J, Benedetti E. Successful living donor intestinal transplantation in cross-match positive recipients: Initial experience. World J Gastrointest Surg 2016; 8:101-105. [PMID: 26843919 PMCID: PMC4724584 DOI: 10.4240/wjgs.v8.i1.101] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 08/18/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
Sensitized patients tend to have longer waiting times on the deceased donor list and are at increased risk of graft loss from acute or chronic rejection compared to non-sensitized candidates. Desensitization protocols are utilized to decrease the levels of alloantibodies and to convert an initial positive cross-match to prospective donors into a negative crossmatch. These procedures are mostly available in the setting of living donation. Due to the elective nature of the procedure, desensitization protocols can be extended until the desire result is obtained prior to transplantation. We present two cases of successful desensitization protocol applied to living donor intestinal transplant candidates that converted to negative cross-match to their donors. We present two cases of intestinal transplant candidates with a potential living donor to whom they are sensitized. Both cases underwent successful transplantation after desensitization protocol. No evidence of humoral rejection has occurred in either recipient. Living donor intestinal transplantation in sensitized recipients against the prospective donors provides the ability to implement a desensitization protocol to convert to negative cross-match.
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Prospective Monitoring of Donor-specific Anti-HLA Antibodies After Intestine/Multivisceral Transplantation: Significance of De Novo Antibodies. Transplantation 2015; 99:e49-56. [PMID: 25769071 DOI: 10.1097/tp.0000000000000614] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Presence of circulating donor-specific antibodies (DSA) may be associated with worse clinical outcomes after intestine/multivisceral transplantation. METHODS In 79 intestine/multivisceral recipients, sera were prospectively screened for DSA by Luminex Single antigen test at 1, 3, 6, 9, 12, 18, 24, and 36 months after transplantation. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus-prednisone maintenance. C4d staining was performed retrospectively on biopsies in patients that developed acute rejection (AR). RESULTS Twenty-two (28%) patients developed de novo DSA at a median posttransplant period of 3 (1-36) months. De novo DSA were observed in 10 of 40 liver-including and 12 of 39 liver-excluding transplants (P = 0.57). Occurrence of AR was slightly higher in patients with de novo DSA (45% vs 33%, respectively; P = 0.41). Similarly, chronic rejection (14% vs 5%; P = 0.21) and graft loss due to AR (18% vs 7%; P = 0.14) were numerically higher in patients with de novo DSA. Only 35% patients experiencing AR had circulating de novo DSA at the time of AR. Antibody-mediated rejection was diagnosed in 6 patients based on C4d staining, of these 2 patients had circulating de novo DSA at the time of biopsy. CONCLUSIONS De novo DSA formation, particularly early in the posttransplant course may be associated with trends toward worse outcomes. However, its significance in the pathophysiology of AR remains uncertain. Studies focusing mechanisms of DSA-related graft injury and intragraft DSA detection might provide further insight into this issue.
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39
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Liver inclusion improves outcomes of intestinal retransplantation in adults. [Corrected]. Transplantation 2015; 99:1265-72. [PMID: 25427167 DOI: 10.1097/tp.0000000000000488] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Retransplantation is a viable treatment option for patients with primary intestinal graft loss. METHODS We analyzed outcomes of retransplantations (n = 23) in adults from May 2000 to May 2010 at our center and compared patients who received liver-free retransplantations (n = 13) with those who received liver-inclusive retransplantations (n = 10). RESULTS The overall survival rates at 1, 3, and 5 years in retransplantations were 90.9%, 67.1%, and 59.7% (patient) and 82.2%, 58.6%, and 51.3% (graft), respectively, which were similar to the rates in primary transplants. The patient survival rates at 1, 3, and 5 years were 91.7%, 55.6%, and 41.7%, respectively, in liver-free retransplantations, as compared to rates of 90.0%, 80.0%, and 80.0% in liver-inclusive retransplantations. The graft survival rates at 1, 3, and 5 years in liver-free retransplantations were 76.2%, 40.6%, and 27.1%, respectively, which were significantly worse than those in liver-inclusive retransplantations (P = 0.03). Within an average follow-up of 32.3 months, 8 of 13 (61.5%) of liver-free retransplantations underwent enterectomy because of severe acute cellular rejection (n = 3) or chronic rejection (n = 5). Six of 13 (46.2%) recipients succumbed to rejection-related complications. Compared to liver-free retransplantations, the rate and severity of acute rejection were markedly de creased in liver-inclusive retransplantations, and no chronic rejection was seen. Within an average follow-up of 44.5 months, two of 10 (20%) died due to graft-versus-host disease and infection, respectively. CONCLUSION A liver-inclusive retransplantation offers a better long-term patient and graft survival, suggesting that including the liver as part of an intestinal graft should be considered in adult recipients when retransplantation is necessary.
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40
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Fan J, Tryphonopoulos P, Tekin A, Nishida S, Selvaggi G, Amador A, Jebrock J, Weppler D, Levi D, Vianna R, Ruiz P, Tzakis A. Eculizumab Salvage Therapy for Antibody-Mediated Rejection in a Desensitization-Resistant Intestinal Re-Transplant Patient. Am J Transplant 2015; 15:1995-2000. [PMID: 25649227 DOI: 10.1111/ajt.13183] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 11/26/2014] [Accepted: 12/19/2014] [Indexed: 01/25/2023]
Abstract
The presence of elevated calculated panel reactive antibody (cPRA) and anti-HLA donor specific antibodies (DSA) are high risk factors for acute antibody-mediated rejection (AAMR) in intestinal transplantation that may lead to graft loss. Eculizumab has been used for the treatment of AAMR in kidney transplantation of sensitized patients that do not respond to other treatment. Here, we report a case where eculizumab was used to treat AAMR in a desensitization-resistant intestinal re-transplant patient. A male patient lost his intestinal graft to AAMR 8.14 years after his primary transplant. He received a second intestinal graft that had to be explanted a month later due to refractory AAMR. The patient remained highly sensitized despite multiple treatments. He received a multivisceral graft and presented with severe AAMR on day 3 posttransplantation. The AAMR was successfully treated with eculizumab. The patient presently maintains an elevated cPRA level above 90% but his DSAs have decreased from 18 000 MFI (mean fluorescent intensity) to below the positive cut-off value of 3000 MFI and remains rejection free with a 2-year follow-up since his multivisceral transplant. Eculizumab offers an alternative to treat AAMR in intestinal transplantation in desensitization-resistant patients.
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Affiliation(s)
- J Fan
- Miami Transplant Institute, University of Miami, Miami, FL
| | | | - A Tekin
- Miami Transplant Institute, University of Miami, Miami, FL
| | - S Nishida
- Miami Transplant Institute, University of Miami, Miami, FL
| | - G Selvaggi
- Miami Transplant Institute, University of Miami, Miami, FL
| | - A Amador
- Miami Transplant Institute, University of Miami, Miami, FL
| | - J Jebrock
- Miami Transplant Institute, University of Miami, Miami, FL
| | | | - D Levi
- Carolinas Medical Center, Charlotte, NC
| | - R Vianna
- Miami Transplant Institute, University of Miami, Miami, FL
| | - P Ruiz
- Miami Transplant Institute, University of Miami, Miami, FL
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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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42
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O'Leary JG, Kaneku H, Banuelos N, Jennings LW, Klintmalm GB, Terasaki PI. Impact of IgG3 subclass and C1q-fixing donor-specific HLA alloantibodies on rejection and survival in liver transplantation. Am J Transplant 2015; 15:1003-13. [PMID: 25772599 DOI: 10.1111/ajt.13153] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 10/08/2014] [Accepted: 10/29/2014] [Indexed: 01/25/2023]
Abstract
Recent literature confirms donor-specific HLA alloantibodies (DSA) impair 5-year survival in some but not all liver transplant recipients. In an effort to improve DSA testing's association with rejection and death, we retrospectively evaluated 1270 liver transplant recipients for the presence of IgG3 and C1q-fixing DSA. In patients with preformed DSA, 29 and 51% had IgG3 and C1q-fixing DSA, respectively. In patients with de novo DSA, 62% and 67% had IgG3 and C1q-fixing DSA, respectively. When different types of DSA positive patients were compared to DSA negative patients, multivariable analysis showed that IgG3 DSA positivity had the highest numerical hazard ratio for death (IgG3: HR = 2.4, p < 0.001; C1q: HR = 1.9, p < 0.001; standard DSA: HR = 1.6, p < 0.001). Similarly, multivariable analysis demonstrated de novo IgG3 DSA positivity compared to no DSA had the highest hazard ratio for death (IgG3: HR = 2.1, p = 0.004; C1q: HR = 1.9, p = 0.02; standard DSA: HR = 1.8, p = 0.007). Preformed C1q-fixing class II DSA showed the strongest correlation with early rejection. In conclusion, preformed and de novo IgG3 subclass DSA positive patients had the highest absolute HR for death in side-by-side comparison with C1q and standard DSA positive versus DSA negative patients; however, IgG3 negative DSA positive patients still had inferior outcomes compared to DSA negative patients.
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Affiliation(s)
- J G O'Leary
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
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43
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Kubal CA, Mangus RS, Tector AJ. Intestine and multivisceral transplantation: current status and future directions. Curr Gastroenterol Rep 2015; 17:427. [PMID: 25613179 DOI: 10.1007/s11894-014-0427-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.
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Affiliation(s)
- Chandrashekhar A Kubal
- Transplant Division, Department of Surgery, Indiana University School of Medicine, 550 N University Blvd, Room 4601, Indianapolis, IN, 46202-5250, USA,
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44
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Grant D, Abu-Elmagd K, Mazariegos G, Vianna R, Langnas A, Mangus R, Farmer DG, Lacaille F, Iyer K, Fishbein T. Intestinal transplant registry report: global activity and trends. Am J Transplant 2015; 15:210-9. [PMID: 25438622 DOI: 10.1111/ajt.12979] [Citation(s) in RCA: 296] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 07/16/2014] [Accepted: 08/12/2014] [Indexed: 01/25/2023]
Abstract
The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan-Meier survival curves and a multiple variable analysis. Eighty-two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune-suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.
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Affiliation(s)
- D Grant
- Department of Surgery, University Health Network, Toronto, Canada
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45
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Donor-specific human leukocyte antigen antibodies in intestinal transplantation. Curr Opin Organ Transplant 2014; 19:261-6. [PMID: 24811437 DOI: 10.1097/mot.0000000000000078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Early outcomes following intestinal transplantation (ITx) have markedly improved in recent years. However, there has been a lack of improvement in long-term outcomes. Increasing amounts of data suggest the humoral immune system is a major contributor to rejection and late allograft loss. This review will summarize the available data on donor-specific human leukocyte antigen antibodies (DSAs) in ITx, with a focus on the clinical significance of DSAs, diagnosis of antibody-mediated rejection (AMR), and available treatment modalities. Areas requiring further investigation will also be identified. RECENT FINDINGS Mounting evidence shows that pre- and/or posttransplant DSAs are associated with rejection and allograft loss following ITx. Preformed DSAs are present in nearly one-third of ITx recipients, and de-novo DSAs develop in up to 40% of patients. Diagnosis and treatment of AMR remains challenging, but reports indicate that when optimal induction and maintenance immunosuppressive agents are used, the impact of DSAs may be negligible. SUMMARY Although data are limited due to center differences with regard to patient population, induction and maintenance immunosuppression protocols, and monitoring strategies, DSAs are associated with poor outcomes following ITx. A consensus to define AMR and optimal treatment strategies is needed.
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Updates on acute and chronic rejection in small bowel and multivisceral allografts. Curr Opin Organ Transplant 2014; 19:293-302. [PMID: 24807213 DOI: 10.1097/mot.0000000000000075] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW The surgical management of short bowel syndrome now includes intestinal (ITx) and multivisceral transplantation (MVTx), which has advanced and is now a sustainable option for the treatment of intestinal failure. Improvements in immunosuppressive therapies, excellence in surgical and medical management and enhanced post-transplant monitoring have all contributed to optimizing this solid organ transplant as a means of supplanting the diseased native bowel and alimentary tract with a functional alternative. RECENT FINDINGS Post-transplant management is a critical and challenging phase of gastrointestinal transplantation, and the transplant pathologist is an essential member of the transplant team who identifies many of the early and late complications after ITx and MVTx. Among the most injurious and common complications of ITx and MVTx is acute rejection and, to a lesser degree, chronic rejection. Both of these broad categories of rejection are principally identified by histopathological changes in the allograft; however, biomarkers and other laboratory analytes are rapidly evolving into critical ancillary tools in identifying and further characterizing the rejection process. Thus, the transplant pathologist must also be able to utilize numerous other laboratory tests and panels of molecular biomarkers that provide supplementary information to accompany the biopsy interpretation and clinical suspicion of rejection. SUMMARY Using biopsies and an assortment of additional approaches, the transplant pathologist is now able to provide swift and detailed information regarding the rejection process in the gastrointestinal transplant. This enables the clinical team to properly and successfully intercede, contributing to enhanced patient and graft survival.
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Zhang W, Shen ZY, Song HL, Yang Y, Wu BJ, Fu NN, Liu T. Protective effect of bone marrow mesenchymal stem cells in intestinal barrier permeability after heterotopic intestinal transplantation. World J Gastroenterol 2014; 20:7442-7451. [PMID: 24966614 PMCID: PMC4064089 DOI: 10.3748/wjg.v20.i23.7442] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the protective effect of bone marrow mesenchymal stem cells (BM MSCs) in the small intestinal mucosal barrier following heterotopic intestinal transplantation (HIT) in a rat model.
METHODS: BM MSCs were isolated from male Lewis rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. The HIT models were divided into a non-rejection group, saline-treated rejection group (via penile vein), and BM MSC–treated group (via penile vein). Intestinal mucosal barrier injury was estimated by diamine oxidase (DAO) and D-lactic acid (D-LA) expression levels. Tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) were detected by enzyme-linked immunosorbent assay. Ultrastructural change of tight junctions (TJs) was observed under transmission electron microscope. Expression levels of the TJ proteins occludin and zona occludens (ZO)-1, affected by the inflammatory factors, were measured using real-time polymerase chain reaction and Western blotting.
RESULTS: The pathological score at each time point after surgery indicated significantly less serious injury in the BM MSCs-treated group than in the rejection group (P < 0.05). In the former, graft levels of DAO and D-LA were reduced, and TNF-α and INF-γ production was inhibited (at day 7: 10.6473 ± 0.0710 vs 17.2128 ± 0.4991, P < 0.05; 545.1506 ± 31.9416 vs 810.2637 ± 25.1175, P < 0.05). IL-10 and TGF-β production was increased greatly (at day 7: 125.7773 ± 4.7719 vs 80.3756 ± 2.5866, P < 0.05; 234.5273 ± 9.3980 vs 545.1506 ± 31.9416, P < 0.05). There was increased expression of occludin and ZO-1 protein (at day 7: 0.2674 ± 0.0128 vs 0.1352 ± 0.0142, P < 0.05; at day 5: 0.7189 ± 0.0289 vs 0.4556 ± 0.0242, P < 0.05) and mRNA (at day 7: 0.3860 ± 0.0254 vs 0.1673 ± 0.0369, P < 0.05; at day 5: 0.5727 ± 0.0419 vs 0.3598 ± 0.0242, P < 0.05).
CONCLUSION: BM MSCs can improve intestinal barrier permeability, repair TJs, and increase occludin and ZO-1 protein expression. With altered cytokine levels, they can protect the intestinal mucosa after transplantation.
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MESH Headings
- Amine Oxidase (Copper-Containing)/metabolism
- Animals
- Bone Marrow Transplantation
- Cells, Cultured
- Cytokines/metabolism
- Graft Survival
- Inflammation Mediators/metabolism
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/transplantation
- Intestinal Mucosa/ultrastructure
- Intestine, Small/metabolism
- Intestine, Small/transplantation
- Intestine, Small/ultrastructure
- Lactic Acid/metabolism
- Male
- Mesenchymal Stem Cell Transplantation
- Microscopy, Electron, Transmission
- Occludin/genetics
- Occludin/metabolism
- Permeability
- RNA, Messenger/metabolism
- Rats, Inbred BN
- Rats, Inbred Lew
- Tight Junctions/metabolism
- Tight Junctions/ultrastructure
- Time Factors
- Transplantation, Heterotopic
- Zonula Occludens-1 Protein/genetics
- Zonula Occludens-1 Protein/metabolism
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Hibi T, Shinoda M, Itano O, Kitagawa Y. Current status of the organ replacement approach for malignancies and an overture for organ bioengineering and regenerative medicine. Organogenesis 2014; 10:241-9. [PMID: 24836922 DOI: 10.4161/org.29245] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Significant achievements in the organ replacement approach for malignancies over the last 2 decades opened new horizons, and the age of "Transplant Oncology" has dawned. The indications of liver transplantation for malignancies have been carefully expanded by a strict patient selection to assure comparable outcomes with non-malignant diseases. Currently, the Milan criteria, gold standard for hepatocellular carcinoma, are being challenged by high-volume centers worldwide. Neoadjuvant chemoradiation therapy and liver transplantation for unresectable hilar cholangiocarcinoma has been successful in specialized institutions. For other primary and metastatic liver tumors, clinical evidence to establish standardized criteria is lacking. Intestinal and multivisceral transplantation is an option for low-grade neoplasms deemed unresectable by conventional surgery. However, the procedure itself is in the adolescent stage. Solid organ transplantation for malignancies inevitably suffers from "triple distress," i.e., oncological, immunological, and technical. Organ bioengineering and regenerative medicine should serve as the "triple threat" therapy and revolutionize "Transplant Oncology."
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Affiliation(s)
- Taizo Hibi
- Department of Surgery; Keio University School of Medicine; Tokyo, Japan
| | - Masahiro Shinoda
- Department of Surgery; Keio University School of Medicine; Tokyo, Japan
| | - Osamu Itano
- Department of Surgery; Keio University School of Medicine; Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery; Keio University School of Medicine; Tokyo, Japan
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Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol 2014; 1034:41-70. [PMID: 23775730 DOI: 10.1007/978-1-62703-493-7_2] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Until recently, allograft rejection was thought to be mediated primarily by alloreactive T cells. Consequently, immunosuppressive approaches focused on inhibition of T cell activation. While short-term graft survival has significantly improved and rejection rates have dropped, acute rejection has not been eliminated and chronic rejection remains the major threat to long-term graft survival. Increased attention to humoral immunity in experimental systems and in the clinic has revealed that donor specific antibodies (DSA) can mediate and promote acute and chronic rejection. Herein, we detail the effects of alloantibody, particularly HLA antibody, binding to graft vascular and other cells, and briefly summarize the experimental methods used to assess such outcomes.
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Affiliation(s)
- Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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Trevizol AP, David AI, Yamashita ET, Pecora RA, D'Albuquerque LA. Intestinal and multivisceral retransplantation results: literature review. Transplant Proc 2013; 45:1133-6. [PMID: 23622645 DOI: 10.1016/j.transproceed.2013.03.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Intestinal/multivisceral transplantation (IT/MVT) is the gold standard treatment for patients with intestinal failure and complications related to total parenteral nutrition, gastrointestinal inoperable indolent tumors, or diffuse portal trombosis. Currently, the reported 1-year patient survival rate is around 80%, similar to other solid organ abdominal transplantations. Unfortunately, the patient survival decreases after the first year with the 5-year rate not close to 70% yet. Acute cellular rejection is the main cause of graft loss. Its early diagnosis may make it possible to improve survival of retransplantations. OBJECTIVE To analyze the reported results published in the last 5 years by leading transplant centers to evaluate IT/MVT retransplantation results. METHODS We performed a literature review using PubMed focusing on multivisceral and intestinal retransplantation in articles published between 2006 and 2012. In relation to the first transplantation, we analyzed demographics, imunosuppression, rejection, infection as well as graft and patient survival rates. RESULTS Two centers reported results on intestinal and multivisceral retransplantations. Mazariegos et al reported their experience with 15 intestinal retransplantations in 14 pediatric recipients. Four patients died from posttransplant lymphoperliferative disease, severe acute cellular rejection, fungal sepsis, or bleeding from a pseudoaneurysm at a mean time of 5.7 months post-transplantation. Total parenteral nutrition was weaned at a median time of 32 days. Abu-Elmaged et al reported 47 cases with a 5-year survival of 47% for all retransplant modalities. Retransplantation with liver-contained visceral allograft achieved a 5-year survival rate of 61% compared with 16% for liver-free visceral grafts. CONCLUSION Despite those huge improvements, some transplanted patients develop severe acute cellular rejection, culminating in graft loss and retransplantation. Repots on multivisceral and intestinal retransplantation outcomes suggest that it is a viable procedure with appropriate patient survival after primary graft loss.
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