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Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
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Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
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Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury. Nat Rev Nephrol 2021; 17:591-603. [PMID: 34031575 DOI: 10.1038/s41581-021-00428-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/03/2023]
Abstract
In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss.
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Andrade-Sierra J, Cueto-Manzano AM, Rojas-Campos E, Cardona-Muñoz E, Cerrillos-Gutiérrez JI, González-Espinoza E, Evangelista-Carrillo LA, Medina-Pérez M, Jalomo-Martínez B, Nieves Hernández J, Pazarín-Villaseñor L, Mendoza-Cerpa CA, Gómez-Navarro B, Miranda-Díaz AG. Donor-specific antibodies development in renal living-donor receptors: Effect of a single cohort. Int J Immunopathol Pharmacol 2021; 35:20587384211000545. [PMID: 33787382 PMCID: PMC8020398 DOI: 10.1177/20587384211000545] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Minimization in immunosuppression could contribute to the appearance the donor-specific HLA antibodies (DSA) and graft failure. The objective was to compare the incidence of DSA in renal transplantation (RT) in recipients with immunosuppression with and without steroids. A prospective cohort from March 1st, 2013 to March 1st, 2014 and follow-up (1 year), ended in March 2015, was performed in living donor renal transplant (LDRT) recipients with immunosuppression and early steroid withdrawal (ESW) and compared with a control cohort (CC) of patients with steroid-sustained immunosuppression. All patients were negative cross-matched and for DSA pre-transplant. The regression model was used to associate the development of DSA antibodies and acute rejection (AR) in subjects with immunosuppressive regimens with and without steroids. Seventy-seven patients were included (30 ESW and 47 CC). The positivity of DSA class I (13% vs 2%; P < 0.05) and class II (17% vs 4%, P = 0.06) antibodies were higher in ESW versus CC. The ESW tended to predict DSA class II (RR 5.7; CI (0.93–34.5, P = 0.06). T-cell mediated rejection presented in 80% of patients with DSA class I (P = 0.07), and 86% with DSA II (P = 0.03), and was associated with DSA class II, (RR 7.23; CI (1.2–44), P = 0.03). ESW could favor the positivity of DSA. A most strictly monitoring the DSA is necessary for the early stages of the transplant to clarify the relationship between T-cell mediated rejection and DSA.
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Affiliation(s)
- Jorge Andrade-Sierra
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México.,Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
| | - Alfonso M Cueto-Manzano
- Medical Research Unit in Renal Diseases, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Enrique Rojas-Campos
- Medical Research Unit in Renal Diseases, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Ernesto Cardona-Muñoz
- Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
| | - José I Cerrillos-Gutiérrez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Eduardo González-Espinoza
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Luis A Evangelista-Carrillo
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Miguel Medina-Pérez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Basilio Jalomo-Martínez
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Juan Nieves Hernández
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Leonardo Pazarín-Villaseñor
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Claudia A Mendoza-Cerpa
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Benjamin Gómez-Navarro
- Department of Nephrology and Organ Transplant Unit, Specialties Hospital, National Western Medical Centre, Mexican Institute of Social Security, Guadalajara, Jalisco, México
| | - Alejandra G Miranda-Díaz
- Department of Physiology, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, México
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Wang J, Wang P, Wang S, Tan J. Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2019; 000:1-11. [DOI: 10.14218/erhm.2019.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Oellerich M, Shipkova M, Asendorf T, Walson PD, Schauerte V, Mettenmeyer N, Kabakchiev M, Hasche G, Gröne H, Friede T, Wieland E, Schwenger V, Schütz E, Beck J. Absolute quantification of donor-derived cell-free DNA as a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study. Am J Transplant 2019; 19:3087-3099. [PMID: 31062511 PMCID: PMC6899936 DOI: 10.1111/ajt.15416] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 04/04/2019] [Accepted: 04/28/2019] [Indexed: 01/25/2023]
Abstract
Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 μg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.
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Affiliation(s)
- Michael Oellerich
- Department of Clinical PharmacologyUniversity Medical Center GoettingenGoettingenGermany
| | - Maria Shipkova
- Central Institute for Clinical Chemistry and Laboratory MedicineKlinikum StuttgartStuttgartGermany
| | - Thomas Asendorf
- Department of Medical StatisticsUniversity Medical Center GoettingenGoettingenGermany
| | - Philip D. Walson
- Department of Clinical PharmacologyUniversity Medical Center GoettingenGoettingenGermany
| | - Verena Schauerte
- Department of NephrologyTransplant CenterKlinikum StuttgartStuttgartGermany
| | - Nina Mettenmeyer
- Department of Clinical PharmacologyUniversity Medical Center GoettingenGoettingenGermany
- Chronix BiomedicalGoettingenGermany
| | - Mariana Kabakchiev
- Central Institute for Clinical Chemistry and Laboratory MedicineKlinikum StuttgartStuttgartGermany
| | | | - Hermann‐Josef Gröne
- Department of Cellular and Molecular PathologyGerman Cancer Research CenterHeidelbergGermany
| | - Tim Friede
- Department of Medical StatisticsUniversity Medical Center GoettingenGoettingenGermany
| | - Eberhard Wieland
- Central Institute for Clinical Chemistry and Laboratory MedicineKlinikum StuttgartStuttgartGermany
| | - Vedat Schwenger
- Department of NephrologyTransplant CenterKlinikum StuttgartStuttgartGermany
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Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs 2017; 22:123-136. [PMID: 28503959 DOI: 10.1080/14728214.2017.1330884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection. Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored. Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.
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Affiliation(s)
- Tiffany Cl Wong
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - Chung-Mau Lo
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - James Yy Fung
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
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Everly MJ, Briley KP, Haisch CE, Dieplinger G, Bolin P, Kendrick SA, Morgan C, Maldonado AQ, Rebellato LM. Racial differences in incident de novo
donor-specific anti-HLA antibody among primary renal allograft recipients: results from a single center cohort study. Transpl Int 2017; 30:566-578. [DOI: 10.1111/tri.12937] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 11/14/2016] [Accepted: 02/13/2017] [Indexed: 12/16/2022]
Affiliation(s)
| | - Kimberly P. Briley
- Department of Pathology; Brody School of Medicine at East Carolina University; Greenville NC USA
| | - Carl E. Haisch
- Department of Surgery; Brody School of Medicine at East Carolina University; Greenville NC USA
| | | | - Paul Bolin
- Department of Medicine; Brody School of Medicine at East Carolina University; Greenville NC USA
| | | | - Claire Morgan
- Department of Medicine; Brody School of Medicine at East Carolina University; Greenville NC USA
| | | | - Lorita M. Rebellato
- Department of Pathology; Brody School of Medicine at East Carolina University; Greenville NC USA
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Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S80-92. [PMID: 26418704 DOI: 10.1097/ftd.0000000000000230] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In response to the urgent need for new reliable biomarkers to complement the guidance of the immunosuppressive therapy, a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors, and levels of similarity to other molecules, etc. In addition, a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes, a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of "fitness for purpose" is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between laboratories and between methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions. This overview focuses on preanalytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation, and commercialization.
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Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, Neil D, Colvin RB, McCaughan G, Fung JJ, Del Bello A, Reinholt FP, Haga H, Adeyi O, Czaja AJ, Schiano T, Fiel MI, Smith ML, Sebagh M, Tanigawa RY, Yilmaz F, Alexander G, Baiocchi L, Balasubramanian M, Batal I, Bhan AK, Bucuvalas J, Cerski CTS, Charlotte F, de Vera ME, ElMonayeri M, Fontes P, Furth EE, Gouw ASH, Hafezi-Bakhtiari S, Hart J, Honsova E, Ismail W, Itoh T, Jhala NC, Khettry U, Klintmalm GB, Knechtle S, Koshiba T, Kozlowski T, Lassman CR, Lerut J, Levitsky J, Licini L, Liotta R, Mazariegos G, Minervini MI, Misdraji J, Mohanakumar T, Mölne J, Nasser I, Neuberger J, O'Neil M, Pappo O, Petrovic L, Ruiz P, Sağol Ö, Sanchez Fueyo A, Sasatomi E, Shaked A, Shiller M, Shimizu T, Sis B, Sonzogni A, Stevenson HL, Thung SN, Tisone G, Tsamandas AC, Wernerson A, Wu T, Zeevi A, Zen Y. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016; 16:2816-2835. [PMID: 27273869 DOI: 10.1111/ajt.13909] [Citation(s) in RCA: 414] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/01/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Affiliation(s)
- A J Demetris
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C Bellamy
- The University of Edinburgh, Edinburgh, Scotland
| | | | - J O'Leary
- Baylor University Medical Center, Dallas, TX
| | - P S Randhawa
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Feng
- University of California San Francisco Medical Center, San Francisco, CA
| | - D Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - R B Colvin
- Massachusetts General Hospital, Boston, MA
| | - G McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia
| | | | | | - F P Reinholt
- Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H Haga
- Kyoto University Hospital, Kyoto, Japan
| | - O Adeyi
- University Health Network and University of Toronto, Toronto, Canada
| | - A J Czaja
- Mayo Clinic College of Medicine, Rochester, MN
| | - T Schiano
- Mount Sinai Medical Center, New York, NY
| | - M I Fiel
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - M L Smith
- Mayo Clinic Health System, Scottsdale, AZ
| | - M Sebagh
- AP-HP Hôpital Paul-Brousse, Paris, France
| | - R Y Tanigawa
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - F Yilmaz
- University of Ege, Faculty of Medicine, Izmir, Turkey
| | | | - L Baiocchi
- Policlinico Universitario Tor Vergata, Rome, Italy
| | | | - I Batal
- Columbia University College of Physicians and Surgeons, New York, NY
| | - A K Bhan
- Massachusetts General Hospital, Boston, MA
| | - J Bucuvalas
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - C T S Cerski
- Universidade Federal do Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - M ElMonayeri
- Ain Shams University, Wady El-Neel Hospital, Cairo, Egypt
| | - P Fontes
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - E E Furth
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - A S H Gouw
- University Medical Center Groningen, Groningen, the Netherlands
| | | | - J Hart
- University of Chicago Hospitals, Chicago, IL
| | - E Honsova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - W Ismail
- Beni-Suef University, Beni-Suef, Egypt
| | - T Itoh
- Kobe University Hospital, Kobe, Japan
| | | | - U Khettry
- Lahey Hospital and Medical Center, Burlington, MA
| | | | - S Knechtle
- Duke University Health System, Durham, NC
| | - T Koshiba
- Soma Central Hospital, Soma, Fukushima, Japan
| | - T Kozlowski
- University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - C R Lassman
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - J Lerut
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - J Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - L Licini
- Pope John XXIII Hospital, Bergamo, Italy
| | - R Liotta
- Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - G Mazariegos
- Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA
| | - M I Minervini
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - J Misdraji
- Massachusetts General Hospital, Boston, MA
| | - T Mohanakumar
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ
| | - J Mölne
- University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - I Nasser
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - J Neuberger
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - M O'Neil
- University of Kansas Medical Center, Kansas City, KS
| | - O Pappo
- Hadassah Medical Center, Jerusalem, Israel
| | - L Petrovic
- University of Southern California, Los Angeles, CA
| | - P Ruiz
- University of Miami, Miami, FL
| | - Ö Sağol
- School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | | | - E Sasatomi
- University of North Carolina School of Medicine, Chapel Hill, NC
| | - A Shaked
- University of Pennsylvania Health System, Philadelphia, PA
| | - M Shiller
- Baylor University Medical Center, Dallas, TX
| | - T Shimizu
- Toda Chuo General Hospital, Saitama, Japan
| | - B Sis
- University of Alberta Hospital, Edmonton, Canada
| | - A Sonzogni
- Pope John XXIII Hospital, Bergamo, Italy
| | | | - S N Thung
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - G Tisone
- University of Rome-Tor Vergata, Rome, Italy
| | | | - A Wernerson
- Karolinska University Hospital, Stockholm, Sweden
| | - T Wu
- Tulane University School of Medicine, New Orleans, LA
| | - A Zeevi
- University of Pittsburgh, Pittsburgh, PA
| | - Y Zen
- Kobe University Hospital, Kobe, Japan
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Gentile G, Remuzzi G. Novel Biomarkers for Renal Diseases? None for the Moment (but One). SLAS DISCOVERY 2016; 21:655-670. [DOI: 10.1177/1087057116629916] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation 2016; 100:39-53. [PMID: 26680372 PMCID: PMC4683034 DOI: 10.1097/tp.0000000000000869] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.
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Michel K, Santella R, Steers J, Sahajpal A, Downey FX, Thohan V, Oaks M. Many de novo donor-specific antibodies recognize β2 -microglobulin-free, but not intact HLA heterodimers. HLA 2016; 87:356-66. [PMID: 27060279 PMCID: PMC5071754 DOI: 10.1111/tan.12775] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/16/2016] [Accepted: 02/24/2016] [Indexed: 11/27/2022]
Abstract
Solid‐phase single antigen bead (SAB) assays are standard of care for detection and identification of donor‐specific antibody (DSA) in patients who receive solid organ transplantation (SOT). While several studies have documented the reproducibility and sensitivity of SAB testing for DSA, there are little data available concerning its specificity. This study describes the identification of antibodies to β2‐microglobulin‐free human leukocyte antigen (β2‐m‐fHLA) heavy chains on SAB arrays and provides a reassessment of the clinical relevance of DSA testing by this platform. Post‐transplant sera from 55 patients who were positive for de novo donor‐specific antibodies on a SAB solid‐phase immunoassay were tested under denaturing conditions in order to identify antibodies reactive with β2‐m‐fHLA or native HLA (nHLA). Antibodies to β2‐m‐fHLA were present in nearly half of patients being monitored in the post‐transplant period. The frequency of antibodies to β2‐m‐fHLA was similar among DSA and HLA antigens that were irrelevant to the transplant (non‐DSA). Among the seven patients with clinical or pathologic antibody‐mediated rejection (AMR), none had antibodies to β2‐m‐fHLA exclusively; thus, the clinical relevance of β2‐m‐fHLA is unclear. Our data suggests that SAB testing produces false positive reactions due to the presence of β2‐m‐fHLA and these can lead to inappropriate assignment of unacceptable antigens during transplant listing and possibly inaccurate identification of DSA in the post‐transplant period.
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Affiliation(s)
- K Michel
- Transplant Program, Aurora St. Luke's Medical Center, Milwaukee, WI, USA
| | - R Santella
- Transplant Institute, Avera McKennan Hospital and University System, Sioux Falls, SD, USA
| | - J Steers
- Transplant Institute, Avera McKennan Hospital and University System, Sioux Falls, SD, USA
| | - A Sahajpal
- Transplant Program, Aurora St. Luke's Medical Center, Milwaukee, WI, USA
| | - F X Downey
- Transplant Program, Aurora St. Luke's Medical Center, Milwaukee, WI, USA
| | - V Thohan
- Transplant Program, Aurora St. Luke's Medical Center, Milwaukee, WI, USA
| | - M Oaks
- Transplant Program, Aurora St. Luke's Medical Center, Milwaukee, WI, USA
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13
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Ildstad ST, Leventhal J, Wen Y, Yolcu E. Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance. CHIMERISM 2016; 6:33-9. [PMID: 26745761 DOI: 10.1080/19381956.2015.1130780] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future.
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Affiliation(s)
- Suzanne T Ildstad
- a Institute for Cellular Therapeutics, University of Louisville , Louisville , KY , USA
| | - Joseph Leventhal
- b Comprehensive Transplant Center, Northwestern Memorial Hospital , Chicago , IL , USA
| | - Yujie Wen
- a Institute for Cellular Therapeutics, University of Louisville , Louisville , KY , USA
| | - Esma Yolcu
- a Institute for Cellular Therapeutics, University of Louisville , Louisville , KY , USA
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14
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Zsom L, Wagner L, Fülöp T. Minimization vs tailoring: Where do we stand with personalized immunosuppression during renal transplantation in 2015? World J Transplant 2015; 5:73-80. [PMID: 26421259 PMCID: PMC4580929 DOI: 10.5500/wjt.v5.i3.73] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 06/13/2015] [Accepted: 07/11/2015] [Indexed: 02/05/2023] Open
Abstract
The introduction of novel immunosuppressive agents over the last two decades and the improvement of our diagnostic tools for early detection of antibody-mediated injury offer us an opportunity, if not a mandate, to better match the immunosuppression needs of the individual patients with side effects of the therapy. However, immunosuppressive regimens in the majority of programs remain mostly protocol-driven, with relatively little inter-program heterogeneity in certain areas of the world. Emerging data showing different outcomes with a particular immunosuppressive strategy in populations with varying immunological risks underscore a real potential for "personalized medicine" in renal transplantation. Studies demonstrating marked differences in the adverse-effect profiles of individual drugs including the risk for viral infections, malignancy and renal toxicity call for a paradigm shift away from a "one size fits all" approach to an individually tailored immunosuppressive therapy for renal transplant recipients, assisted by both screening for predictors of graft loss and paying close attention to dose or class-related adverse effects. Our paper explores some of the opportunities during the care of these patients. Potential areas of improvements may include: (1) a thorough assessment of immunological and metabolic risk profile of each renal transplant recipient; (2) screening for predictors of graft loss and early signs of antibody-mediated rejection with donor-specific antibodies, protocol biopsies and proteinuria (including close follow up of adverse effects with dose adjustments or conversions as necessary); and (3) increased awareness of the possible link between poor tolerance of a given drug at a given dose and non-adherence with the prescribed regimen. Altogether, these considerations may enable the most effective use of the drugs we already have.
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15
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Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
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16
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Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants. Transplantation 2015; 99:288-98. [PMID: 25594553 DOI: 10.1097/tp.0000000000000605] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.
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17
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Laftavi MR, Pankewycz O, Feng L, Said M, Patel S. Combined induction therapy with rabbit antithymocyte globulin and rituximab in highly sensitized renal recipients. Immunol Invest 2015; 44:373-84. [PMID: 25942348 DOI: 10.3109/08820139.2015.1014097] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Compared to non-sensitized renal transplant recipients, patients with preformed alloantibodies are at greater risk of cellular and humoral rejection and premature graft failure. We explored the effects of adding B-cell depleting agent (rituximab) to standard rabbit anti-thymocyte globulin (rATG) induction regimen for patients with panel reactive antibody levels >50%. Following induction therapy, 14 recipients were given two doses of rituximab (375 mg/m(2)) within the first month post-transplantation. Their long-term outcomes were compared to a historical control group of 23 recipients who received rATG alone. Graft survival at 5 years was superior with combination therapy compared to induction therapy alone (92.9 versus 48.3%, respectively, p = 0.02). While 30% of the rATG alone group experienced cellular rejection and 26% humoral rejection, none of rituximab plus rATG renal transplant recipients group had rejection. Thus, addition of rituximab to rATG provided superior outcomes to rATG alone. This combination induction therapy should be considered for a high-risk population.
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Affiliation(s)
- Mark Reza Laftavi
- Department of Surgery, SUNY at Buffalo , Buffalo, New York , USA and
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18
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19
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Athavale D, Worthington J, Webb NJA, Roberts D, Martin S, Shenoy M. Pediatric kidney recipients may benefit from monitoring for donor-specific antibodies. Pediatr Transplant 2014; 18:258-65. [PMID: 24646402 DOI: 10.1111/petr.12247] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/30/2014] [Indexed: 11/29/2022]
Abstract
There are limited data regarding the presence of DSAs and their effect on graft function in pediatric renal transplantation. The role for serial DSA monitoring in routine clinical practice is unclear. All patients attending a regional transplant clinic were tested for DSAs, measured using Luminex single/mixed antigen beads. Any patient having a positive result subsequently underwent historic testing on samples previously obtained. DSA-positive patients underwent prospective monitoring of DSAs, and correlation with clinical events was studied. Nine of a total of 50 patients (18%) were DSA-positive, of whom six had graft dysfunction. The DSA-positive cohort had significantly increased episodes of AR (p = 0.01). There were two graft losses in the DSA-positive group and none in the DSA-negative group. Eight of the DSA-positive group had potentially reduced exposure to IS because of either adherence issues or clinical indications. DSAs were associated with increased risk of rejection. There appears to be a role for serial monitoring of DSAs in patients where there has been a reduced exposure to IS so that early intervention with optimized IS can be considered.
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Affiliation(s)
- Deepa Athavale
- Department of Paediatric Nephrology, The University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester, UK
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20
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Abstract
Although surgical techniques, post-transplant care medicine, and immunosuppressants have been greatly improved, permanent acceptance of renal allograft remains a clinical challenge owing to the appearance of various influencing factors. To predict graft dysfunction, development of noninvasive biomarkers is becoming a highlighted research topic in the field of renal transplantation, which provides a possibility for physicians to give preemptive rescue treatment. From the viewpoint of diagnostic techniques, repetitive sampling is prerequisite to identify applicable biomarkers in the clinic. Early biomarkers can be used to dynamically monitor renal graft status and accurately predict transplant outcome independent of various confounders. This review highlights recent studies on the predictive value of biomarkers and methods to quantify biomarkers for monitoring kidney transplant. It is important to analyze and compare different biomarkers for living, and nonliving donors. Analysis of identified clinically relevant biomarkers will advance our understanding of distinct molecular and cellular mechanisms of transplantation and provide insight into developing novel potential approaches to induce transplant tolerance.
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Affiliation(s)
- Fangmin Ge
- Hospital Administration Office, People's Republic of China ; Department of Medicine, Second Affiliated Hospital Zhejiang University School of Medicine, People's Republic of China ; Health Bureau of Shangcheng District Hangzhou, People's Republic of China
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21
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Tissue biopsy monitoring of operational tolerance in liver allograft recipients. Curr Opin Organ Transplant 2013; 18:345-53. [PMID: 23619515 DOI: 10.1097/mot.0b013e3283615d48] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Highly selected, long-surviving, liver allograft recipients with normal/near normal liver injury tests can be weaned from immunosuppression. Baseline biopsies document changes before weaning and can help stratify risk of rejection or dysfunction after weaning; biopsies after weaning are used to study mechanisms of operational tolerance and to monitor for subclinical events. RECENT FINDINGS Clinicopathological features associated with successful weaning include a lack of sensitization [negative donor-specific antibodies (DSA) and lack of tissue C4d deposits]; 'inexperienced' recipient immune system with limited potential for cross-reactivity (less immunological memory; infant recipients); noninflamed allograft in those with nonviral, nonimmunological original diseases; upregulation of liver genes associated with iron metabolism; allograft colonization with 'immunosuppressive' cells (Treg and γδ-1>γδ-2); and longer time on immunosuppression, which might signal slow clonal deletion or silencing. The differential diagnosis of histopathological findings detected before and after weaning includes emerging infections, typical and atypical cellular rejection, indolent antibody-mediated rejection, 'autoimmunity', and other causes of progressive fibrosis. SUMMARY Operationally tolerant liver allograft recipients can be successfully managed with very low, and sometimes no immunosuppression, but challenges exist. Newer approaches to tissue pathology and tissue, serum, and cross-platform analytics are needed to predict successful weaning and to monitor for subclinical events.
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22
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Salvadori M, Bertoni E. Is it time to give up with calcineurin inhibitors in kidney transplantation? World J Transplant 2013; 3:7-25. [PMID: 24175203 PMCID: PMC3782241 DOI: 10.5500/wjt.v3.i2.7] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/17/2013] [Accepted: 05/09/2013] [Indexed: 02/05/2023] Open
Abstract
Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti-human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.
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23
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Piemonti L, Everly MJ, Maffi P, Scavini M, Poli F, Nano R, Cardillo M, Melzi R, Mercalli A, Sordi V, Lampasona V, Espadas de Arias A, Scalamogna M, Bosi E, Bonifacio E, Secchi A, Terasaki PI. Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes 2013; 62:1656-64. [PMID: 23274902 PMCID: PMC3636624 DOI: 10.2337/db12-1258] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.
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Affiliation(s)
- Lorenzo Piemonti
- Diabetes Research Institute, San Raffaele Hospital Scientific Institute, Milan, Italy.
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The pits and pearls in translating operational tolerance biomarkers into clinical practice. Curr Opin Organ Transplant 2013; 17:655-62. [PMID: 23080065 DOI: 10.1097/mot.0b013e32835a6f62] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review highlights the importance and the role of key biomarker studies in liver and kidney transplant tolerance, discusses the most recent findings with respect to organ-type and cell-type specificity in blood and tissue, and points out the novel research directions in the field of immunological tolerance that involve both adult and pediatric recipients. RECENT FINDINGS Recent studies indicate that biomarkers for solid organ transplant tolerance are distinct with respect to organ type and cell type, suggesting distinct tolerogenic mechanisms for different organs. In both liver and kidney transplant tolerant recipients, novel cellular mechanisms have been proposed for natural killer cells, B cells, and dendritic cells in the maintenance of stable operational tolerance. SUMMARY Major advances have been made with respect to the understanding of mechanisms and the process of discovery and early validation of peripheral blood biomarkers for operational transplant tolerance both in kidney and liver transplantation. These studies have shed light on the findings that these tolerance mechanisms may be organ specific, as the peripheral blood transcriptional profiling attempts by microarrays and PCR reveal distinct differences and suggest roles for specific cell types. Although these studies are mostly in adults and limited in children, the first tolerance gene signature for pediatric liver transplant tolerance suggests that there are common mechanisms, yet distinct peripheral biomarkers across age. Prospective trials and organ integrative studies are now needed to further develop these biomarkers for future clinical application in addition to expanding novel approaches such as the investigation of miRNAs to better understand the tolerance mechanisms.
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Chandrasekharan D, Issa F, Wood KJ. Achieving operational tolerance in transplantation: how can lessons from the clinic inform research directions? Transpl Int 2013; 26:576-89. [PMID: 23517251 DOI: 10.1111/tri.12081] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 11/23/2012] [Accepted: 02/04/2013] [Indexed: 01/03/2023]
Abstract
Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful immunosuppressive regimens towards tolerogenic strategies that promote long-term graft survival. This has required a concerted multinational effort with scientists and clinicians working towards a common goal. Reports of immunosuppression-free kidney and liver allograft recipients have provided the proof-of-principle, but intentional generation of tolerance in clinical transplantation is still only achieved infrequently. Recently, there have been an increasing number of encouraging developments in the field in both experimental and clinical studies. In this article, we review the latest advances in tolerance research and consider possible future barriers and solutions in achieving reliable graft acceptance in the long term.
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Affiliation(s)
- Deepak Chandrasekharan
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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