|
1
|
Pașatu‑Cornea AM, Ciciu E, Tuță LA. Perforin: An intriguing protein in allograft rejection immunology (Review). Exp Ther Med 2022; 24:519. [DOI: 10.3892/etm.2022.11446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/05/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
| | - Elena Ciciu
- Department of Nephrology, Constanta County Emergency Hospital, 900591 Constanta, Romania
| | - Liliana-Ana Tuță
- Department of Nephrology, Constanta County Emergency Hospital, 900591 Constanta, Romania
| |
Collapse
|
|
2
|
Fadel F, Shouman MG, Ibrahim AA, Wahby AA, Awadallah E, Abdel Mawla MA, Selim A, Salah DM. Perforin A and granzyme B as non invasive markers in early acute rejection in pediatric renal transplantation. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
3
|
Shaw BI, Cheng DK, Acharya CR, Ettenger RB, Lyerly HK, Cheng Q, Kirk AD, Chambers ET. An age-independent gene signature for monitoring acute rejection in kidney transplantation. Theranostics 2020; 10:6977-6986. [PMID: 32550916 PMCID: PMC7295062 DOI: 10.7150/thno.42110] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
Collapse
Affiliation(s)
- Brian I Shaw
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Daniel K. Cheng
- Department of Pediatrics, Duke University Medical Center, Durham, United States
| | | | - Robert B Ettenger
- Department of Pediatrics, UCLA Mattel Children's Hospital, Los Angeles, United States
| | - Herbert Kim Lyerly
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Qing Cheng
- Department of Surgery, Duke University Medical Center, Durham, United States
| | - Allan D Kirk
- Department of Surgery, Duke University Medical Center, Durham, United States
- Department of Pediatrics, Duke University Medical Center, Durham, United States
| | - Eileen T Chambers
- Department of Surgery, Duke University Medical Center, Durham, United States
- Department of Pediatrics, Duke University Medical Center, Durham, United States
| |
Collapse
|
|
4
|
Meng H, Liang Y, Hao J, Lu J. Comparison of Rejection-Specific Genes in Peripheral Blood and Allograft Biopsy From Kidney Transplant. Transplant Proc 2018; 50:115-123. [PMID: 29407293 DOI: 10.1016/j.transproceed.2017.11.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 11/03/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Although improved understanding and assessment of organ rejection significantly contribute to long-term allograft survival after kidney transplantation, reliable and predictive biomarkers that enable diagnoses of rejection state are lacking. Patient rejection of a kidney graft displays a specific blood and biopsy transcriptional pattern, raising the question of whether transcript biomarkers in blood could reflect events within the allograft. METHODS Differential expression genes were screened on large-scale transcriptomic data from blood and allograft biopsies, which included recipients undergoing rejection and recipients with stable renal function. RESULTS We found that the number of rejection-related genes in biopsy samples was much greater than in blood. We observed only one overlapping gene, HIST1H4A, consistently expressed in biopsy samples and blood. Functional association of the identified genes in biopsies implicated a strong involvement of inflammatory-immune pathways. Rejection-related genes in the mammalian target of rapamycin-signaling pathway were down-regulated, and genes related to allograft rejection and graft-versus-host disease were up-regulated in allograft biopsy samples. We also recognized the core signaling elements (PIK3R2 and EGFR) in inflammatory-immune pathways based on biopsy samples. CONCLUSIONS We have expanded our understanding of rejection-specific gene expression pattern in allograft biopsy and peripheral blood, and provided a candidate set of overlapping genes for screening of rejection in kidney transplant recipients.
Collapse
Affiliation(s)
- H Meng
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Y Liang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - J Hao
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - J Lu
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
| |
Collapse
|
|
5
|
Salcido-Ochoa F, Hue SSS, Peng S, Fan Z, Li RL, Iqbal J, Allen Jr JC, Loh AHL. Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant. World J Transplant 2017; 7:222-234. [PMID: 28900605 PMCID: PMC5573898 DOI: 10.5500/wjt.v7.i4.222] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/21/2017] [Accepted: 07/03/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes.
METHODS A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively.
RESULTS In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss.
CONCLUSION Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.
Collapse
Affiliation(s)
- Francisco Salcido-Ochoa
- Tregs and HLA Research Force and Renal Medicine Department, Singapore General Hospital, Singapore 169856, Singapore
| | - Susan Swee-Shan Hue
- Tregs and HLA Research Force and Department of Pathology, National University Hospital, Singapore 119074, Singapore
| | - Siyu Peng
- Tregs and HLA Research Force and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Zhaoxiang Fan
- Tregs and HLA Research Force and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Reiko Lixiang Li
- Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
| | - Jabed Iqbal
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore,
| | - John Carson Allen Jr
- Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore 169856, Singapore
| | - Alwin Hwai Liang Loh
- Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore,
| |
Collapse
|
|
6
|
Jacquemont L, Soulillou JP, Degauque N. Blood biomarkers of kidney transplant rejection, an endless search? Expert Rev Mol Diagn 2017; 17:687-697. [PMID: 28571481 DOI: 10.1080/14737159.2017.1337512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION The tailoring of immunosuppressive treatment is recognized as a promising strategy to improve long-term kidney graft outcome. To guide the standard care of transplant recipients, physicians need objective biomarkers that can identify an ongoing pathology with the graft or low intensity signals that will be later evolved to accelerated transplant rejection. The early identification of 'high-risk /low-risk' patients enables the adjustment of standard of caring, including managing the frequency of clinical visits and the immunosuppression dosing. Given their ease of availability and the compatibility with a large technical array, blood-based biomarkers have been widely scrutinized for use as potential predictive and diagnostic biomarkers. Areas covered: Here, the authors report on non-invasive biomarkers, such as modification of immune cell subsets and mRNA and miRNA profiles, identified in the blood of kidney transplant recipients collected before or after transplantation. Expert commentary: Combined with functional tests, the identification of biomarkers will improve our understanding of pathological processes and will contribute to a global improvement in clinical management.
Collapse
Affiliation(s)
- Lola Jacquemont
- a Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM , Université de Nantes , Nantes , France.,b Institut de Transplantation Urologie Néphrologie (ITUN) , CHU Nantes , Nantes , France
| | - Jean-Paul Soulillou
- a Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM , Université de Nantes , Nantes , France.,b Institut de Transplantation Urologie Néphrologie (ITUN) , CHU Nantes , Nantes , France
| | - Nicolas Degauque
- a Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM , Université de Nantes , Nantes , France.,b Institut de Transplantation Urologie Néphrologie (ITUN) , CHU Nantes , Nantes , France.,c LabEx IGO , "Immunotherapy, Graft, Oncology" , Nantes , France
| |
Collapse
|
|
7
|
Jung HY, Kim YJ, Choi JY, Cho JH, Park SH, Kim YL, Kim HK, Huh S, Won DI, Kim CD. Increased Circulating T Lymphocytes Expressing HLA-DR in Kidney Transplant Recipients with Microcirculation Inflammation. J Korean Med Sci 2017; 32:908-918. [PMID: 28480647 PMCID: PMC5426246 DOI: 10.3346/jkms.2017.32.6.908] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/19/2017] [Indexed: 01/27/2023] Open
Abstract
We consecutively enrolled 82 kidney transplant recipients (KTRs) with stable renal function and 24 KTRs who underwent indication biopsy to compare the histological grading of renal allografts with the activity of circulating T lymphocyte subsets and monocytes determined by flow cytometry, which were obtained at 2 weeks after kidney transplantation (KT) and at the time of indication biopsy, respectively. The sum of the scores of glomerulitis (g) + peritubular capillaritis (ptc), inflammation (i) + tubulitis (t), interstitial fibrosis (ci) + tubular atrophy (ct), and fibrointimal thickening (cv) + arteriolar hyaline thickening (ah) was used to assign a histological grade to the renal allograft samples. The frequencies of CD4⁺HLA-DR⁺/CD4⁺ T cells and CD8⁺HLA-DR⁺/CD8⁺ T cells were significantly increased in KTRs with a microcirculation inflammation (MI) sum score ≥ 1 when compared with KTRs with an MI sum score = 0 as well as stable KTRs. In these 2 subsets, only CD4⁺HLA-DR⁺/CD4⁺ T cells were positively correlated with MI sum scores. Analysis using the receiver operating characteristic (ROC) curve showed that antibody-mediated rejection (AMR) could be predicted with a sensitivity of 80.0% and a specificity of 94.7%, using a cutoff value of 29.6% frequency of CD4⁺HLA-DR⁺/CD4⁺ T cells. MI was significantly associated with an increased frequency of activated T lymphocytes expressing human leukocyte antigen-antigen D related (HLA-DR). Further studies should focus on validating the utility of circulating CD4⁺HLA-DR⁺/CD4⁺ T cells as a noninvasive, immunologic monitoring tool for the prediction of AMR.
Collapse
Affiliation(s)
- Hee Yeon Jung
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Yong Jin Kim
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ji Young Choi
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jang Hee Cho
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Sun Hee Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Yong Lim Kim
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Hyung Kee Kim
- Department of Surgery, Kyungpook National University School of Medicine, Daegu, Korea
| | - Seung Huh
- Department of Surgery, Kyungpook National University School of Medicine, Daegu, Korea
| | - Dong Il Won
- Department of Clinical Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Chan Duck Kim
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
| |
Collapse
|
|
8
|
Heng B, Ding H, Ren H, Shi L, Chen J, Wu X, Lai C, Yu G, Xu Y, Su Z. Diagnostic Performance of Fas Ligand mRNA Expression for Acute Rejection after Kidney Transplantation: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0165628. [PMID: 27812144 PMCID: PMC5094747 DOI: 10.1371/journal.pone.0165628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 10/15/2016] [Indexed: 01/25/2023] Open
Abstract
Background The value of Fas ligand (FASL) as a diagnostic immune marker for acute renal rejection is controversial; this meta-analysis aimed to clarify the role of FASL in acute renal rejection. Methods The relevant literature was included by systematic searching the MEDLINE, EMBASE, and Cochrane Library databases. Accuracy data for acute rejection (AR) and potential confounding variables (the year of publication, area, sample source, quantitative techniques, housekeeping genes, fluorescence staining, sample collection time post-renal transplantation, and clinical classification of AR) were extracted after carefully reviewing the studies. Data were analyzed by Meta-DiSc 1.4, RevMan 5.0, and the Midas module in Stata 11.0 software. Results Twelve relevant studies involving 496 subjects were included. The overall pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio, together with the 95% CI were 0.64 (0.57–0.70), 0.90 (0.85–0.93), 5.66 (3.51–9.11), 0.30 (0.16–0.54), and 30.63 (14.67–63.92), respectively. The area under the summary receiver operating characteristic curve (AUC) was 0.9389. Fagan’s nomogram showed that the probability of AR episodes in the kidney transplant recipient increased from 15% to 69% when FASL was positive, and was reduced to 4% when FASL was negative. No threshold effect, sensitivity analyses, meta-regression, and subgroup analyses based on the potential variables had a significant statistical change for heterogeneity. Conclusions Current evidence suggests the diagnostic potential for FASL mRNA detection as a reliable immune marker for AR in renal allograft recipients. Further large, multicenter, prospective studies are needed to validate the power of this test marker in the non-invasive diagnosis of AR after renal transplantation.
Collapse
Affiliation(s)
- Baoli Heng
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Hongwen Ding
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Haolin Ren
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liping Shi
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jie Chen
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xun Wu
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Caiyong Lai
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ganshen Yu
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yin Xu
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zexuan Su
- Department of Urology, the First Affiliated Hospital of Jinan University, Guangzhou, China
- * E-mail:
| |
Collapse
|
|
9
|
Oghumu S, Nori U, Bracewell A, Zhang J, Bott C, Nadasdy GM, Brodsky SV, Pelletier R, Satoskar AR, Nadasdy T, Satoskar AA. Differential gene expression pattern in biopsies with renal allograft pyelonephritis and allograft rejection. Clin Transplant 2016; 30:1115-1133. [PMID: 27352120 PMCID: PMC5256948 DOI: 10.1111/ctr.12795] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2016] [Indexed: 02/02/2023]
Abstract
Differentiating acute pyelonephritis (APN) from acute rejection (AR) in renal allograft biopsies can sometimes be difficult because of overlapping clinical and histologic features, lack of positive urine cultures,and variable response to antibiotics. We wanted to study differential gene expression between AR and APN using biopsy tissue. Thirty-three biopsies were analyzed using NanoString multiplex platform and PCR (6 transplant baseline biopsies, 8 AR, 15 APN [8 culture positive, 7 culture negative], and 4 native pyelonephritis [NP]). Additional 22 biopsies were tested by PCR to validate the results. CXCL9, CXCL10, CXCL11, and IDO1 were the top differentially expressed genes, upregulated in AR. Lactoferrin (LTF) and CXCL1 were higher in APN and NP. No statistically significant difference in transcript levels was seen between culture-positive and culture-negative APN biopsies. Comparing the overall mRNA signature using Ingenuity pathway analysis, interferon-gamma emerged as the dominant upstream regulator in AR and allograft APN, but not in NP (which clustered separately). Our study suggests that chemokine pathways in graft APN may differ from NP and in fact resemble AR, due to a component of alloreactivity, resulting in variable response to antibiotic treatment. Therefore, cautious addition of steroids might help in resistant cases of graft APN.
Collapse
Affiliation(s)
- Steve Oghumu
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Uday Nori
- Nephrology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Anna Bracewell
- Nephrology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jianying Zhang
- Department of Biostatistics, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Cherri Bott
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Gyongyi M Nadasdy
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sergey V Brodsky
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ronald Pelletier
- Department of Surgery, Comprehensive Transplant Center, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Abhay R Satoskar
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Tibor Nadasdy
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Anjali A Satoskar
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA.
| |
Collapse
|
|
10
|
A Meta-analysis of the Significance of Granzyme B and Perforin in Noninvasive Diagnosis of Acute Rejection After Kidney Transplantation. Transplantation 2016; 99:1477-86. [PMID: 25643139 DOI: 10.1097/tp.0000000000000567] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Previous studies have reported that granzyme B (GZMB) and perforin (PRF) could serve as noninvasive biomarkers in the diagnosis of acute rejection (AR) after kidney transplant. Yet, their noninvasive diagnostic value in clinical practice is still unknown. METHODS To assess the noninvasive diagnostic performance of GZMB and PRF for AR, we performed a systematic search. After reviewing published studies in which both GZMB and PRF were detected, data on the diagnostic accuracy of separate and combined evaluation of GZMB and PRF were pooled. RESULTS Across 16 studies (680 subjects), summary sensitivity, specificity, positive likelihood ratios, and negative likelihood ratios with 95% confidence intervals were calculated. For overall GZMB analysis, the indices were 0.76 (0.71-0.81), 0.86 (0.82-0.89), 4.58 (3.36-6.25), and 0.32 (0.22-0.47), respectively. For overall PRF analysis, the indices were 0.83 (0.78-0.88), 0.86 (0.82-0.89), 4.82 (3.66-6.35), and 0.26 (0.18-0.37), respectively. Subgroup analyses showed similar results compared to overall study analyses. In analyses of combined evaluation of GZMB and PRF, the above indices were 0.65 (0.53-0.76), 0.96 (0.91-0.98), 12.66 (5.83-27.50), and 0.40 (0.23-0.69), respectively, when both markers were positive. The probability of developing AR in kidney transplant recipients increased from 15% to 73% when both GZMB and PRF tests were positive and was reduced to 2% if that were negative. CONCLUSIONS Currently, neither GZMB nor PRF, if evaluated alone, could be a convincing noninvasive diagnostic marker for AR in clinical practice. Combined use of PRF and GZMB post-kidney transplant may be a better choice in AR evaluation to direct allograft biopsy execution and earlier therapeutic intervention.
Collapse
|
|
11
|
Fadel FI, Elshamaa MF, Salah A, Nabhan M, Rasheed M, Kamel S, Kandil D, Thabet EH. Fas/Fas Ligand pathways gene polymorphisms in pediatric renal allograft rejection. Transpl Immunol 2016; 37:28-34. [PMID: 27109035 DOI: 10.1016/j.trim.2016.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 03/28/2016] [Accepted: 04/20/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND An essential milestone in pediatric transplantation is to find noninvasive biomarkers to monitor acute rejection (AR). In this retrospective (Case-control) study, we examined the role of Fas -670A/G and Fas Ligand (FasL) -843C/T gene polymorphisms in allograft nephropathy in pediatric renal transplant recipients. METHODS In 47 pediatric kidney transplant recipients and 20 healthy controls, Fas -670A/G and FasL -843C/T gene polymorphisms as well as serum soluble Fas Ligand level (sFasL) were measured. RESULTS Serum sFasL levels were significantly higher in transplant recipients children than that in controls (548.25±298.64pg/ml vs 143.17±44.55pg/ml, p=0.0001). There was no significant difference between patients with AR and those without AR in regards to serum sFasL levels (567.70±279.87pg/ml vs 507.85±342.80pg/ml, p=0.56). Fas -670A/G genotypes or alleles were not significantly different between controls and transplant recipients and among transplant recipients with and without AR. (P>0.05 for all). FasL -843C/T genotypes were not different between transplant recipients and controls and among transplant recipients with and without AR (P>0.05 for all). However, Frequency of C allele in transplant patients was significantly higher than that in the control group (44.68% vs 25%, P=0.03). FasL -843C/T alleles were significantly different between patients with and without AR (P=0.03). The percentages of C allele were higher in children with AR (58.82% vs 36.67%). We found that serum FasL and serum creatinine were variables that were independently associated with AR. CONCLUSION This study suggests that FasL gene polymorphisms in peripheral blood might be accurate in detecting cellular AR.
Collapse
Affiliation(s)
- Fatina I Fadel
- Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | | | - Ahmed Salah
- Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Marwa Nabhan
- Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Maha Rasheed
- Clinical & Chemical Pathology Department, National Research Centre, Cairo, Egypt.
| | - Solaf Kamel
- Clinical & Chemical Pathology Department, National Research Centre, Cairo, Egypt.
| | - Dina Kandil
- Clinical & Chemical Pathology Department, National Research Centre, Cairo, Egypt.
| | - Eman H Thabet
- Clinical & Chemical Pathology Department, National Research Centre, Cairo, Egypt
| |
Collapse
|
|
12
|
Abstract
The immune management of organ transplant recipients is imperfect. Beyond general dosing guidelines for immunosuppressive agents and clinical diagnostic tests for rejection or infection, there are few objective tools to determine the aggregate status of a patient's alloimmune response or protective immune capacity. The lack of prognostic precision significantly contributes to patient morbidity and reduces long-term allograft survival after kidney transplantation. Noninvasive biomarkers that could serve as predictive tools or surrogate end points for rejection might help clinicians individualize immunosuppression and allow for early intervention, ideally prior to clinically evident organ dysfunction. Although the growing understanding of organ rejection has provided numerous candidate biomarkers, none has been confirmed in robust validation studies as sufficiently useful to guide clinical practice independent of traditional clinical methods. In this Review, the general characteristics of biomarkers and surrogate end points; current biomarkers under active clinical investigation; and the prominent barriers to the translation of biomarkers into clinical practice are discussed.
Collapse
Affiliation(s)
- Denise J Lo
- Emory Transplant Center, Emory University, 101 Woodruff Circle, #5105-WMB, Atlanta, GA 30322, USA
| | - Bruce Kaplan
- University of Kansas Medical Center, Center for Transplantation, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Allan D Kirk
- Emory Transplant Center, Emory University, 101 Woodruff Circle, #5105-WMB, Atlanta, GA 30322, USA
| |
Collapse
|
|
13
|
Relationship Between Ischemia/Reperfusion Injury and Acute Rejection of Allogeneic Liver Transplant in Rats. Transplant Proc 2014; 46:50-5. [DOI: 10.1016/j.transproceed.2013.06.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 05/05/2013] [Accepted: 06/18/2013] [Indexed: 12/26/2022]
|
|
14
|
Immunologic monitoring in kidney transplant recipients. Kidney Res Clin Pract 2013; 32:52-61. [PMID: 26877913 PMCID: PMC4713911 DOI: 10.1016/j.krcp.2013.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 01/10/2013] [Indexed: 01/07/2023] Open
Abstract
Transplant biopsy has always been the gold standard for assessing the immune response to a kidney allograft (Chandraker A: Diagnostic techniques in the work-up of renal allograft dysfunction-an update. Curr Opin Nephrol Hypertens 8:723-728, 1999). A biopsy is not without risk and is unable to predict rejection and is only diagnostic once rejection has already occurred. However, in the past two decades, we have seen an expansion in assays that can potentially put an end to the "drug level" era, which until now has been one of the few tools available to clinicians for monitoring the immune response. A better understanding of the mechanisms of rejection and tolerance, and technological advances has led to the development of new noninvasive methods to monitor the immune response. In this article, we discuss these new methods and their potential uses in renal transplant recipients.
Collapse
|
|
15
|
Sequential monitoring of TIM-3 gene expression in peripheral blood for diagnostic and prognostic evaluation of acute rejection in renal graft recipients. Transplant Proc 2012; 43:3669-74. [PMID: 22172823 DOI: 10.1016/j.transproceed.2011.08.106] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 02/07/2011] [Accepted: 08/19/2011] [Indexed: 11/20/2022]
Abstract
BACKGROUND TIM-3 is expressed on primary T effector cells, including th1, ctl, and Th17, which play essential roles in acute allograft rejection (AR). In this study we monitored sequential changes of TIM-3 gene expression among peripheral blood leukocytes (PBL) from renal transplant recipients. METHODS The study consisted of an AR group (n=24), a no AR group (n=20), and a stable group (n=18). Prospective serial blood samples were collected after allotransplantation and during AR episodes. The mRNA encoding for TIM-3 was quantified using real-time reverse-transcription polymerase chain reaction (RT-PCR). Statistical analyses were performed to correlate gene transcript measurements with clinical events. RESULTS TIM-3 mRNA in PBL showed significantly higher expression in the AR compared with the no AR and stable groups: 286.72±86.28 vs 126.10±28.31 vs 96.91±17.88, respectively (P=.00). The receiver operating characteristic curve showed a specificity of 100% and a sensitivity of 87.5% for the utility of TIM-3 for rejection diagnosis. Antirejection therapy decreased TIM-3 mRNA expression in all AR patients. There was a positive correlation between TIM-3 mRNA expression and serum creatinine (r2=0.716; P=.00). CONCLUSIONS TIM-3 mRNA quantification by RT-PCR in PBL may be a promising tool for a noninvasive diagnosis of AR. But the utility for predicting the prognosis of AR after antirejection treatment was limited, owing to the great variations of TIM-3 mRNA expression during AR episodes.
Collapse
|
|
16
|
TING YITIAN, COATES PTOBY, WALKER ROBERTJ, MCLELLAN ALEXANDERD. Urinary tubular biomarkers as potential early predictors of renal allograft rejection. Nephrology (Carlton) 2011; 17:11-6. [DOI: 10.1111/j.1440-1797.2011.01536.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
|
17
|
Yu Y, Miller J, Leventhal JR, Tambur AR, Chandrasekaran D, Levitsky J, Luo X, Mathew JM. Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR. PLoS One 2011; 6:e22450. [PMID: 21799858 PMCID: PMC3142165 DOI: 10.1371/journal.pone.0022450] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Accepted: 06/22/2011] [Indexed: 11/27/2022] Open
Abstract
Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4+ Tregs on CD8+ cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4+CD127−CD25+FOXP3+ Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechanisms were then tested using modified 51Chromium release assays (Micro-CML), MLRs and CFSE-based multi-fluorochrome flow cytometry proliferation assays. It was observed that increased numbers of CD4+CD127−CD25+FOXP3+ cells were generated after a 7 day MLR. After immunoselection for CD4+CD127−CD25+ cells, they were designated as MLR-Tregs. When added as third component modulators, MLR-Tregs inhibited the alloreactive proliferation of autologous PBMC in a concentration dependent manner. The inhibition was quasi-antigen specific, in that the inhibition was non-specific at higher MLR-Treg modulator doses, but non-specificity disappeared with lower numbers at which specific inhibition was still significant. When tested in micro-CML assays CTL inhibition occurred with PBMC and purified CD8+ responders. However, antigen specificity of CTL inhibition was observed only with unpurified PBMC responders and not with purified CD8+ responders or even with CD8+ responders plus Non-T “APC”. However, allospecificity of CTL regulation was restored when autologous purified CD4+ T cells were added to the CD8+ responders. Proliferation of CD8+ cells was suppressed by MLR-Tregs in the presence or absence of IL-2. Inhibition by MLR-Tregs was mediated through down-regulation of intracellular perforin, granzyme B and membrane-bound CD25 molecules on the responding CD8+ cells. Therefore, it was concluded that human CD4+CD127−CD25+FOXP3+ MLR-Tregs down-regulate alloreactive cytotoxic responses. Regulatory allospecificity, however, requires the presence of cognate responding CD4+ T cells. CD8+ CTL regulatory mechanisms include impaired proliferation, reduced expression of cytolytic molecules and CD25+ activation epitopes.
Collapse
Affiliation(s)
- Yuming Yu
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Joshua Miller
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Jesse Brown VA Medical Center, Chicago, Illinois, United States of America
| | - Joseph R. Leventhal
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Anat R. Tambur
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Dhivya Chandrasekaran
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Josh Levitsky
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Division of Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Xunrong Luo
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - James M. Mathew
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- Jesse Brown VA Medical Center, Chicago, Illinois, United States of America
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- * E-mail:
| |
Collapse
|
|
18
|
Heidt S, San Segundo D, Shankar S, Mittal S, Muthusamy ASR, Friend PJ, Fuggle SV, Wood KJ. Peripheral blood sampling for the detection of allograft rejection: biomarker identification and validation. Transplantation 2011; 92:1-9. [PMID: 21494177 DOI: 10.1097/tp.0b013e318218e978] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.
Collapse
Affiliation(s)
- Sebastiaan Heidt
- Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Roedder S, Vitalone M, Khatri P, Sarwal MM. Biomarkers in solid organ transplantation: establishing personalized transplantation medicine. Genome Med 2011; 3:37. [PMID: 21658299 PMCID: PMC3218811 DOI: 10.1186/gm253] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay.
Collapse
Affiliation(s)
- Silke Roedder
- Department of Pediatrics and Immunology, Stanford University, G306 300 Pasteur Drive, Palo Alto, CA 94304, USA.
| | | | | | | |
Collapse
|
|
20
|
Asaoka T, Island ER, Tryphonopoulos P, Selvaggi G, Moon J, Tekin A, Amador A, Levi DM, Garcia J, Smith L, Nishida S, Weppler D, Tzakis AG, Ruiz P. Characteristic immune, apoptosis and inflammatory gene profiles associated with intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies. Transpl Int 2011; 24:697-707. [DOI: 10.1111/j.1432-2277.2011.01259.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
|
|
21
|
Grimbert P, Audard V, Diet C, Matignon M, Plonquet A, Mansour H, Desvaux D, Durrbach A, Cohen JL, Lang P. T-cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept-mediated co-stimulatory blockade. Nephrol Dial Transplant 2010; 26:1087-93. [PMID: 20667993 DOI: 10.1093/ndt/gfq453] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Belatacept is thought to disrupt the interaction between CD80/86 and CD28, thus preventing T-cell activation by blocking the co-stimulatory second signal. However, the consequences on the T-cell profile in human renal transplant cases have not been determined. METHODS In this study, we analysed intra-graft levels of the mRNAs for Treg (FOXP3), cytotoxic CD8 T cells (Granzyme B), Th1 (INFγ, Tbet), Th2 (GATA3) and Th17 (RORγt and IL-17) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with Belatacept or calcineurin inhibitor (CNI). RESULTS Only the intra-graft abundance of FOXP3 mRNA was significantly lower (P < 0.001) in the Belatacept group than the CNI group. Conclusions. These results are in agreement with in vitro data suggesting that CD28 is a major co-stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1-year graft function and a lower incidence of chronic allograft nephropathy in patients receiving Belatacept than patients treated with CNI. They suggest that immune benefits induced by Belatacept are not mediated by Treg expansion and that FOXP3 is not by itself a prognostic marker of long-term graft function in a non-inflammatory context. These results have to be, however, considered as preliminary since the size of our study population is limited.
Collapse
Affiliation(s)
- Philippe Grimbert
- Department of Nephrology and Transplantation, Institut Mondor de Recherche Biomédicale INSERM U955, CHU Henri Mondor and Université Paris XII, Association pour l’Utilisation du Rein Artificiel, Créteil, France.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Abstract
Identifying surrogate markers of renal allograft outcome and biomarkers of acute and chronic graft injury is a critical issue for the transplant community. Measurement of serum creatinine and biopsy remain the current gold standards for the evaluation of renal allografts. These tests have significant limitations in predicting which patients are destined for immune tolerance or immune-mediated graft loss, and aiding in the management of long-term immunosuppression. The goal of biomarkers is to diagnose rejection early, determine prognosis and tailor immunosuppressive therapy in a noninvasive, cost-effective manner. Biomarker research has focused on primary areas of kidney injury, the tubules and the cells that infiltrate them. This article reviews biomarkers currently under investigation in the setting of renal allograft transplantation.
Collapse
Affiliation(s)
- Avrum Gillespie
- Temple University School of Medicine, Nephrology & Kidney Transplantation, 3322 North Broad Street, MOB, 1st Floor, Philadelphia, PA 19140, USA
| | | |
Collapse
|
|
23
|
Abstract
PURPOSE OF REVIEW Acute rejection is an immune process that begins with the recognition of the allograft as nonself and ends in graft destruction. Histological features of the allograft biopsy are currently used for the differential diagnosis of allograft dysfunction. In view of the safety and the opportunity for repetitive sampling, development of noninvasive biomarkers of allograft status is an important objective in transplantation. Herein, we review some of the progress towards the development of noninvasive biomarkers of human allograft status. RECENT FINDINGS Urinary cell and peripheral blood cell mRNA profiles have been associated with acute rejection of human renal allografts. Emerging data support the idea that development of noninvasive biomarkers predictive of antibody-mediated rejection is feasible. The demonstration that intragraft microRNA expression predicts renal allograft status suggests that noninvasively ascertained microRNA profiles may be of value. SUMMARY We are pleased with the progress to date, and anticipate clinical trials investigating the hypotheses that noninvasively ascertained mRNA profiles will minimize the need for invasive biopsy procedures, predict the development of acute rejection and chronic allograft nephropathy, facilitate preemptive therapy capable of preserving graft function, and facilitate personalization of immunosuppressive therapy for the allograft recipient.
Collapse
|
|
24
|
Lymphocyte markers and prediction of long-term renal allograft acceptance. Curr Opin Nephrol Hypertens 2009; 18:489-94. [DOI: 10.1097/mnh.0b013e3283318f82] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
25
|
Øzbay A, Tørring C, Olsen R, Carstens J. Transcriptional Profiles in Urine During Acute Rejection, Bacteriuria, CMV Infection and Stable Graft Function After Renal Transplantation. Scand J Immunol 2009; 69:357-65. [DOI: 10.1111/j.1365-3083.2009.02226.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
26
|
Noninvasive prediction of organ graft rejection and outcome using gene expression patterns. Transplantation 2008; 86:192-9. [PMID: 18645476 DOI: 10.1097/tp.0b013e31817eef7b] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Development of predictive, diagnostic, and prognostic biomarkers of allograft status and outcome is important and challenging, and may be rewarded with individualized therapy for the organ graft recipient. Herein, we summarize noninvasive messenger RNA profiling studies for ascertaining allograft status and outcome. Nucleic acid-based biomarkers of allograft status have been developed by several laboratories, but the studies have primarily been single center investigations. Ongoing multicenter trials including the Clinical Trials in Organ Transplantation (https://www.ctotstudies.org) should help further to define the clinical utility of noninvasively developed messenger RNA profiles as biomarkers of allograft status and outcome.
Collapse
|
|
27
|
Abstract
PURPOSE OF REVIEW Chronic injury and late allograft loss remain major causes of morbidity in clinical transplantation. Biomarkers that can reliably assess the risk of posttransplant complications are required to direct and individualize therapy aimed at prolonging graft survival and improving patient health. The purpose of this review is to provide a framework for understanding how to use biomarkers in the context of clinical transplantation and to summarize current data on available noninvasive cellular-based immune monitoring methods to predict transplant outcome. RECENT FINDINGS New microarray and gene profiling data reveal peripheral blood cell gene expression patterns that identify operational tolerance, raising the possibility that the measurements can be used to direct immunosuppression withdrawal. Additional data support the use of selective urine gene products and soluble CD30 measurements in serum as reliable biomarkers of acute graft injury. Finally, recent studies demonstrate that measurement of T-cell alloimmunity by cytokine enzyme-linked immunospot is a promising, supplementary pretransplant risk assessment tool. SUMMARY Recently published studies in organ transplantation suggest that results derived from assays focused on markers of T-cell immunity can segregate transplant candidates or recipients into high and low-risk subgroups for posttransplant graft injury. Larger prospective studies are needed, however, before any proposed biomarker can be incorporated into the transplant physicians' armamentarium to guide individualized therapeutic decision-making.
Collapse
Affiliation(s)
- Rajani Dinavahi
- Mount Sinai School of Medicine, Division of Nephrology Recanati Miller Transplantation Institute, Immunology Institute New York, New York, USA
| | | |
Collapse
|
|
28
|
Truong DQ, Cornet A, Wieërs G, Robert A, Reding R, Latinne D. Pre- and post-transplant monitoring of granzyme B enzyme-linked immunosorbent spot assay in pediatric liver recipients. Transpl Immunol 2008; 19:215-9. [PMID: 18602007 DOI: 10.1016/j.trim.2008.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2008] [Revised: 06/03/2008] [Accepted: 06/09/2008] [Indexed: 01/12/2023]
Abstract
UNLABELLED This study aims to investigate potential role of granzyme B enzyme-linked immunosorbent spot (GrB ELISPOT) for immunological monitoring in pediatric liver transplantation. PATIENTS AND METHODS Peripheral blood mononuclear cells from 28 pediatric recipients were serially tested for GrB-producing donor-reactive cells at day 0 pre-transplantation (baseline) and days 7, 14, and 28 post-transplantation. RESULTS At baseline, no difference of GrB value was found in acute rejection (14/28) compared to normal graft function patients (day 0: 4(3.9) spots versus 5(2.9) spots, respectively: p=0.65). At day 7 post-transplantation, acute rejection patients showed frequencies of GrB ELISPOT higher than those with normal graft function, but the differences observed were not statistically significant (day 7: 15(4.9) spots versus 10(4.0) spots, respectively: p=0.55). GrB increased significantly at day 7 from baseline in the rejection group (15(4.9) spots versus 4(3.9), respectively p=0.04), whereas corresponding changes were not significant in the group without rejection (10(4.0) versus 5(2.9), respectively: p=0.15). CONCLUSION GrB ELISPOT pre-transplantation could not predict the occurrence of early post-transplant acute rejection; similarly frequencies at days 7, 14 and 28 could not be correlated with acute rejection in pediatric liver recipients. However, a kinetic study of GrB ELISPOT could be helpful to predict or confirm early rejection in the small group of liver allograft recipients analyzed in this study.
Collapse
Affiliation(s)
- Dinh Quang Truong
- Pediatric Liver Transplant Program, Saint-Luc University Clinics, Université catholique de Louvain, Brussels, Belgium
| | | | | | | | | | | |
Collapse
|
|
29
|
Aquino-Dias EC, Joelsons G, da Silva DM, Berdichevski RH, Berdichewski RH, Ribeiro AR, Veronese FJV, Veronose FJV, Gonçalves LF, Manfro RC. Non-invasive diagnosis of acute rejection in kidney transplants with delayed graft function. Kidney Int 2008; 73:877-84. [PMID: 18216781 DOI: 10.1038/sj.ki.5002795] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Delayed graft function (DGF) often occurs in kidney transplants from deceased donors. We wanted to provide studies giving more accurate non-invasive tests for acute rejection (AR). Using real-time PCR, we examined the expression of cytolytic molecules such as perforin, granzyme B, and fas-ligand along with serpin proteinase inhibitor-9. We also measured the expression of FOXP3, a characteristic gene of T-regulatory cells known to be involved in AR. These studies were conducted on peripheral blood monocytes, urinary cells, and 48 surveillance kidney biopsies taken from a total of 35 patients with DGF. Of these patients, 20 had a histopathological diagnosis of AR, whereas other 28 had characteristics of acute tubular necrosis (ATN). Expression of cytolytic and apoptotic-associated genes in the biopsy tissue, peripheral blood leukocytes, and urinary cells was significantly higher in patients with AR than that in patients with ATN. Diagnostic parameters associated with FOXP3 gene expression were most accurate in peripheral blood leukocytes and urine cells with sensitivity, specificity, positive and negative predictive values, and accuracy between 94 and 100%. Our study shows that quantification of selected genes in peripheral blood leukocytes and urinary cells from renal transplant patients with DGF may provide a useful and accurate non-invasive diagnosis of AR.
Collapse
Affiliation(s)
- E C Aquino-Dias
- Post-Graduate Medical Sciences-Nephrology Program, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Alakulppi NS, Kyllönen LE, Partanen J, Salmela KT, Laine JT. Diagnosis of Acute Renal Allograft Rejection by Analyzing Whole Blood mRNA Expression of Lymphocyte Marker Molecules. Transplantation 2007; 83:791-8. [PMID: 17414714 DOI: 10.1097/01.tp.0000258726.13363.ab] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Currently, the diagnosis of acute rejection after kidney transplantation is based on a kidney biopsy taken after clinical rejection suspicion. A robust, noninvasive diagnostic method would allow easier and more frequent monitoring of the patient and the graft. Potentially, a straightforward method would be the analysis of lymphocyte marker molecule expression from whole blood samples. METHODS Whole blood samples were collected prospectively in a single kidney transplantation center from 50 adult kidney recipients transplanted between 2001 and 2005. The mRNA expression of granzyme B, perforin, FasL, granulysin, CD154, ICOS, CTLA4 and PD-1 were analyzed with real-time quantitative polymerase chain reaction. RESULTS The expression of ICOS and CD154 were significantly lower in rejection patients than in control patients (P<0.001). Both genes gave statistically significant area under receiver operating characteristic curve (AUC; 0.87, 0.88) with 84% sensitivity and 100% specificity for CD154 and 76% and 86% for ICOS, respectively. In paired rejection and postrejection therapy samples, the expression of both genes significantly increased during rejection therapy (P<0.001). When rejection patients were compared to patients biopsied because of other reasons of graft dysfunction, both CD154 and ICOS were lower in rejection patients but only CD154 was statistically significant (P=0.028, AUC=0.740, sensitivity 52%, specificity 90%). The other studied genes gave no consistent statistically significant results. CONCLUSIONS The whole blood gene expression quantities of costimulatory molecules CD154 and ICOS reasonably robustly differentiated rejection patients from control patients. The clinical use of the analysis is limited by poor capability to differentiate patients with rejection from patients with other causes of graft dysfunction.
Collapse
MESH Headings
- Adolescent
- Adult
- Aged
- Antigens, CD/blood
- Antigens, CD/genetics
- Antigens, Differentiation/blood
- Antigens, Differentiation/genetics
- Antigens, Differentiation, T-Lymphocyte/blood
- Antigens, Differentiation, T-Lymphocyte/genetics
- Apoptosis Regulatory Proteins/blood
- Apoptosis Regulatory Proteins/genetics
- CD40 Ligand/blood
- CD40 Ligand/genetics
- CTLA-4 Antigen
- Fas Ligand Protein/blood
- Fas Ligand Protein/genetics
- Female
- Graft Rejection/blood
- Graft Rejection/diagnosis
- Granzymes/blood
- Granzymes/genetics
- Humans
- Inducible T-Cell Co-Stimulator Protein
- Kidney Transplantation
- Male
- Membrane Glycoproteins/blood
- Membrane Glycoproteins/genetics
- Middle Aged
- Perforin
- Pore Forming Cytotoxic Proteins/blood
- Pore Forming Cytotoxic Proteins/genetics
- Programmed Cell Death 1 Receptor
- Prospective Studies
- RNA, Messenger/blood
- RNA, Messenger/metabolism
- Transplantation, Homologous
Collapse
Affiliation(s)
- Noora S Alakulppi
- Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland
| | | | | | | | | |
Collapse
|
|
31
|
Veale JL, Liang LW, Zhang Q, Gjertson DW, Du Z, Bloomquist EW, Jia J, Qian L, Wilkinson AH, Danovitch GM, Pham PTT, Rosenthal JT, Lassman CR, Braun J, Reed EF, Gritsch HA. Noninvasive Diagnosis of Cellular and Antibody-Mediated Rejection by Perforin and Granzyme B in Renal Allografts. Hum Immunol 2006; 67:777-86. [PMID: 17055354 DOI: 10.1016/j.humimm.2006.07.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2006] [Revised: 06/30/2006] [Accepted: 07/11/2006] [Indexed: 11/24/2022]
Abstract
A major milestone in transplantation would be the use of biomarkers to monitor rejection. We examined the association between perforin and granzyme-B gene expression detected in the peripheral blood of renal allograft recipients with cellular and antibody-mediated rejection. Furthermore, we judged the appropriateness of assigning negative rejection statuses to persons without a biopsy whose grafts were functioning well clinically. Of the 46 patients who completed the study, recipients with cellular rejection had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.006). Interestingly, recipients with antibody-mediated rejection also had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.04). Patients with high levels of granzyme B had a probability of rejecting that was 26.7 times greater than those patients with low levels of granzyme B. Perforin and granzyme B had sensitivities of 50% and specificities of 95% in predicting rejection (cutoff value = 140). Assigning negative rejection statuses to recipients without a biopsy whose grafts were functioning well did not have a major effect on the direction or significance of covariate values. This study suggests that perforin and granzyme-B gene expressions in peripheral blood are accurate in detecting both cellular and antibody-mediated rejection.
Collapse
Affiliation(s)
- Jeffrey L Veale
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|