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Hielscher F, Schmidt T, Enders M, Leyking S, Gerhart M, van Bentum K, Mihm J, Schub D, Sester U, Sester M. The inactivated herpes zoster vaccine HZ/su induces a varicella zoster virus specific cellular and humoral immune response in patients on dialysis. EBioMedicine 2024; 108:105335. [PMID: 39265505 PMCID: PMC11416227 DOI: 10.1016/j.ebiom.2024.105335] [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: 05/17/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND To evaluate the immunogenicity of the inactivated herpes-zoster vaccine HZ/su in patients at increased risk for VZV-reactivation, we analysed the quantity and quality of the vaccine-induced cellular and humoral immunity in patients on dialysis with uremic immunodeficiency. METHODS In this observational study, 29 patients and 39 immunocompetent controls underwent standard dual-dose vaccination. Blood samples were analysed before and two weeks after each vaccination, and after one year. Specific T-cells were characterized after stimulation with VZV-gE-peptides based on induction of cytokines and CTLA-4-expression using flow-cytometry. Antibodies were analysed using ELISA. FINDINGS Both groups showed an increase in VZV-gE-specific CD4 T-cell levels over time (p < 0.0001), although median levels reached after second vaccination were lower in patients (0.17% (IQR 0.21%)) than in controls (0.24% (IQR 0.3%), p = 0.042). VZV-gE specific CD8 T-cells were only poorly induced. CTLA-4 expression on VZV-gE-specific CD4 T-cells was strongest after second dose with no differences between the groups (p = 0.45). Multifunctional cells co-expressing IFNγ, IL-2, and TNF were higher in patients after first vaccination (p = 0.028). Median VZV-specific IgG-levels reached a maximum after second vaccination with significantly lower levels in patients (10796 (IQR 12482) IU/l) than in controls (16899 (IQR 14019) IU/l, p = 0.009). Despite similar CD4 T-cell levels after one year (p = 0.415), antibody levels remained significantly lower in patients (p = 0.0008). INTERPRETATION VZV-gE vaccination induced specific antibodies and CD4 T-cells in both patients and controls, whereas CD8 T-cell-induction was poor. Quantitative and qualitative differences in immunity may indicate reduced duration of protection which may necessitate booster vaccinations in patients on dialysis. FUNDING HOMFORexzellent (to D.S.).
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Affiliation(s)
- Franziska Hielscher
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Tina Schmidt
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | | | | | - Markus Gerhart
- Nieren- und Dialysezentrum St. Wendel, St. Wendel, Germany
| | - Kai van Bentum
- Heimdialyse Saar e.V. Dialysezentrum Homburg, Homburg, Germany
| | - Janine Mihm
- Department of Nephrology, SHG-Klinikum Völklingen, Germany
| | - David Schub
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Urban Sester
- Department of Nephrology, SHG-Klinikum Völklingen, Germany
| | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany; Center for Gender-specific Biology and Medicine (CGBM), Saarland University; Homburg, Germany.
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Lenzing E, Harboe ZB, Sørensen SS, Rasmussen A, Nielsen SD, Rezahosseini O. Evidence for Immunity against Tetanus, Diphtheria, and Pertussis through Natural Infection or Vaccination in Adult Solid Organ Transplant Recipients: A Systematic Review. Microorganisms 2024; 12:847. [PMID: 38792678 PMCID: PMC11123279 DOI: 10.3390/microorganisms12050847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 04/19/2024] [Accepted: 04/21/2024] [Indexed: 05/26/2024] Open
Abstract
(1) Background: We aim to systematically review the current evidence on immunity against tetanus, diphtheria, and pertussis in adult solid organ transplantation (SOT) recipients, either through natural infection or vaccination. (2) Methods: This systematic review was conducted per PRISMA guidelines. We assessed the risk of bias using the Cochrane RoB 2 and ROBINS-I and summarized the findings narratively due to the heterogeneity of the studies. (3) Results: Of the 315 screened articles, 11 were included. Tetanus immunity varied between 55% and 86%, diphtheria immunity from 23% to 75%, and pertussis immunity was between 46% and 82%. Post-vaccination immunity showed variation across the studies, with some indicating reductions and others no change, with antibody responses influenced by transplanted organs, gender, age, and immunosuppressive regimens. The single randomized study exhibited a low risk of bias, while of the ten non-randomized studies, six showed moderate and four serious risks of bias, necessitating cautious interpretation of results. (4) Conclusions: SOT recipients exhibit considerable immunity against tetanus and diphtheria at transplantation, but this immunity decreases over time. Although vaccination can enhance this immunity, the response may be suboptimal, and the increased antibody levels may not persist, underscoring the need for tailored vaccination strategies in this vulnerable population.
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Affiliation(s)
- Emil Lenzing
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (E.L.); (Z.B.H.); (S.D.N.)
| | - Zitta Barrella Harboe
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (E.L.); (Z.B.H.); (S.D.N.)
- Department of Pulmonary Medicine and Infectious Diseases, Copenhagen University Hospital at Nordsjællands, 3400 Hillerød, Denmark
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - Søren Schwartz Sørensen
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Allan Rasmussen
- Department of Surgical Gastroenterology and Transplantation, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark;
| | - Susanne Dam Nielsen
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (E.L.); (Z.B.H.); (S.D.N.)
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - Omid Rezahosseini
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (E.L.); (Z.B.H.); (S.D.N.)
- Department of Pulmonary Medicine and Infectious Diseases, Copenhagen University Hospital at Nordsjællands, 3400 Hillerød, Denmark
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Laganà A, Visalli G, Di Pietro A, Facciolà A. Vaccinomics and adversomics: key elements for a personalized vaccinology. Clin Exp Vaccine Res 2024; 13:105-120. [PMID: 38752004 PMCID: PMC11091437 DOI: 10.7774/cevr.2024.13.2.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/07/2024] [Accepted: 03/12/2024] [Indexed: 05/18/2024] Open
Abstract
Vaccines are one of the most important and effective tools in the prevention of infectious diseases and research about all the aspects of vaccinology are essential to increase the number of available vaccines more and more safe and effective. Despite the unquestionable value of vaccinations, vaccine hesitancy has spread worldwide compromising the success of vaccinations. Currently, the main purpose of vaccination campaigns is the immunization of whole populations with the same vaccine formulations and schedules for all individuals. A personalized vaccinology approach could improve modern vaccinology counteracting vaccine hesitancy and giving great benefits for human health. This ambitious purpose would be possible by facing and deepening the areas of vaccinomics and adversomics, two innovative areas of study investigating the role of a series of variables able to influence the immune response to vaccinations and the development of serious side effects, respectively. We reviewed the recent scientific knowledge about these innovative sciences focusing on genetic and non-genetic basis involved in the individual response to vaccines in terms of both immune response and side effects.
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Affiliation(s)
- Antonio Laganà
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
- Istituto Clinico Polispecialistico C.O.T., Cure Ortopediche Traumatologiche S.P.A., Messina, Italy
| | - Giuseppa Visalli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Angela Di Pietro
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Alessio Facciolà
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
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Bronder S, Mihm J, Urschel R, Klemis V, Schmidt T, Marx S, Abu-Omar A, Hielscher F, Guckelmus C, Widera M, Sester U, Sester M. Potent induction of humoral and cellular immunity after bivalent BA.4/5 mRNA vaccination in dialysis patients. NPJ Vaccines 2024; 9:25. [PMID: 38326340 PMCID: PMC10850212 DOI: 10.1038/s41541-024-00816-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 01/26/2024] [Indexed: 02/09/2024] Open
Abstract
Knowledge on immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients and the effect of a previous infection is limited. Therefore, vaccine-induced humoral and cellular immunity was analyzed in dialysis patients and immunocompetent controls with and without prior infection. In an observational study, 33 dialysis patients and 58 controls matched for age, sex and prior infection status were recruited. Specific IgG, neutralizing antibody activity and cellular immunity towards the spike-antigen from parental SARS-CoV-2 and Omicron-subvariants BA.1, BA.2 and BA.4/5 were analyzed before and 13-18 days after vaccination. The bivalent vaccine led to a significant induction of IgG, neutralizing titers, and specific CD4+ and CD8+ T-cell levels. Neutralizing activity towards the parental strain was higher than towards the Omicron-subvariants, whereas specific T-cell levels towards parental spike and Omicron-subvariants did not differ indicating substantial cross-reactivity. Dialysis patients with prior infection had significantly higher spike-specific CD4+ T-cell levels with lower CTLA-4 expression compared to infection-naive patients. When compared to controls, no differences were observed between infection-naive individuals. Among convalescent individuals, CD4+ T-cell levels were higher in patients and neutralizing antibodies were higher in controls. Vaccination was overall well tolerated in both dialysis patients and controls with significantly less adverse events among patients. In conclusion, our study did not provide any evidence for impaired immunogenicity of the bivalent Omicron BA.4/5 vaccine in dialysis patients. Unlike in controls, previous infection of patients was even associated with higher levels of spike-specific CD4+ T cells, which may reflect prolonged encounter with antigen during infection.
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Affiliation(s)
- Saskia Bronder
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | | | - Rebecca Urschel
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Verena Klemis
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Tina Schmidt
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Stefanie Marx
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Amina Abu-Omar
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Franziska Hielscher
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Candida Guckelmus
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Marek Widera
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | | | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.
- Center for Gender-specific Biology and Medicine (CGBM), Saarland University, Homburg, Germany.
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Beilhack G, Monteforte R, Frommlet F, Gaggl M, Strassl R, Vychytil A. Antibody Response and Safety After mRNA-1273 SARS-CoV-2 Vaccination in Peritoneal Dialysis Patients - the Vienna Cohort. Front Immunol 2021; 12:780594. [PMID: 34925359 PMCID: PMC8674530 DOI: 10.3389/fimmu.2021.780594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/11/2021] [Indexed: 11/21/2022] Open
Abstract
Background Dialysis patients are at high risk for a severe clinical course after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Safety and early immune responses after mRNA-based vaccination have been reported mostly in patients on hemodialysis (HD), whereas reports of peritoneal dialysis (PD) patients remain rare. Methods In this retrospective observational study, 39 PD patients had received two doses of the mRNA-1273 Moderna® vaccine. We analyzed SARS-CoV-2 Spike (S) antibody titers 4 weeks after each dose of mRNA-1273 and report local and systemic side effects in PD patients that occurred within one week after each mRNA-1273 dose. Using a quantile regression model we examined factors that might influence SARS-CoV-2 S antibody levels in PD patients. Results Four weeks after the first dose of mRNA-1273 vaccine 33 of 39 (84.6%) PD patients seroconverted and presented with 6.62 U/mL (median; IQR 1.57-22.5) anti-SARS-CoV-2 S antibody titers. After the second dose, 38 of 39 (97.4%) PD patients developed anti-SARS-CoV-2 S antibodies and titers increased significantly (median 968 U/mL; IQR 422.5-2500). Pain at the injection site was the most common local adverse event (AE) (71%). Systemic AEs occurring after the first dose were mostly fatigue (33%) and headache (20%). No severe systemic AEs were reported after the first injection. After the second dose the incidence and the severity of the systemic AEs increased. The most common systemic AEs were: fatigue (40.5%), headache (22.5%), joint pain (20%), myalgia (17.5%) and fever (13%). Lower Davies Comorbidity Score (p=0.04) and shorter dialysis vintage (p=0.017) were associated with higher antibody titers after the first dose. Patients with higher antibody titers after the first dose tended to have higher antibody titers after the second dose (p=1.53x10-05). Conclusions Peritoneal dialysis patients in this cohort had a high seroconversion rate of 97.4%, showed high antibody titers after full vaccination and tolerated the anti-SARS-CoV-2 mRNA-1273 vaccine well without serious adverse events.
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Affiliation(s)
- Georg Beilhack
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rossella Monteforte
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Florian Frommlet
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Martina Gaggl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Robert Strassl
- Division of Clinical Virology, Medical University of Vienna, Vienna, Austria
| | - Andreas Vychytil
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Muir L, Jaffer A, Rees-Spear C, Gopalan V, Chang FY, Fernando R, Vaitkute G, Roustan C, Rosa A, Earl C, Rajakaruna GK, Cherepanov P, Salama A, McCoy LE, Motallebzadeh R. Neutralizing Antibody Responses After SARS-CoV-2 Infection in End-Stage Kidney Disease and Protection Against Reinfection. Kidney Int Rep 2021; 6:1799-1809. [PMID: 33942026 PMCID: PMC8081267 DOI: 10.1016/j.ekir.2021.03.902] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Patients with end-stage kidney disease (ESKD) represent a vulnerable group with multiple risk factors that are associated with poor outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite established susceptibility to infectious complications and the importance of humoral immunity in protection against SARS-CoV-2, few studies have investigated the humoral immune response to SARS-CoV-2 within this population. Here, we evaluate the seroprevalence of SARS-CoV-2 in patients awaiting renal transplantation and determine whether seroconverted patients with ESKD have durable and functional neutralizing activity against SARS-CoV-2. METHODS Serum samples were obtained from 164 patients with ESKD by August 2020. Humoral immune responses were evaluated by SARS-CoV-2 spike S1 subunit and nucleoprotein semiquantitative enzyme-linked immunosorbent assay (ELISA) and SARS-CoV-2 spike pseudotype neutralization assay. RESULTS All patients with ESKD with reverse-transcriptase polymerase chain reaction (RT-PCR)-confirmed infection (n = 17) except for 1 individual seroconverted against SARS-CoV-2. Overall seroprevalence (anti-S1 and/or anti-N IgG) was 36% and was higher in patients on hemodialysis (44.2%). A total of 35.6% of individuals who seroconverted were asymptomatic. Seroconversion in the absence of a neutralizing antibody (nAb) titer was observed in 12 patients, all of whom were asymptomatic. Repeat measurements at a median of 93 days from baseline sampling revealed that most individuals retained detectable responses although a significant drop in S1, N and nAb titers was observed. CONCLUSION Patients with ESKD, including those who develop asymptomatic disease, routinely seroconvert and produce detectable nAb titers against SARS-CoV-2. Although IgG levels wane over time, the neutralizing antibodies remain detectable in most patients, suggesting some level of protection is likely maintained, particularly in those who originally develop stronger responses.
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Affiliation(s)
- Luke Muir
- UCL Institute of Immunity & Transplantation, University College London, London, UK
- UCL Division of Infection & Immunity, University College London, London, UK
| | - Aneesa Jaffer
- Department of Nephrology & Transplantation, Royal Free London NHS Trust, London, UK
| | - Chloe Rees-Spear
- UCL Institute of Immunity & Transplantation, University College London, London, UK
- UCL Division of Infection & Immunity, University College London, London, UK
| | - Vignesh Gopalan
- Department of Nephrology & Transplantation, Royal Free London NHS Trust, London, UK
| | - Fernando Y. Chang
- Research Department of Surgical Biotechnology, UCL Division of Surgery and Interventional Science, University College London, London, UK
| | - Raymond Fernando
- Department of Nephrology & Transplantation, Royal Free London NHS Trust, London, UK
| | - Gintare Vaitkute
- Research Department of Surgical Biotechnology, UCL Division of Surgery and Interventional Science, University College London, London, UK
| | | | | | | | - Gayathri K. Rajakaruna
- Centre for Transplantation, Department of Renal Medicine, University College London, London, UK
| | | | - Alan Salama
- Department of Nephrology & Transplantation, Royal Free London NHS Trust, London, UK
- Centre for Transplantation, Department of Renal Medicine, University College London, London, UK
| | - Laura E. McCoy
- UCL Institute of Immunity & Transplantation, University College London, London, UK
- UCL Division of Infection & Immunity, University College London, London, UK
| | - Reza Motallebzadeh
- UCL Institute of Immunity & Transplantation, University College London, London, UK
- Department of Nephrology & Transplantation, Royal Free London NHS Trust, London, UK
- Research Department of Surgical Biotechnology, UCL Division of Surgery and Interventional Science, University College London, London, UK
- Centre for Transplantation, Department of Renal Medicine, University College London, London, UK
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Babu TM, Kotton CN. Immunizations in Chronic Kidney Disease and Kidney Transplantation. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2021; 13:47-65. [PMID: 34025219 PMCID: PMC8126514 DOI: 10.1007/s40506-021-00248-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Infection is a significant cause of morbidity and mortality in both patients with chronic kidney disease (CKD) and in recipients of a kidney transplant (KT). We review the current data in patients with CKD, on dialysis, and in KT recipients to provide further guidance for clinicians regarding vaccine optimization in this patient population. RECENT FINDINGS This patient population remains under-vaccinated and thus more vulnerable to vaccine-preventable illness. Despite diminished responses to immunization in this population, significant protection is generally achieved. SUMMARY Vaccines are an important preventative tool and offer protection against infection. In the setting of suboptimal and waning immunity in this patient population, future studies are indicated to determine optimal vaccination regimens.
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Affiliation(s)
- Tara M. Babu
- Division of Allergy and Infectious Diseases, University of Washington, 908 Jefferson Street, Suite 11NJ-1166, Seattle, WA 98104 USA
- Division of Infectious Diseases, University of Rochester Medical Center, Rochester, NY USA
| | - Camille N. Kotton
- Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 5, Boston, MA 02114 USA
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Hasenmajer V, Puliani G, Minnetti M, Sbardella E, Mastroianni CM, D'Ettorre G, Isidori AM, Gianfrilli D. Beyond Bone: Infectious Diseases and Immunity in Parathyroid Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1369:17-32. [PMID: 33782903 DOI: 10.1007/5584_2021_629] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Parathyroid disorders are characterized by alterations in calcium and phosphate homeostasis due to inappropriately high or low levels of parathyroid hormone (PTH). Despite PTH receptor type 1 has been described in almost all immune lineages and calcium signalling has been confirmed as a crucial mediator for immune response, in vitro studies on the physiological interactions between PTH and immunity are conflicting and not representative of the clinical scenarios seen in patients with parathyroid disorders. Infectious diseases are among the main causes of increased morbidity and mortality in patients with secondary hyperparathyroidism and chronic kidney disease. More, immune alterations have been described in primary hyperparathyroidism. Recent studies have unveiled an increased risk of infections also in hypoparathyroidism, suggesting that not only calcium, but also physiological levels of PTH may be necessary for a proper immune response. Finally, calcium/phosphate imbalance could affect negatively the prognosis of infectious diseases. Our review aimed to collect available data on infectious disease prevalence in patients with parathyroid disorders and new evidence on the role of PTH and calcium in determining the increased risk of infections observed in these patients.
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Affiliation(s)
- Valeria Hasenmajer
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
| | - Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.,Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Emilia Sbardella
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Gabriella D'Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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Seroprevalence of Antibodies against Diphtheria, Tetanus and Pertussis in Adult At-Risk Patients. Vaccines (Basel) 2021; 9:vaccines9010018. [PMID: 33406698 PMCID: PMC7824683 DOI: 10.3390/vaccines9010018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/16/2020] [Accepted: 12/30/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with chronic diseases are at increased risk of complications following infection. It remains, however, unknown to what extend they are protected against vaccine-preventable diseases. We assessed seroprevalence of antibodies against diphtheria, tetanus and pertussis to evaluate whether current vaccination programs in Belgium are adequate. Antibody titers were assessed with a bead-based multiplex assay in serum of 1052 adults with chronic diseases. We included patients with diabetes mellitus type 1 (DM1) (n = 172), DM2 (n = 77), chronic kidney disease (n = 130), chronic obstructive pulmonary disease (COPD) (n = 170), heart failure (n = 77), HIV (n = 196) and solid organ transplant (SOT) recipients (n = 230). Factors associated with seroprevalence were analysed with multiple logistic regression. We found seroprotective titers in 29% for diphtheria (≥0.1 IU/mL), in 83% for tetanus (≥0.1 IU/mL) and 22% had antibodies against pertussis (≥5 IU/mL). Seroprotection rates were higher (p < 0.001) when vaccinated within the last ten years. Furthermore, diphtheria seroprotection decreased with age (p < 0.001). Tetanus seroprotection was less reached in women (p < 0.001) and older age groups (p < 0.001). For pertussis, women had more often a titer suggestive of a recent infection or vaccination (≥100 IU/mL, p < 0.01). We conclude that except for tetanus, the vast majority of at-risk patients remains susceptible to vaccine-preventable diseases such as diphtheria and pertussis.
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Hypervolemia-Induced Immune Disturbances Do Not Involve IL-1ß but IL-6 and IL-10 Activation in Haemodialysis Patients. Toxins (Basel) 2020; 12:toxins12030159. [PMID: 32138278 PMCID: PMC7150829 DOI: 10.3390/toxins12030159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/28/2020] [Accepted: 03/01/2020] [Indexed: 12/29/2022] Open
Abstract
Dysregulated fluid homeostasis is frequent in haemodialysis (HD) patients and is linked to inflammation which may be elicited by endotoxemia. The impact of hypervolemia on immune cells has not been studied in detail. Therefore, we analysed the hypervolemic activation of peripheral blood mononuclear cells (PBMCs) in HD with special focus on the NLRP3 inflammasome response. First, 45 HD were included in the observational study. Immune parameters including cell counts, caspase-1, oxidative stress, cytokine gene expression and serum analysis (IL-1ß, IL-6, IL-10) were all measured at two time points. Fluid status was evaluated by electrical bioimpedance vector analysis, defining hypervolemia (H) as >75 vector percentile. Then, 17 patients were classified as hypervolemic (H-HD), 19 as normovolemic (N-HD) and 9 failed to meet the inclusion criteria. Monocytes were elevated and lymphocytes were decreased by hypervolemia. NLRP3 inflammasome components, caspase-1 and IL-1ß expression were not statistically different between the two groups. Serum IL-6 levels were significantly elevated in H-HD. IL-10 mRNA transcripts were elevated by 2-fold in H-HD but were not efficiently translated. We conclude that the NLRP3 inflammasome is not activated by hypervolemia thus refuting the thesis that endotoxemia may be a main driver for inflammation in H-HD. Nevertheless, inflammation is generally higher in H-HD compared to N-HD patients and is not sufficiently balanced by anti-inflammatory mechanisms.
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Betjes MGH, Langerak AW, Klepper M, Litjens NHR. A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation. IMMUNITY & AGEING 2020; 17:4. [PMID: 32082402 PMCID: PMC7020578 DOI: 10.1186/s12979-020-00175-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 02/02/2020] [Indexed: 12/27/2022]
Abstract
Background End-stage renal disease is associated with premature ageing of the T cell immune system but inter-individual variation is substantial. The hypothesis was tested that advanced immunological T cell ageing assessed by peripheral T cell differentiation increases the long-term mortality risk after renal transplantation. Results Circulating T cells of 211 recipients of a kidney from a living donor were analyzed before and in the first year after transplantation. The number of CD31-positive naive T cells (as a marker for recent thymic emigrants) and the differentiation status of the memory T cells was assessed. Thirty recipients died during follow-up of at least 5 years. Absolute numbers of naive CD4+ (living:258 cells/μl vs. deceased:101 cells/μl, p < 0.001) and naive CD8+ T cells (living:97 cells/μl vs. deceased:37 cells/μl, p < 0.001) were significantly lower in the deceased group prior to transplantation. In a multivariate proportional hazard analysis the number of naive CD4+ T cells remained associated with all-cause mortality (HR 0.98, CI 0.98–0.99, p < 0.001). The low number of naive T cells in the deceased patient group was primarily caused by a decrease in recent thymic emigrants (i.e. less CD31+ naive T cells) indicating a lowered thymus function. In addition, the physiological age-related compensatory increase in CD31− naïve T cells was not observed. Within the first year after transplantation, the number and characteristics of naive T cells remained stable. Conclusions A severe reduction in circulating naïve T cells because of a decrease in recent thymic emigrants is highly associated with all-cause mortality after renal transplantation.
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Affiliation(s)
- Michiel G H Betjes
- 1Department of Internal Medicine, section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Anton W Langerak
- 2Department of Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Mariska Klepper
- 1Department of Internal Medicine, section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Nicolle H R Litjens
- 1Department of Internal Medicine, section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
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Abstract
There is substantial variation between individuals in the immune response to vaccination. In this review, we provide an overview of the plethora of studies that have investigated factors that influence humoral and cellular vaccine responses in humans. These include intrinsic host factors (such as age, sex, genetics, and comorbidities), perinatal factors (such as gestational age, birth weight, feeding method, and maternal factors), and extrinsic factors (such as preexisting immunity, microbiota, infections, and antibiotics). Further, environmental factors (such as geographic location, season, family size, and toxins), behavioral factors (such as smoking, alcohol consumption, exercise, and sleep), and nutritional factors (such as body mass index, micronutrients, and enteropathy) also influence how individuals respond to vaccines. Moreover, vaccine factors (such as vaccine type, product, adjuvant, and dose) and administration factors (schedule, site, route, time of vaccination, and coadministered vaccines and other drugs) are also important. An understanding of all these factors and their impacts in the design of vaccine studies and decisions on vaccination schedules offers ways to improve vaccine immunogenicity and efficacy.
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13
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Syed-Ahmed M, Narayanan M. Immune Dysfunction and Risk of Infection in Chronic Kidney Disease. Adv Chronic Kidney Dis 2019; 26:8-15. [PMID: 30876622 DOI: 10.1053/j.ackd.2019.01.004] [Citation(s) in RCA: 217] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 01/16/2019] [Indexed: 02/08/2023]
Abstract
Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.
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Litjens NHR, Huang L, Dedeoglu B, Meijers RWJ, Kwekkeboom J, Betjes MGH. Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies. Front Immunol 2017; 8:1137. [PMID: 28955345 PMCID: PMC5600906 DOI: 10.3389/fimmu.2017.01137] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 08/29/2017] [Indexed: 11/13/2022] Open
Abstract
The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMVneg patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMVneg patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137+IFNγ+CD4+ and CD137+IFNγ+CD8+ memory T cells were present in 46 and 39% of CMVneg patients (n = 28) although at much lower frequencies compared to CMVpos patients (median 0.01 versus 0.58% for CD4+ and 0.05 versus 0.64% for CD8+ T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4+ and CD8+ T cells were observed in CMVneg patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG antibody-secreting cells (ASC) could be detected at low frequency in 36% of CMVneg patients (1 versus 45 ASC/105 cells in CMVpos patients). CMVneg patients with pretransplant CMV-specific CD137+IFNγ+CD4+ T cells had a lower risk to develop CMV viremia after transplantation with a CMVpos donor kidney (relative risk: 0.43, P = 0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV infection following transplantation with a kidney from a CMVpos donor.
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Affiliation(s)
- Nicolle H R Litjens
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Ling Huang
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Burç Dedeoglu
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Ruud W J Meijers
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Michiel G H Betjes
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
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Assing K, Nielsen C, Jakobsen M, Scholze A, Nybo M, Soerensen G, Mortensen S, Vejen K, Barington T, Bistrup C. Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end-stage renal disease. IMMUNITY INFLAMMATION AND DISEASE 2016; 4:225-234. [PMID: 27957330 PMCID: PMC4879468 DOI: 10.1002/iid3.108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/11/2016] [Accepted: 04/15/2016] [Indexed: 11/08/2022]
Abstract
INTRODUCTION End-stage renal disease (ESRD) is associated with increased infectious susceptibility and with reduced vaccine responses consistent with compromised humoral immunity. Whether the compromised humoral immunity is due to reduced antibody diversity (reduced somatic hypermutation [SHM]) or altered germinal center (GC) dynamics is not known. The GC-derived chemokine CXCL13 as well as peripheral T follicular helper cells (pTFH) reflect GC dynamics, but have, similar to SHM, never been characterized in relation to ESRD. METHODS Serum CXCL 13 was determined by ELISA. PTFH were flow-cytometrically defined as CD4+ CD45RA- CCR7+ CXCR5+ lymphocytes. Apoptotic lymphocyte subsets were in addition annexin V+. SHM was determined, by next-generation sequencing and bioinformatics, as nucleotide mutations within the IgG VH (comprising the important antigen-binding domains of IgG, CDR1, and CDR2). RESULTS Elevated CXCL13 levels characterized ESRD (n = 19; [median] 90 pg/ml, P < 0.01) (controls, n = 18; 62 pg/ml). ESRD pTFH frequencies (n = 19; 11.6% [of CD4+ memory T cells], P < 0.02*, *Bonferroni corrected) (controls, n = 22; 14.9%) and concentrations (n = 19; 0.03 × 109/L, P < 0.02*) (controls, n = 22; 0.07 × 109/L) were reduced. ESRD pTFH were more apoptotic (n = 9; 25.7%, P = 0.04*) (controls, n = 10; 15.9%). SHM did not discriminate between ESRD (n = 10; 7.4%, P = 0.21) and controls (n = 10; 8.4%). CONCLUSIONS Elevated CXCL13 levels, reduced pTFH levels, and increased pTFH apoptosis suggest that perturbed GC dynamics, and not reduced antibody diversity, underlie the diminished vaccine responses and the compromised humoral immunity in ESRD. However, largely preserved SHM provides a rationale for pursuing vaccination in relation to ESRD.
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Affiliation(s)
- Kristian Assing
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Christian Nielsen
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Marianne Jakobsen
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Alexandra Scholze
- Clinical Research UnitDepartment of NephrologyOdense University HospitalOdenseDenmark; Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | - Mads Nybo
- Department of Clinical Biochemistry Odense University Hospital Odense Denmark
| | - Grete Soerensen
- Department of Nephrology Odense University Hospital Odense Denmark
| | - Sussie Mortensen
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Knud Vejen
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Torben Barington
- Department of Clinical Immunology Odense University Hospital Odense Denmark
| | - Claus Bistrup
- Department of Nephrology Odense University Hospital Odense Denmark
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Dedeoglu B, Meijers RWJ, Klepper M, Hesselink DA, Baan CC, Litjens NHR, Betjes MGH. Uremia-Associated Premature Aging of T Cells Does Not Predict Infectious Complications After Renal Transplantation. Am J Transplant 2016; 16:2324-33. [PMID: 26914971 DOI: 10.1111/ajt.13759] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 01/26/2016] [Accepted: 02/13/2016] [Indexed: 01/25/2023]
Abstract
Patients with end-stage renal disease have prematurely aged T cell systems. We tested whether T cell aging parameters were associated with the risk of infections after renal transplantation (RTx). We studied 188 patients over 1 year. Peripheral T cells were analyzed before and at 3 and 6 mo after RTx for frequency of recent thymic emigrants, relative telomere length and differentiation status. These parameters were related to the occurrence of opportunistic and serious infections. Overall, 84 patients developed an infection. In this group, 50 developed an opportunistic infection and 53 developed a serious infection. T cell aging parameters assessed before RTx were not associated with infection risk. The memory T cells showed a decrease within the first 3 mo in both groups (p < 0.001). The CD4(+) memory T cells increased between 3 and 6 mo within the infection group (p = 0.015). The number of CD8(+) memory T cells increased in both groups (p < 0.001) but reached baseline levels only in the infection group. In the infection group, the CD8(+) CD28(null) T cell percentage increased between 3 and 6 mo (p = 0.024), tending to be higher than at baseline (p = 0.061). These differences in post-RTx dynamics resulted from infections. Parameters of uremia-associated premature aging of peripheral T cells do not predict posttransplant infections.
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Affiliation(s)
- B Dedeoglu
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - R W J Meijers
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - M Klepper
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - D A Hesselink
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - C C Baan
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - N H R Litjens
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - M G H Betjes
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
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17
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Dedeoglu B, Meijers RWJ, Klepper M, Hesselink DA, Baan CC, Litjens NHR, Betjes MGH. Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation. PLoS One 2016; 11:e0150826. [PMID: 26950734 PMCID: PMC4780739 DOI: 10.1371/journal.pone.0150826] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 02/20/2016] [Indexed: 01/26/2023] Open
Abstract
Background End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). Methods 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters. Results Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001). Conclusion Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.
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Affiliation(s)
- Burç Dedeoglu
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
- * E-mail:
| | - Ruud W. J. Meijers
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
| | - Mariska Klepper
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
| | - Dennis A. Hesselink
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
| | - Carla C. Baan
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
| | - Nicolle H. R. Litjens
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
| | - Michiel G. H. Betjes
- Department of Internal Medicine, section Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, South Holland, the Netherlands
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18
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Meijers RWJ, Litjens NHR, Hesselink DA, Langerak AW, Baan CC, Betjes MGH. Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients. Am J Transplant 2015; 15:3143-56. [PMID: 26211927 DOI: 10.1111/ajt.13396] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 04/30/2015] [Accepted: 05/24/2015] [Indexed: 01/25/2023]
Abstract
Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4(+) CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31(+) naïve T cell numbers and relative telomere length (RTL) pre-KT and 12 months post-KT. CMV-seronegative KT recipients, receiving a kidney from a CMV-seropositive donor (D+/R-) were compared to D+/R+ KT recipients. Eleven out of the 22 D+/R- KT recipients had CMV viremia post-KT. They developed CMV-specific CD4(+) and CD8(+) T cells and their T cell compartment shifted towards a more differentiated memory phenotype with expansion of CD4(+) CD28null and CD8(+) CD28null cells. One year post-KT, the CD8(+) T cell count was almost doubled compared to nonviremic D+/R- and D+/R+ KT recipients. In addition, the RTL of the CD8(+) T cell was significantly lower and both the TREC content and CD31(+) naïve T cell numbers significantly decreased. Moreover, primary CMV infection was associated with a negative impact on glomerular filtration rate. In conclusion, primary CMV infection has a substantial impact on the number and phenotype of peripheral T cells and may negatively affect renal allograft function.
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Affiliation(s)
- R W J Meijers
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - N H R Litjens
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - D A Hesselink
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - A W Langerak
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - C C Baan
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - M G H Betjes
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Sadarangani SP, Whitaker JA, Poland GA. "Let there be light": the role of vitamin D in the immune response to vaccines. Expert Rev Vaccines 2015; 14:1427-40. [PMID: 26325349 DOI: 10.1586/14760584.2015.1082426] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vitamin D's non-skeletal actions, including immunomodulatory role, have been increasingly recognized. Of significance, many immune cells are able to synthesize a biologically active form of vitamin D from circulating 25-hydroxyvitamin D with subsequent intracrine actions, and the vitamin D receptor is broadly distributed. In this review, we discuss vitamin D's potent role in innate and adaptive immune responses and published studies evaluating the impact of serum vitamin D, vitamin D gene pathway polymorphisms or empiric vitamin D supplementation on vaccine immunogenicity. We highlight existing knowledge gaps and propose the steps needed to advance the science and answer the question of whether vitamin D may prove valuable as a vaccine adjuvant for certain vaccines against infectious diseases.
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Affiliation(s)
- Sapna P Sadarangani
- a 1 Mayo Vaccine Research Group, Rochester, MN, USA.,b 2 Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA
| | | | - Gregory A Poland
- a 1 Mayo Vaccine Research Group, Rochester, MN, USA.,c 3 Mayo Clinic Division of General Internal Medicine, Rochester, MN, USA
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20
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Hahn M, Schnitzler P, Schweiger B, Kunz C, Ho AD, Goldschmidt H, Schmitt M. Efficacy of single versus boost vaccination against influenza virus in patients with multiple myeloma. Haematologica 2015; 100:e285-8. [PMID: 25820335 DOI: 10.3324/haematol.2014.116772] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Michael Hahn
- Internal Medicine V, University Hospital Heidelberg, Germany
| | | | - Brunhilde Schweiger
- Robert Koch-Institut, National Reference Center for Influenza, Berlin, Germany
| | - Christina Kunz
- German Cancer Research Center (DKFZ), Dept. of Biostatistics, Heidelberg, Germany
| | - Anthony D Ho
- Internal Medicine V, University Hospital Heidelberg, Germany
| | | | - Michael Schmitt
- Internal Medicine V, University Hospital Heidelberg, Germany
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21
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Meijers RWJ, Betjes MGH, Baan CC, Litjens NHR. T-cell ageing in end-stage renal disease patients: Assessment and clinical relevance. World J Nephrol 2014; 3:268-276. [PMID: 25374821 PMCID: PMC4220360 DOI: 10.5527/wjn.v3.i4.268] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 07/08/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
End-stage renal disease (ESRD) patients have a defective T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated pro-inflammatory milieu, created by loss of renal function. Therefore, ESRD patients are highly susceptible for infections, have an increased risk for virus-associated cancers, respond poorly to vaccination and have an increased risk for atherosclerotic diseases. Three ageing parameters can be used to assess an immunological T-cell age. First, thymic output can be determined by assessing the T-cell receptor excision circles-content together with CD31 expression within the naïve T cells. Second, the telomere length of T cells and third the T-cell differentiation status are also indicators of T-cell ageing. Analyses based on these parameters in ESRD patients revealed that the immunological T-cell age is increased by on average 20 years compared to the chronological age. After kidney transplantation (KTx) the aged T-cell phenotype persists although the pro-inflammatory milieu is diminished. This might be explained by epigenetic modifications at hematopoietic stem cells level. Assessment of an immunological T-cell age could be an important tool to identify KTx recipients who are at risk for allograft rejection or to prevent over-immunosuppression.
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22
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Meijers RWJ, Litjens NHR, de Wit EA, Langerak AW, Baan CC, Betjes MGH. Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation. Transpl Int 2014; 27:1272-84. [DOI: 10.1111/tri.12416] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/21/2014] [Accepted: 07/26/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Ruud W. J. Meijers
- Department of Internal Medicine; Section Nephrology and Transplantation; Erasmus MC, University Medical Center; Rotterdam The Netherlands
| | - Nicolle H. R. Litjens
- Department of Internal Medicine; Section Nephrology and Transplantation; Erasmus MC, University Medical Center; Rotterdam The Netherlands
| | - Elly A. de Wit
- Department of Internal Medicine; Section Nephrology and Transplantation; Erasmus MC, University Medical Center; Rotterdam The Netherlands
| | - Anton W. Langerak
- Department of Immunology; Erasmus MC, University Medical Center; Rotterdam The Netherlands
| | - Carla C. Baan
- Department of Internal Medicine; Section Nephrology and Transplantation; Erasmus MC, University Medical Center; Rotterdam The Netherlands
| | - Michiel G. H. Betjes
- Department of Internal Medicine; Section Nephrology and Transplantation; Erasmus MC, University Medical Center; Rotterdam The Netherlands
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23
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Fallahzadeh MK, Sajjadi S, Singh N, Khajeh M, Sagheb MM. Effect of levamisole supplementation on tetanus vaccination response rates in haemodialysis patients: a randomized double-blind placebo-controlled trial. Nephrology (Carlton) 2014; 19:27-31. [PMID: 24341659 DOI: 10.1111/nep.12158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Levamisole as an immunomodulator drug has been demonstrated to improve the immune response to hepatitis B virus vaccination in haemodialysis patients. The aim of this randomized double-blind placebo-controlled trial was to evaluate the effect of levamisole supplementation on tetanus-diphtheria (Td) vaccine response rates in haemodialysis patients. Forty haemodialysis patients who had not received tetanus vaccination in a year before investigation and had unprotective anti-tetanus immunoglobulin G (IgG) levels (<0.1 international unit/mL) were enrolled and randomized into two equal groups to receive one dose of intramuscular Td vaccine supplemented with either levamisole (100 mg) or placebo daily, for 6 days before and 6 days after vaccination. The anti-tetanus IgG levels were measured 1 and 6 months after vaccination. One month post-vaccination, four patients were excluded from the levamisole group and two from the placebo group because of either death or renal transplantation. At 1 month, 13 out of 16 (81%) patients in the levamisole group as compared with six out of 18 (33%) patients in the placebo group developed protective anti-tetanus IgG levels (relative risk = 2.44, 95% confidence interval (CI) = 1.21, 4.88). From 1 to 6 months post-vaccination, one more patient in the levamisole group and two more patients in the placebo group were excluded because of renal transplantation. At 6 months, 11 out of 15 (73%) patients in the levamisole group as compared with four out of 16 (25%) patients in the placebo group still had protective anti-tetanus IgG levels (relative risk = 2.93, 95% CI = 1.19, 7.23). Supplementation of Td vaccination with levamisole may enhance seroconversion against tetanus in haemodialysis patients.
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Affiliation(s)
- Mohammad Kazem Fallahzadeh
- Shiraz Nephrology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; WK John C. McDonald Regional Transplant Center and Division of Nephrology, Department of Medicine, LSUHSC-S, Shreveport, Louisiana, USA
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24
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Mathew R, Mason D, Kennedy JS. Vaccination issues in patients with chronic kidney disease. Expert Rev Vaccines 2014; 13:285-98. [PMID: 24405403 DOI: 10.1586/14760584.2014.874950] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Infections are an important cause of morbidity and mortality among patients at all stages of chronic kidney disease. Prevention through vaccination remains the best strategy to minimize the adverse consequences associated with these infectious diseases in this, and all, populations. Unfortunately, patients with chronic kidney disease demonstrate inadequacies of specific immune-cell function that are required for generating a protective vaccine response. Nevertheless, early vaccination of this high-risk population has demonstrated good clinical outcomes during progression to late-stage disease. We review the available evidence linking immune impairment in adult patients with late-stage chronic kidney disease to diminished vaccine responses. We highlight the importance of early vaccination in disease with high risk for development of CKD and novel vaccine approaches in development that may help to address improvement in protective boosting of immunity during late-stage disease.
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Affiliation(s)
- Roy Mathew
- Department of Medicine, Division of Nephrology, Stratton VA Medical Center, Albany, NY, USA
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Serial influenza-vaccination reveals impaired maintenance of specific T-cell memory in patients with end-stage renal failure. Vaccine 2013; 31:4111-20. [PMID: 23845814 DOI: 10.1016/j.vaccine.2013.06.076] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 06/14/2013] [Accepted: 06/25/2013] [Indexed: 11/22/2022]
Abstract
To investigate correlates for the well-known impaired response of haemodialysis-patients to a variety of recommended vaccinations, the induction of antigen-specific cellular and humoral immunity was characterised after influenza-vaccination in two following seasons where the identical vaccine-composition was used. Influenza-specific T-cells were flow-cytometrically characterised from whole blood of 24 healthy controls and 26 haemodialysis-patients by proliferation-assays, induction of IFN-γ and TNF-α, and maturation markers. Antibody-titres were quantified using ELISA and hemagglutination-inhibition test. Influenza-specific CD4 T-cells were recently activated CD45RO+/CD27+ Th1-cells. Specific T-cell frequencies significantly increased 1-2 weeks after the first vaccination in both controls (mean increase by 0.50±0.64%, max: 3.01%) and haemodialysis-patients (by 0.55±0.71%, max: 3.44%). Thereafter, T-cell levels continuously decreased to pre-vaccination levels within approximately 7 weeks, whereas antibody-titres were more stable over time. By 6 months, haemodialysis-patients had significantly lower precursor-frequencies of proliferating influenza-specific memory T-cells (p=0.006). In the following season, memory-maintenance in immunocompetent individuals led to a significantly less pronounced increase in cellular immunity after re-vaccination (by only 0.12±0.09%, p=0.003), whereas the vaccine induced a strong increase in a second group of vaccination-naïve controls. Of note, haemodialysis-patients responded like vaccination-naïve individuals, as they showed a strong increase in cellular immunity after re-vaccination that was as pronounced as in the year before. In conclusion, the less pronounced T-cell increase after re-vaccination in controls may indicate maintenance of sufficient immunological memory. In contrast, the more rapid loss of proliferating cells in haemodialysis-patients may represent a sign of relative immunodeficiency and contribute to an increased incidence of recurrent infectious complications.
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Afzali B, Edozie FC, Fazekasova H, Scottà C, Mitchell PJ, Canavan JB, Kordasti SY, Chana PS, Ellis R, Lord GM, John S, Hilton R, Lechler RI, Lombardi G. Comparison of regulatory T cells in hemodialysis patients and healthy controls: implications for cell therapy in transplantation. Clin J Am Soc Nephrol 2013; 8:1396-405. [PMID: 23580782 DOI: 10.2215/cjn.12931212] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND OBJECTIVES Cell-based therapy with natural (CD4(+)CD25(hi)CD127(lo)) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Healthy controls and age- and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays. RESULTS Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product. CONCLUSIONS Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.
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Affiliation(s)
- Behdad Afzali
- Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, United Kingdom
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27
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Abstract
Uraemia causes inflammation and reduces immune system function as evidenced by an increased risk of viral-associated cancers, increased susceptibility to infections and decreased vaccination responses in patients with end-stage renal disease (ESRD). The substantially increased risk of atherosclerosis in these patients is also probably related to uraemia-associated inflammation. Uraemia is associated with a reduction in the number and function of lymphoid cells, whereas numbers of myeloid cells in uraemic patients are normal or increased with increased production of inflammatory cytokines and reactive oxygen species. Similar to healthy elderly individuals, patients with ESRD have increased numbers of specific proinflammatory subsets of T cells and monocytes, suggesting the presence of premature immunological ageing in these patients. These cells might contribute to inflammation and destabilization of atherosclerotic plaques, and have, therefore, been identified as novel nonclassical cardiovascular risk factors. The cellular composition of the immune system does not normalize after successful kidney transplantation despite a rapid reduction in inflammation and oxidative stress. This finding suggests that premature ageing of the immune system in patients with ESRD might be related to a permanent skewing of the haematopoetic stem cell population towards myeloid-generating subsets, similar to that seen in healthy elderly individuals.
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Eckerle I, Rosenberger KD, Zwahlen M, Junghanss T. Serologic vaccination response after solid organ transplantation: a systematic review. PLoS One 2013; 8:e56974. [PMID: 23451126 PMCID: PMC3579937 DOI: 10.1371/journal.pone.0056974] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 01/16/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Infectious diseases after solid organ transplantation (SOT) are one of the major complications in transplantation medicine. Vaccination-based prevention is desirable, but data on the response to active vaccination after SOT are conflicting. METHODS In this systematic review, we identify the serologic response rate of SOT recipients to post-transplantation vaccination against tetanus, diphtheria, polio, hepatitis A and B, influenza, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, tick-borne encephalitis, rabies, varicella, mumps, measles, and rubella. RESULTS Of the 2478 papers initially identified, 72 were included in the final review. The most important findings are that (1) most clinical trials conducted and published over more than 30 years have all been small and highly heterogeneous regarding trial design, patient cohorts selected, patient inclusion criteria, dosing and vaccination schemes, follow up periods and outcomes assessed, (2) the individual vaccines investigated have been studied predominately only in one group of SOT recipients, i.e. tetanus, diphtheria and polio in RTX recipients, hepatitis A exclusively in adult LTX recipients and mumps, measles and rubella in paediatric LTX recipients, (3) SOT recipients mount an immune response which is for most vaccines lower than in healthy controls. The degree to which this response is impaired varies with the type of vaccine, age and organ transplanted and (4) for some vaccines antibodies decline rapidly. CONCLUSION Vaccine-based prevention of infectious diseases is far from satisfactory in SOT recipients. Despite the large number of vaccination studies preformed over the past decades, knowledge on vaccination response is still limited. Even though the protection, which can be achieved in SOT recipients through vaccination, appears encouraging on the basis of available data, current vaccination guidelines and recommendations for post-SOT recipients remain poorly supported by evidence. There is an urgent need to conduct appropriately powered vaccination trials in well-defined SOT recipient cohorts.
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Affiliation(s)
- Isabella Eckerle
- Section of Clinical Tropical Medicine, Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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29
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Neu AM. Immunizations in children with chronic kidney disease. Pediatr Nephrol 2012; 27:1257-63. [PMID: 22048175 PMCID: PMC3382633 DOI: 10.1007/s00467-011-2042-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 10/04/2011] [Accepted: 10/05/2011] [Indexed: 11/29/2022]
Abstract
Children with chronic kidney disease (CKD) are at increased risk for vaccine-preventable diseases. These patients may have a reduced response to and/or reduced duration of antibody after immunization and therefore monitoring of antibody levels or titers is indicated for some vaccines. In addition, pediatric CKD patients require immunizations not routinely provided to healthy children. Unfortunately, studies in pediatric CKD patients, including those on dialysis and awaiting kidney transplantation, have demonstrated sub-optimal immunization rates. In order to minimize the risk for vaccine-preventable disease in pediatric CKD patients, it is imperative that all who care for these patients remain abreast of the recommended childhood immunization schedule, as well as alterations to this schedule required for children with CKD, including end-stage kidney disease. This article reviews recent changes to the recommended childhood immunization schedule and alterations and additions to this schedule recommended for children with CKD. Where available, data on antibody response to immunizations in children with CKD are presented.
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Affiliation(s)
- Alicia M Neu
- Pediatric Nephrology, The Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3065, Baltimore, MD 21287, USA.
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31
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Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2012; 19:1509-16. [PMID: 22837094 DOI: 10.1128/cvi.00034-12] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.
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Abstract
The number of patients with impaired immune response has been steadily increasing within the last years, not only with the onset of the AIDS epidemic, but also due to increasing numbers of subjects on immunosuppressive therapies. These patients are at an increased risk for infections, many of which are preventable by immunization. Inactivated vaccines are generally safe in subjects with underlying immunosuppression. However, immune response and protection may be hampered, depending on the extent of immunosuppression. In contrast, live vaccines such as yellow fever, measles, rubella, herpes zoster, and cholera may lead to severe reactions in immunocompromised patients and have been shown to deteriorate some immune-mediated diseases such as multiple sclerosis. Data on the efficacy of vaccines in biological therapies is scarce. Where necessary vaccines should be updated before immunosuppressive therapies are started. To improve the vaccination status several guidelines exist for immunosuppressed patients at risk such as those with rheumatic diseases, asplenia or solid organ and hematopoietic stem cell transplantation.
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Dikow R, Eckerle I, Ksoll-Rudek D, Hampel H, Schwenger V, Zeier M, Schnitzler P, Sommerer C. Immunogenicity and Efficacy in Hemodialysis Patients of an AS03A-Adjuvanted Vaccine for 2009 Pandemic Influenza A(H1N1): A Nonrandomized Trial. Am J Kidney Dis 2011; 57:716-23. [DOI: 10.1053/j.ajkd.2010.11.031] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 11/24/2010] [Indexed: 11/11/2022]
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Effects of parathyroid hormone on immune function. Clin Dev Immunol 2010; 2010. [PMID: 20886005 PMCID: PMC2945648 DOI: 10.1155/2010/418695] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2010] [Accepted: 06/15/2010] [Indexed: 12/04/2022]
Abstract
Parathyroid hormone (PTH) function as immunologic mediator has become interesting with the recent usage of PTH analogue (teriparatide) in the management of osteoporosis. Since the early 1980s, PTH receptors were found on most immunologic cells (neutrophils, B and T cells). The in vitro evaluations for a possible role of PTH as immunomodulator have shown inconsistent results mainly due to methodological heterogeneity of these studies: it used different PTH formulations (rat, bovine, and human), at different dosages and different incubating periods. In some of these studies, the lymphocytes were collected from uremic patients or animals, which renders the interpretation of the results problematic due to the effect of uremic toxins. Parathyroidectomy has been found to reverse the immunologic defect in patients with high PTH levels. Nonetheless, the clinical significance of these findings is unclear. Further studies are needed to define if PTH does have immunomodulatory effects.
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Contin-Bordes C, Lacraz A, de Précigout V. Potential role of the soluble form of CD40 in deficient immunological function of dialysis patients: new findings of its amelioration using polymethylmethacrylate (PMMA) membrane. NDT Plus 2010; 3:i20-i27. [PMID: 27045744 PMCID: PMC4813818 DOI: 10.1093/ndtplus/sfq033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Even though numerous studies have helped to better delineate abnormalities of either innate or adaptive immune system in end-stage renal disease (ESRD) patients, understanding immune dysfunctions in ESRD patients remains a very complex puzzle with missing pieces. In this context, we showed that the soluble form of CD40 (sCD40) is elevated in ESRD patients and is associated with a lack of response to hepatitis B vaccination. Interestingly, although most dialysis membranes are unable to clear sCD40, we demonstrated that polymethylmethacrylate (PMMA) BK-F membranes (Toray Medical Company, Japan) allow a dramatic diminution of the molecule. We took advantage of this observation to address the question of the potential usefulness of PMMA membrane (BK-F series) in the improvement of humoral immune response of ESRD patients. We, thus, present our recent data highlighting the potential role of BK-F membrane in the improvement of hepatitis B vaccination of ESRD patients who failed to mount a protective immune response despite one or more well-conducted anterior vaccination. Taken as a whole, our findings reinforced the concept of seeing dialysis membranes not just as a simple diffusive device but as a tool to tailor dialysis procedure to improve the global quality of life of ESRD patients. This opens a wide area of investigation, notably for the management of immunological dysfunction of ESRD patients.
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Affiliation(s)
- Cécile Contin-Bordes
- UMR-CNRS 5164 CIRID, Université Victor Segalen, Bordeaux, France; Department of Immunology, Pellegrin Hospital, Bordeaux, France
| | - Adeline Lacraz
- Department of Nephrology , Pellegrin Hospital , Bordeaux , France
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36
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Sagheb MM, Sajjadi S, Sajjady G. A Study on the Protection of Hemodialysis Patients Against Diphtheria and Tetanus. Ren Fail 2009; 31:904-9. [DOI: 10.3109/08860220903268353] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Sester M, Gärtner BC, Girndt M, Sester U. Vaccination of the solid organ transplant recipient. Transplant Rev (Orlando) 2008; 22:274-84. [PMID: 18684606 DOI: 10.1016/j.trre.2008.07.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Active immunization is the most important way to protect immunocompromised patients from vaccine-preventable infectious diseases. Although live vaccines are contraindicated for most immunocompromised patients, many inactivated or conjugate vaccines are safe and generally recommended. Some vaccines are known to be of suboptimal immunogenicity in transplant recipients. As a consequence, this may be associated with an impaired ability to mount protective immunity. Nevertheless, even partial protection has been shown to confer significant benefit to this vulnerable patient group. To increase efficacy in generating protective immunity, patients should complete the full complement of recommended vaccinations early in the course of disease before transplantation. This review summarizes the general recommendations for vaccinations of adult transplant recipients and candidates including special considerations for household contacts and health care workers.
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Affiliation(s)
- Martina Sester
- Department of Internal Medicine IV, University of the Saarland, Homburg, Germany.
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38
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Litjens NHR, Huisman M, van den Dorpel M, Betjes MGH. Impaired immune responses and antigen-specific memory CD4+ T cells in hemodialysis patients. J Am Soc Nephrol 2008; 19:1483-90. [PMID: 18480314 DOI: 10.1681/asn.2007090971] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Serologic responses to T cell-dependent vaccinations are severely attenuated in patients with ESRD, but the reasons for this is unknown. In this study, a detailed analysis of antigen-specific T cell responses was performed. Patients on hemodialysis and age- and gender-matched healthy control subjects were vaccinated with hepatitis B surface antigen (HBsAg), antigen-specific CD4(+) T cells were monitored at regular intervals with intracellular cytokine staining and proliferation assays. IL-2-and IFN-gamma-producing CD4(+) T cells were identified as either central or effector memory CD4(+) T cells using antibodies directed against CD45RO and the chemokine receptor CCR7. Control subjects mounted a memory T cell response comprising both central and effector memory CD4(+) T cells, with the central memory response occurring 1 wk before the effector memory response. IL-2(+) HBsAg-specific memory CD4(+) T cells were primarily detected within the effector population. Patients with ESRD showed a delayed response of IL-2-and IFN-gamma-producing central memory CD4(+) T cells, but their maximal responses were similar to those of control subjects. In contrast, patients with ESRD produced only 6.3% of the IL-2(+) HBsAg-specific effector memory CD4(+) T cells produced by control subjects (0.5 +/- 0.2 x 10(4)/L versus 8 +/- 3.5 x 10(4)/L; P < 0.001), and this impaired response correlated with antigen-specific T cell proliferation and anti-HBsAg IgG titers. In conclusion, the production of antigen-specific effector memory CD4(+) T cells after vaccination, which is critical to achieve an adequate humoral response, is severely impaired in patients with ESRD.
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Friedrich N, Kramer A, Mentel R, Gürtler L, John U, Völzke H. No influence of atopic diseases on antibody titres following tetanus, diphtheria and hepatitis B immunisation among adults. Eur J Clin Microbiol Infect Dis 2007; 26:887-94. [PMID: 17891427 DOI: 10.1007/s10096-007-0374-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Several studies have reported associations between reduced humoral immune response to vaccine antigens and diseases with modified reactions of the immune system. We have investigated the influence of atopic diseases on specific IgG levels to tetanus, diphtheria and hepatitis B (HB), following immunisation, in a general adult population. From the Study of Health in Pomerania, a total number of 3,920 subjects aged 20 to 79 years were included in the analyses. Information on immunisation history, as well as behavioural and socio-demographic characteristics were collected. Anti-tetanus IgG, anti-diphtheria IgG and anti-HBs IgG were measured by indirect enzyme-linked immunosorbent assay (ELISA). Odds ratios and 95% confidence intervals were calculated using logistic regression. Atopic diseases were reported by 14% of participants. Proportions of 67%, 34% and 10% had been vaccinated against tetanus, diphtheria and hepatitis B within the past ten years, respectively. Multi-variable analyses revealed no associations between the presence of atopic diseases and all of the three vaccine-specific antibody titres. We conclude that there is no reduced immune response related to antibody production following immunisations against tetanus, diphtheria and hepatitis B in adults with atopic diseases.
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Affiliation(s)
- N Friedrich
- Institute of Community Medicine, Ernst Moritz Arndt University of Greifswald, Walther-Rathenau-Strasse 48, Greifswald, Germany.
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40
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Eleftheriadis T, Antoniadi G, Liakopoulos V, Kartsios C, Stefanidis I. Disturbances of acquired immunity in hemodialysis patients. Semin Dial 2007; 20:440-451. [PMID: 17897251 DOI: 10.1111/j.1525-139x.2007.00283.x] [Citation(s) in RCA: 246] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acquired immunity disturbances in hemodialysis (HD) patients are many and diverse. They are caused by uremia per se, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Current data suggest that acquired immunity disturbances in HD patients concern mainly the T-lymphocyte and the antigen-presenting cell (APC). The T-lymphocyte-dependent immune response is deficient, predisposing to infections and inadequate response to vaccinations. In addition, APCs are preactivated, which seems to be responsible for the malnutrition-inflammation-atherosclerosis syndrome, and also affects T-lymphocyte function. At the molecular level it is assumed that the interaction between the APC and the T-lymphocyte is impaired. This disturbance is likely to concern the signal that results from the interaction between the major histocompatibility complex:peptide complex on APC surfaces and T-cell receptors on T-lymphocyte surfaces, or the signal that results from the interaction among the co-receptors of these two cells. The aim of the present review was to collect and classify the available clinical and experimental data in this area. Although many pieces are still missing from the puzzle, a better understanding of the responsible molecular mechanisms, will potentially lead to increased survival and a better quality of life in HD patients.
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Dinits-Pensy M, Forrest GN, Cross AS, Hise MK. The use of vaccines in adult patients with renal disease. Am J Kidney Dis 2006; 46:997-1011. [PMID: 16310566 DOI: 10.1053/j.ajkd.2005.08.032] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2005] [Accepted: 08/23/2005] [Indexed: 12/25/2022]
Abstract
In patients with renal disease, infection remains among the most common causes of morbidity and mortality. Alterations in the function of the immune system, as well as unique exposures of this patient population, account for the increased risk. Vaccination is an invaluable tool in preventing many infectious diseases. Unfortunately, responsiveness to vaccination in patients with renal disease can be diminished. In the present review, we examine the available evidence on the use of vaccinations in adult patients at different stages of chronic kidney disease. We address efficacy, clinical outcomes, and potential costs of individual vaccinations and provide our recommendations based on the literature reviewed. We also identify areas in which additional research is needed.
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Affiliation(s)
- Mara Dinits-Pensy
- Department of Medicine, Center for Vaccine Development, University of Maryland Medical Center, Baltimore, MD, USA.
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42
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Litjens NHR, van Druningen CJ, Betjes MGH. Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes. Clin Immunol 2005; 118:83-91. [PMID: 16257266 DOI: 10.1016/j.clim.2005.09.007] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Revised: 09/09/2005] [Accepted: 09/16/2005] [Indexed: 02/07/2023]
Abstract
We hypothesized that progressive loss of renal function specifically affects certain T cell subsets. T lymphocyte subsets of patients with chronic kidney disease and healthy controls were characterized by flow cytometry using heparin-anticoagulated whole blood samples. Plasma interleukin (IL)-7 and IL-15 concentrations were determined as these cytokines are critically involved in T cell homeostasis. The results revealed that a progressive decrease in renal function is associated with activation and selective loss of naive T cells and CD4+ central memory cells and a marked increase in CD8+ memory T cells that lack CD45RO and CCR7. The profile of T cell subsets of patients with CKD 5 with or without hemodialysis treatment was similar except for a pronounced shift to Th1 cells in hemodialysis patients. IL-7 but not IL-15 plasma concentrations were lowered in patients with end-stage renal disease as compared to healthy controls.
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Affiliation(s)
- Nicolle H R Litjens
- Department of Internal Medicine, Division of Nephrology, Room Ee 551, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
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Sester M, Sester U, Clauer P, Heine G, Mack U, Moll T, Sybrecht GW, Lalvani A, Köhler H. Tuberculin skin testing underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kidney Int 2004; 65:1826-34. [PMID: 15086923 DOI: 10.1111/j.1523-1755.2004.00586.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Identification of latent Mycobacterium tuberculosis infection in hemodialysis patients is hampered by reduced sensitivity of the established tuberculin skin test. We investigated whether in vitro quantitation of purified protein derivative (PPD)-specific T cells using a rapid 6-hour assay may represent an alternative approach for detecting latent infection. METHODS One hundred and twenty-seven hemodialysis patients and 218 control patients (blood donors, health care workers, and control patients) were analyzed. Specific T cells toward PPD and early secretory antigenic target-6 (ESAT-6), a protein expressed in Mycobacterium tuberculosis but absent from M. bovis bacillus Calmette-Guerin (BCG) vaccine strains, were flow cytometrically quantified from whole blood, and results were compared with skin testing. RESULTS Compared to blood donors, a high proportion of both health care workers (48.6%) and hemodialysis patients (53.5%) had PPD-specific Th1-type CD4 T-cell reactivity with similar median frequencies of PPD-specific T cells (0.17%; 0.06-3.75% vs. 0.26%; 0.06-4.12%, respectively). In contrast, skin test reactivity was significantly reduced in hemodialysis patients. Whereas 85.7% of control patients with PPD reactivity in vitro were skin test-positive, the respective percentage among hemodialysis patients was 51.4% (P= 0.007). Among individuals with PPD reactivity in vitro, approximately 50% had T cells specific for ESAT-6. CONCLUSION Unlike the skin test, measurement of PPD reactivity by in vitro quantitation of PPD-specific T cells was unaffected by uremia-associated immunosuppression. This whole-blood assay may thus be a valuable alternative to skin testing, and detection of ESAT-6-specific T cells could moreover allow distinction of latent M. tuberculosis infection from BCG-induced reactivity to PPD. The assay is well suited for clinical use and may facilitate targeting of preventative therapy in high-risk individuals.
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Affiliation(s)
- Martina Sester
- Medical Department IV, University of the Saarland, Homburg, Germany
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Moser B, Roth G, Brunner M, Lilaj T, Deicher R, Wolner E, Kovarik J, Boltz-Nitulescu G, Vychytil A, Ankersmit HJ. Aberrant T cell activation and heightened apoptotic turnover in end-stage renal failure patients: a comparative evaluation between non-dialysis, haemodialysis, and peritoneal dialysis. Biochem Biophys Res Commun 2003; 308:581-5. [PMID: 12914790 DOI: 10.1016/s0006-291x(03)01389-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Patients in end-stage renal disease (ESRD) have a high incidence of bacterial and viral infections. Fifteen non-dialysed (ND), 15 haemodialysed (HD), 15 patients with peritoneal dialysis (PD), and 15 healthy controls were included. T cell proliferation was measured by [3H]thymidine uptake. Apoptosis and cell phenotype were determined by FACS. sTNF-R1, sCD95, interleukin-1beta-converting enzyme (sICE), and interleukin (IL)-10 were measured by ELISA. PHA and CD3-driven T cell proliferation were significantly decreased in ESRD patients. CD3(+), CD19(+) B cells, and percentage of CD4(+) T cells were significantly reduced. Percent memory T cells (CD45RO(+)) and cells undergoing apoptosis (CD95(+)/Annexin V+) were significantly increased in ESRF. Moreover, sCD95, sTNFRI, and ICE were significantly increased. Serum level of IL-10, a Th2 cytokine, was enhanced. These findings strongly suggest that in ESRD patients Th1 T cells are selectively susceptible to undergo apoptosis. This observation provides an additional pathophysiological concept in the genesis of Th2 dominance.
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Affiliation(s)
- Bernhard Moser
- Department of Surgery, General Hospital of Vienna, Austria
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Abstract
Solid-organ transplant recipients are at increased risk of various infectious diseases, some of which are vaccine preventable mmunisations are among the most efficient interventions available. Solid-organ tranplant recipients would greatly benefit from effective immunisations, provided the recommendations are based on a careful risk-benefit analysis in which the effectiveness of the vaccine is weighed against possible adverse reactions, including graft rejection. In this review, we summarise the data from studies on relevant immunisations in solid-organ transplant recipients. The major issues are the immunogenicity and safety of immunisations, the factors associated with poor immune response, and recommendations for immunisation schemes.
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Affiliation(s)
- Klaus Stark
- Institute of Tropical Medicine, Charité, Humboldt University, Berlin, Germany.
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Girndt M, Sester U, Sester M, Deman E, Ulrich C, Kaul H, Köhler H. The interleukin-10 promoter genotype determines clinical immune function in hemodialysis patients. Kidney Int 2001; 60:2385-91. [PMID: 11737614 DOI: 10.1046/j.1523-1755.2001.00062.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Immune dysfunction and the impaired hepatitis B vaccination response are complications of chronic renal failure that are tightly associated with inflammation induced by uremia and blood-membrane contacts. Proinflammatory cytokines, such as interleukin (IL)-6, are counter-regulated by IL-10 with a large interindividual variability. Part of the variability of cytokine production is genetically determined since polymorphisms in the cytokine gene promoters lead to high or low production. The aim of this study was to detect the genetic influence of the IL-10 promoter on immune function of chronic hemodialysis patients. METHODS The IL-10 genotype (polymorphic bases at positions -1082 and -819) was determined in 272 chronic hemodialysis patients using highly specific PCR and related to the patients' response to a triple vaccination against hepatitis B. Secretion of IL-10 and IL-6 by peripheral blood leucocytes in vitro was determined by ELISA. RESULTS The prevalence of the IL-10 genotypes in dialysis patients with well-preserved immune function (vaccination responders) was similar to the general population. In contrast, prevalence of the -1082G* allele (associated with high production of IL-10) was low in the nonresponders. The relative risk of vaccination nonresponse in patients homozygous for the -1082A* allele was 1.394 (95% CI, 1.091 to 1.781, P < 0.05) compared to those homozygous for -1082G*. There was no relationship between the IL-10 genotype and the type of renal disease. CONCLUSIONS The IL-10 genotype determines IL-10 production in dialysis patients, which down-regulates uremia- and dialysis-induced chronic inflammation and helps to preserve immune defense functions.
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Affiliation(s)
- M Girndt
- Medical Department IV, University Homburg/Saar, Germany
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Girndt M, Sester M, Sester U, Kaul H, Köhler H. Defective expression of B7-2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect. Kidney Int 2001; 59:1382-9. [PMID: 11260399 DOI: 10.1046/j.1523-1755.2001.0590041382.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Specific cellular immune reactions in patients with chronic renal failure (CRF) are impaired by a defect of the antigen-presenting cells. To elucidate the molecular background for this defect, we determined the expression of human lymphocyte antigen (HLA)-DR and costimulatory molecules on monocytes of hemodialysis patients. METHODS The expression of HLA-DR, B7-1 (CD80), and B7-2 (CD86) molecules was determined on CD14+ monocytes of chronic hemodialysis patients prior to a dialysis session. Mononuclear cells of these patients were cultured, and expression of the respective antigens was determined after in vitro activation by various stimuli. Results were correlated with in vitro proliferation of T cells in a phytohemagglutinin (PHA) assay and the clinical response to a hepatitis B vaccination. All data were compared with healthy controls and patients with CRF who were not on dialysis. RESULTS Monocytes of chronic hemodialysis patients but not CRF patients expressed low levels of costimulatory B7-2, while HLA-DR expression was normal. B7-1 was only expressed on activated monocytes, and the expression reached normal levels in hemodialysis patients. Baseline expression of B7-2 highly correlated with the results of T-cell proliferation assays in hemodialysis patients and also with the clinical immune response. CONCLUSIONS Impaired expression and up-regulation of B7-2 is an important feature of the cellular immune defect in chronic hemodialysis patients. It leads to reduced costimulation and effector activation of T cells and contributes to a molecular explanation for the impaired response of hemodialysis patients to the hepatitis B vaccination.
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Affiliation(s)
- M Girndt
- Medical Department IV, University of the Saarland, Homburg/Saar, Germany
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Abstract
Immune dysregulation and immunosuppression regimens impact on the ability of transplant recipients to respond to immunizations. The distinct challenges of immunizations to benefit stem cell transplant recipients and solid organ transplant recipients are discussed separately. Recommended vaccines for stem cell transplant recipients and solid organ transplant candidates are suggested. New approaches to consider to enhance immune responses of transplant recipients are discussed.
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Affiliation(s)
- D C Molrine
- University of Massachusetts Medical School, Massachusetts Biologic Laboratories, Jamaica Plain, Massachusetts, USA
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Girndt M, Sester M, Sester U, Kaul H, Köhler H. Molecular aspects of T- and B-cell function in uremia. KIDNEY INTERNATIONAL. SUPPLEMENT 2001; 78:S206-11. [PMID: 11169012 DOI: 10.1046/j.1523-1755.2001.59780206.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Chronic renal failure is associated with severe alterations of the immune system. Infections are responsible for a large part of the mortality in hemodialysis patients, and vaccination is mostly ineffective. Global tests of the immune function show greatly diminished activation of T cells. However, the intrinsic function of T and B cells is normal when they are provided with normal signaling from antigen-presenting cells (APCs). Patients with chronic renal failure show a defective function of costimulation derived from APCs leading to impaired activation of effector lymphocytes. Two major components of immune deviation are relevant: reduced signaling caused by impaired expression of the costimulatory molecule B7-2 (CD86) on monocytes leads to low activation of helper T cells. This dysfunction is associated with uremia and may be improved by high-efficiency renal replacement therapy. The other component is inflammatory activation of APCs mainly due to the hemodialysis procedure. Inflammation, characterized by overproduction of cytokines such as interleukin-1beta (IL-1beta) or IL-6, correlates with low effector activation. Furthermore, inflammatory cytokines such as IL-12 deviate the functional pattern of T-cell activation toward Th1 differentiation, thus leading to an additional reduction of Th2- and B-cell function. The individual severity of inflammatory alterations is partially controlled by the negatively regulating cytokine IL-10, which, on a genetic basis, can be up-regulated to a different extent in individual patients. Therapeutic interventions to improve immune dysfunction include the enhancement of dialysis efficiency and the reduction of inflammatory alterations by the use of highly biocompatible dialyzers.
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Affiliation(s)
- M Girndt
- Medical Department IV, University of Homburg/Sarr, Saar, Germany
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Sester U, Sester M, Hauk M, Kaul H, Köhler H, Girndt M. T-cell activation follows Th1 rather than Th2 pattern in haemodialysis patients. Nephrol Dial Transplant 2000; 15:1217-23. [PMID: 10910448 DOI: 10.1093/ndt/15.8.1217] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Patients on chronic intermittent haemodialysis (HD) show an impaired cellular and humoral immune response that clinically appears with frequent infectious complications and low vaccination responses. This immune defect strongly correlates with reduced in vitro proliferative responses of T cells. The defect is localized in antigen presenting cells, which show a decreased co-stimulatory activity. Furthermore, the impaired immune response correlates with an increased production of pro-inflammatory cytokines. In response to primary activation, CD4 positive T helper (Th) cells mainly differentiate into either Th1 or Th2 cells. Th1 cells support cell mediated immunity whereas Th2 cells enhance humoral immune responses. Since both types of responses mutually inhibit each other, the impaired humoral immune response seen in HD patients could either be due to a reduced number of Th2 cells or to a predominant Th1 response. METHODS We analysed the Th cell profile in HD patients using flow cytometry. Monocytic cytokine expression was analysed using both flow cytometry and enzyme linked immunoadsorbant assays. RESULTS Our data demonstrate that the cytokine differentiation profile in circulating T cells from HD patients is dysregulated and characterized by an increase in Th1 cells, but a normal amount of Th2 cells. Moreover, the skewed helper cell responses correlate with a higher percentage of monocytes capable of secreting the Th1 promoting cytokine interleukin 12 (IL-12). CONCLUSIONS Our findings contribute to a better understanding of the pathogenesis of impaired cellular immune functions in dialysis patients and, in particular, the decreased antibody production after vaccination. They provide a link between overproduction of pro-inflammatory cytokines (IL-12) and imbalanced T-cell activation.
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Affiliation(s)
- U Sester
- Medical Department IV, Nephrology, University Homburg, Homburg, Germany
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