|
1
|
Rubino V, Carriero F, Palatucci AT, Giovazzino A, Salemi F, Carrano R, Sabbatini M, Ruggiero G, Terrazzano G. T R3-56 and Treg Regulatory T Cell Subsets as Potential Indicators of Graft Tolerance Control in Kidney Transplant Recipients. Int J Mol Sci 2024; 25:10610. [PMID: 39408939 PMCID: PMC11477056 DOI: 10.3390/ijms251910610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Identification of early signatures of immune rejection represents a key challenge in the clinical management of kidney transplant. To address such an issue, we enrolled 53 kidney transplant recipients without signs of graft rejection, no infectious episodes and no change in the immunosuppressive regimen in the last 6 months. An extensive immune profile revealed increased activation of the T cells, a decreased amount and growth ability of the Treg and a higher level of the TR3-56 regulatory T cell subset, described by us as involved in the preferential control of cytotoxic T lymphocytes. In renal transplant recipients, the high level of the TR3-56 cells associates with a reduction in both the amount and the growth ability of the Treg. Moreover, when the transplanted subjects were categorised according to their stable or unstable disease status, as defined by changes in serum creatinine ≥0.2 mg/dL in two consecutive detections, a higher TR3-56 level and defective Treg growth ability were observed to characterise patients with unstable graft control. Further studies are required to substantiate the hypothesis that immune profiling, including TR3-56 evaluation, might represent a valuable diagnostic tool to identify patients at risk of developing significant anti-donor allo-immune responses.
Collapse
Affiliation(s)
- Valentina Rubino
- Dipartimento di Scienze Mediche Traslazionali, Università di Napoli “Federico II”, 80131 Napoli, Italy; (V.R.); (A.G.)
| | - Flavia Carriero
- Dipartimento di Scienze Della Salute, Università Della Basilicata, 85100 Potenza, Italy; (F.C.); (A.T.P.); (G.T.)
| | - Anna Teresa Palatucci
- Dipartimento di Scienze Della Salute, Università Della Basilicata, 85100 Potenza, Italy; (F.C.); (A.T.P.); (G.T.)
| | - Angela Giovazzino
- Dipartimento di Scienze Mediche Traslazionali, Università di Napoli “Federico II”, 80131 Napoli, Italy; (V.R.); (A.G.)
| | - Fabrizio Salemi
- Percorso Clinico Assistenziale in Nefrologia e Trapianto Renale, Azienda Ospedaliera Universitaria “Federico II”, 80131 Napoli, Italy; (F.S.); (R.C.)
| | - Rosa Carrano
- Percorso Clinico Assistenziale in Nefrologia e Trapianto Renale, Azienda Ospedaliera Universitaria “Federico II”, 80131 Napoli, Italy; (F.S.); (R.C.)
| | - Massimo Sabbatini
- Dipartimento di Sanità Pubblica, Sezione di Nefrologia, Università di Napoli “Federico II”, 80131 Napoli, Italy;
| | - Giuseppina Ruggiero
- Dipartimento di Scienze Mediche Traslazionali, Università di Napoli “Federico II”, 80131 Napoli, Italy; (V.R.); (A.G.)
| | - Giuseppe Terrazzano
- Dipartimento di Scienze Della Salute, Università Della Basilicata, 85100 Potenza, Italy; (F.C.); (A.T.P.); (G.T.)
| |
Collapse
|
|
2
|
Yadav B, Prasad N, Agrawal V, Agarwal V, Jain M. Lower Circulating Cytotoxic T-Cell Frequency and Higher Intragraft Granzyme-B Expression Are Associated with Inflammatory Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Recipients. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1175. [PMID: 37374379 PMCID: PMC10305683 DOI: 10.3390/medicina59061175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: Inflammatory interstitial fibrosis and tubular atrophy (i-IFTA) is an inflammation in the area of tubular atrophy and fibrosis. i-IFTA is poorly associated with graft outcome and associated with infiltration of inflammatory mononuclear cells. A cytotoxic T cell is a granzyme B+CD8+CD3+ T cell, mainly secret granzyme B. Granzyme B is a serine protease that may mediate allograft injury and inflammatory interstitial fibrosis and tubular atrophy (i-IFTA). However, there is no report identifying the association of granzyme B with i-IFTA after a long post-transplant interval. Material and Methods: In this study, we have measured the cytotoxic T-cell frequency with flow cytometry, serum and PBMCs culture supernatants granzyme-B levels with ELISA and intragraft granzyme-B mRNA transcript expression with the RT-PCR in RTRs in 30 patients with biopsy-proven i-IFTA and 10 patients with stable graft function. Result: The frequency of cytotoxic T cells (CD3+CD8+ granzyme B+) in SGF vs. i-IFTA was (27.96 ± 4.86 vs. 23.19 ± 3.85%, p = 0.011), the serum granzyme-B level was (100.82 ± 22.41 vs. 130.32 ± 46.60, p = 0.038 pg/mL) and the intragraft granzyme-B mRNA transcript expression was (1.01 ± 0.048 vs. 2.10 ± 1.02, p < 0.001 fold). The frequency of CD3+ T cells in SGF vs. i-IFTA was (66.08 ± 6.8 vs. 65.18 ± 9.35%; p = 0.68) and that of CD3+CD8+ T cells was (37.29 ± 4.11 vs. 34.68 ± 5.43%; p = 0.28), which were similar between the 2 groups. CTLc frequency was negatively correlated with urine proteinuria (r = -0.51, p < 0.001), serum creatinine (r = -0.28, p = 0.007) and eGFR (r = -0.28, p = 0.037). Similarly, the PBMC culture supernatants granzyme-B level was negatively correlated with urine proteinuria (r = -0.37, p < 0.001) and serum creatinine (r = -0.31, p = 0.002), while the serum granzyme-B level (r = 0.343, p = 0.001) and intragraft granzyme-B mRNA transcript expression (r = 0.38, p < 0.001) were positively correlated with proteinuria. Conclusions: A decrease in the CTLc frequency in circulation and an increased serum granzyme-B level and intragraft granzyme-B mRNA expression shows that cytotoxic T cells may mediate the allograft injury in RTRs with i-IFTA by releasing granzyme B in serum and intragraft tissue.
Collapse
Affiliation(s)
- Brijesh Yadav
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Narayan Prasad
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Vinita Agrawal
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (V.A.); (M.J.)
| | - Vikas Agarwal
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Manoj Jain
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India; (V.A.); (M.J.)
| |
Collapse
|
|
3
|
Antibody-mediated allograft rejection is associated with an increase in peripheral differentiated CD28-CD8+ T cells – Analyses of a cohort of 1032 kidney transplant recipients. EBioMedicine 2022; 83:104226. [PMID: 35988467 PMCID: PMC9420477 DOI: 10.1016/j.ebiom.2022.104226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 06/24/2022] [Accepted: 08/01/2022] [Indexed: 11/22/2022] Open
|
|
4
|
Jacquemont L, Tilly G, Yap M, Doan-Ngoc TM, Danger R, Guérif P, Delbos F, Martinet B, Giral M, Foucher Y, Brouard S, Degauque N. Terminally Differentiated Effector Memory CD8 + T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure. J Am Soc Nephrol 2020; 31:876-891. [PMID: 32165419 DOI: 10.1681/asn.2019080847] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/16/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation. METHODS We investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. RESULTS Increased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity. CONCLUSIONS At 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.
Collapse
Affiliation(s)
- Lola Jacquemont
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Gaëlle Tilly
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Michelle Yap
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Tra-My Doan-Ngoc
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Richard Danger
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | | | | | - Bernard Martinet
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Magali Giral
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Yohann Foucher
- INSERM, Université de Nantes, methodS in Patient-centered outcomes and HEalth ResEarch (SPHERE), UMR1246, Nantes, France
| | - Sophie Brouard
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France.,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| | - Nicolas Degauque
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France; .,CHU Nantes, Université de Nantes, ITUN, Nantes, France
| |
Collapse
|
|
5
|
Matsunami M, Rosales IA, Adam BA, Oura T, Mengel M, Smith RN, Lee H, Cosimi AB, Colvin RB, Kawai T. Long-term Kinetics of Intragraft Gene Signatures in Renal Allograft Tolerance Induced by Transient Mixed Chimerism. Transplantation 2019; 103:e334-e344. [PMID: 31397805 PMCID: PMC6814550 DOI: 10.1097/tp.0000000000002911] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Renal allograft tolerance (TOL) has been successfully induced in nonhuman primates (NHPs) and humans through the induction of transient mixed chimerism. To elucidate the mechanisms of TOL, we compared local immunologic responses in renal allografts with those in T-cell-mediated rejection (TCMR) and chronic antibody-mediated rejection (CAMR) in NHPs. METHODS Using the NanoString nCounter platform, we retrospectively studied 52 mRNAs in 256 kidney allograft samples taken from NHP kidney recipients of donor BMT. No immunosuppression was given after 1-month post-donor BMT. Recipients who achieved TOL (n = 13) survived for >1840 ± 1724 days with normal kidney function, while recipients with CAMR (n = 13) survived for 899 ± 550 days with compromised graft function, and recipients with TCMR (n = 15) achieved only short-term survival (132 ± 69 days). RESULTS The most prominent difference between the groups was FOXP3, which was significantly higher in TOL than in CAMR and TCMR, both early (<1 y, P < 0.01) and late (≥1 y, P < 0.05) after transplant. Other mRNAs related to regulatory T cells (Treg), such as IL10, TGFB, and GATA3, were also high in TOL. In contrast, transcripts of inflammatory cytokines were higher in TCMR, while activated endothelium-associated transcripts were higher in CAMR than in TOL. The receiver operating characteristic analyses revealed that intragraft FOXP3 and CAV1 can reliably distinguish TOL from CAMR. CONCLUSIONS High FOXP3 and other Treg-related mRNAs together with suppressed inflammatory responses and endothelial activation in renal allografts suggest that intragraft enrichment of Treg is a critical mechanism of renal allograft TOL induced by transient mixed chimerism.
Collapse
Affiliation(s)
- Masatoshi Matsunami
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Benjamin A. Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Tetsu Oura
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Rex-Neal Smith
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Hang Lee
- Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - A. Benedict Cosimi
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Tatsuo Kawai
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| |
Collapse
|
|
6
|
Transient increase of activated regulatory T cells early after kidney transplantation. Sci Rep 2019; 9:1021. [PMID: 30705299 PMCID: PMC6355855 DOI: 10.1038/s41598-018-37218-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/29/2018] [Indexed: 12/21/2022] Open
Abstract
Regulatory T cells (Tregs) are crucial in controlling allospecific immune responses. However, studies in human kidney recipients regarding the contribution of polyspecific Tregs have provided differing results and studies on alloreactive Tregs are missing completely. In this retrospective study, we specifically analyzed activated CD4+CD25highFOXP3+GARP+ Tregs in 17 patients of a living donor kidney transplantation cohort longitudinally over 24 months by flow cytometry (FOXP3: forkhead box protein 3, GARP: glycoprotein A repetitions predominant). We could demonstrate that Tregs of patients with end-stage renal disease (ESRD) are already pre-activated when compared to healthy controls. Furthermore, even though total CD4+CD25highFOXP3+ Treg numbers decreased in the first three months after transplantation, frequency of activated Tregs increased significantly representing up to 40% of all peripheral Tregs. In a cohort of living donor kidney transplantation recipients with stable graft function, frequencies of activated Tregs did not correlate with the occurrence of acute cellular rejection or chronic graft dysfunction. Our results will be important for clinical trials using adoptive Treg therapy after kidney transplantation. Adoptively transferred Tregs could be important to compensate the Treg loss at month 3, while they have to compete within the Treg niche with a large number of activated Tregs.
Collapse
|
|
7
|
Kidney Transplant Outcome Is Associated with Regulatory T Cell Population and Gene Expression Early after Transplantation. J Immunol Res 2019; 2019:7452019. [PMID: 30729139 PMCID: PMC6341262 DOI: 10.1155/2019/7452019] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/16/2018] [Accepted: 11/12/2018] [Indexed: 01/08/2023] Open
Abstract
Successful long-term kidney allograft survival with parallel reduction of complications resulting from prolonged immunosuppressive treatment is a goal in kidney transplantation. We studied the immune changes in cell phenotypes and gene expression induced by kidney transplantation. Our goal was to find a phenotypic and/or transcriptional pattern that might be considered prognostic for the kidney transplant outcome. The analysis was performed prospectively on 36 KTx recipients sampled during the first year and followed for five years after transplantation and on 40 long-term KTx recipients (7.9 ± 2.2 y. post-KTx). The research involved flow cytometry assessment of lymphocyte subpopulations (including Tregs and CD3+CD8+CD28− lymphocytes) and gene expression analysis of immune-related genes (CD4, CD8, CTLA4, GZMB, FOXP3, IL10, IL4, ILR2A, NOTCH, PDCD1, PRF1, TGFB, and TNFA). The analysis of patterns observed over the first post-KTx year was confronted with control, pretransplant, and long-term transplant results. Treg counts at months one and three post-KTx correlated positively with the current and future allograft function. FOXP3 gene expression at month one post-KTx was also associated with long-term allograft function. The KTx-induced CD3+CD8+CD28− population correlated with GZMB and PRF1 expression and suggested their cytotoxic properties. The size of the Treg population and regulatory FOXP3 gene expression in the early period after transplantation are associated with kidney transplant outcome. The outlined predictive power of the Treg population needs to be investigated further to be confirmed as one of the immune monitoring strategies that may help achieve the best long-term kidney allograft outcomes.
Collapse
|
|
8
|
Landwehr-Kenzel S, Zobel A, Hoffmann H, Landwehr N, Schmueck-Henneresse M, Schachtner T, Roemhild A, Reinke P. Ex vivo expanded natural regulatory T cells from patients with end-stage renal disease or kidney transplantation are useful for autologous cell therapy. Kidney Int 2018; 93:1452-1464. [PMID: 29792274 DOI: 10.1016/j.kint.2018.01.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 01/05/2018] [Accepted: 01/11/2018] [Indexed: 02/08/2023]
Abstract
Novel concepts employing autologous, ex vivo expanded natural regulatory T cells (nTreg) for adoptive transfer has potential to prevent organ rejection after kidney transplantation. However, the impact of dialysis and maintenance immunosuppression on the nTreg phenotype and peripheral survival is not well understood, but essential when assessing patient eligibility. The current study investigates regulatory T-cells in dialysis and kidney transplanted patients and the feasibility of generating a clinically useful nTreg product from these patients. Heparinized blood from 200 individuals including healthy controls, dialysis patients with end stage renal disease and patients 1, 5, 10, 15, 20 years after kidney transplantation were analyzed. Differentiation and maturation of nTregs were studied by flow cytometry in order to compare dialysis patients and kidney transplanted patients under maintenance immunosuppression to healthy controls. CD127 expressing CD4+CD25highFoxP3+ nTregs were detectable at increased frequencies in dialysis patients with no negative impact on the nTreg end product quality and therapeutic usefulness of the ex vivo expanded nTregs. Further, despite that immunosuppression mildly altered nTreg maturation, neither dialysis nor pharmacological immunosuppression or previous acute rejection episodes impeded nTreg survival in vivo. Accordingly, the generation of autologous, highly pure nTreg products is feasible and qualifies patients awaiting or having received allogenic kidney transplantation for adoptive nTreg therapy. Thus, our novel treatment approach may enable us to reduce the incidence of organ rejection and reduce the need of long-term immunosuppression.
Collapse
Affiliation(s)
- Sybille Landwehr-Kenzel
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Department of Pediatrics, Division of Pneumonology and Immunology, Charité University Medicine Berlin, Berlin, Germany.
| | - Anne Zobel
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany
| | - Henrike Hoffmann
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany
| | - Niels Landwehr
- Leibniz-Institute for Agricultural Engineering and Bioeconomy, Potsdam, Germany; University of Potsdam, Department for Computer Science, Potsdam, Germany
| | - Michael Schmueck-Henneresse
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany; Institute of Medical Immunology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Thomas Schachtner
- Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany
| | - Andy Roemhild
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany
| | - Petra Reinke
- Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany
| |
Collapse
|
|
9
|
Clinical significance of CCR7 +CD8 + T cells in kidney transplant recipients with allograft rejection. Sci Rep 2018; 8:8827. [PMID: 29891963 PMCID: PMC5995850 DOI: 10.1038/s41598-018-27141-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/30/2018] [Indexed: 01/05/2023] Open
Abstract
The regulatory function of CCR7+CD8+ T cells against effector T-cells involved in T-cell mediated rejection (TCMR) in kidney transplant recipients was investigated. In vitro experiments explored the ability of CCR7+CD8+ T cells to suppress T-cell proliferation under T-cell activation conditions or during coculture with human renal proximal tubular epithelial cells (HRPTEpiC). In an ex vivo experiment, the proportion of CCR7+/CD8+, FOXP3+/CCR7+CD8+ T and effector T-cell subsets were compared between the normal biopsy control (NC, n = 17) and TCMR group (n = 17). The CCR7+CD8+ T cells significantly suppressed the proliferation of CD4+ T cells and significantly decreased the proportion of IFN-γ+ and IL-17+/CD4+ T cells and inflammatory cytokine levels (all p < 0.05). After coculturing with HRPTEpiC, CCR7+CD8+ T cells also suppressed T-cell differentiation into IL-2+, IFN-γ+, and IL-17+/CD4+ T cells (all p < 0.05). The TCMR group had significantly fewer CCR7+/CD8+ and FOXP3+/CCR7+CD8+ T in comparison with the NC group, but the proportions of all three effector T-cell subsets were increased in the TCMR group (all p < 0.05). The proportion of CCR7+/CD8+ T was inversely correlated with those of effector T-cell subsets. The results indicate that CCR7+CD8+ T cells may regulate effector T-cells involved in TCMR in an in vitro and in an ex vivo transplant model.
Collapse
|
|
10
|
Early Enrichment and Restitution of the Peripheral Blood Treg Pool Is Associated With Rejection-Free Stable Immunosuppression After Liver Transplantation. Transplantation 2018; 100:e39-40. [PMID: 27326814 DOI: 10.1097/tp.0000000000001190] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
11
|
|
|
12
|
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
|
|
13
|
Behnam Sani K, Sawitzki B. Immune monitoring as prerequisite for transplantation tolerance trials. Clin Exp Immunol 2017; 189:158-170. [PMID: 28518214 DOI: 10.1111/cei.12988] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
Ever since its first application in clinical medicine, scientists have been urged to induce tolerance towards foreign allogeneic transplants and thus avoid rejection by the recipient's immune system. This would circumvent chronic use of immunosuppressive drugs (IS) and thus avoid development of IS-induced side effects, which are contributing to the still unsatisfactory long-term graft and patient survival after solid organ transplantation. Although manifold strategies of tolerance induction have been described in preclinical models, only three therapeutic approaches have been utilized successfully in a still small number of patients. These approaches are based on (i) IS withdrawal in spontaneous operational tolerant (SOT) patients, (ii) induction of a mixed chimerism and (iii) adoptive transfer of regulatory cells. Results of clinical trials utilizing these approaches show that tolerance induction does not work in all patients. Thus, there is a need for reliable biomarkers, which can be used for patient selection and post-therapeutic immune monitoring of safety, success and failure. In this review, we summarize recent achievements in the identification and validation of such immunological assays and biomarkers, focusing mainly on kidney and liver transplantation. From the published findings so far, it has become clear that indicative biomarkers may vary between different therapeutic approaches applied and organs transplanted. Also, patient numbers studied so far are very small. This is the main reason why nearly all described parameters lack validation and reproducibility testing in large clinical trials, and are therefore not yet suitable for clinical practice.
Collapse
Affiliation(s)
- K Behnam Sani
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - B Sawitzki
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
14
|
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
|
|
15
|
Regulatory T Cells as Biomarkers for Rejection and Immunosuppression Tailoring in Solid Organ Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S36-42. [PMID: 26977998 DOI: 10.1097/ftd.0000000000000265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The use of biomarkers to tailor immunosuppression and to predict graft and patient outcomes using biological samples obtained by non-invasive tests is one of the main objectives in solid organ transplantation. Although biopsies give the most accurate information, they are clearly invasive and are associated with potentially adverse effects. To date, regulatory T cells have been shown to play a role in allograft protection; for this reason, extensive research has been performed to define them as biomarkers. However, studies of the measurement of these cells in peripheral blood as biomarkers in solid organ transplantation have been very limited and still not validated in prospective randomized large cohorts with the use of standardized methodology. Such poor evidence has been almost exclusively obtained in renal transplantation. Available data summarized here point for their use as biomarkers in different clinical settings with discordant data in many cases.
Collapse
|
|
16
|
Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S1-20. [PMID: 26977997 DOI: 10.1097/ftd.0000000000000287] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.
Collapse
|
|
17
|
Ezzelarab MB, Thomson AW. Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: The Promise and the Stumbling Blocks. CURRENT TRANSPLANTATION REPORTS 2016; 3:265-274. [PMID: 28529840 PMCID: PMC5435383 DOI: 10.1007/s40472-016-0114-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety. The feasibility of adoptive Treg therapy in the clinic is subject to various parameters, including optimal cell source, isolation procedure, expansion, target dose, time of infusion, as well as generation of a GMP-cell product. Several phase 1/2 Treg dose-escalation studies are underway in organ transplantation. Recent evidence suggests that additional factors are critical to ensure Treg safety and efficacy in allograft recipients, including Treg characterization, stability, longevity, trafficking, concomitant immunosuppression, and donor antigen specificity. Accordingly, Treg therapy in the context of organ transplantation may prove more challenging in comparison to other prospective clinical settings of Treg immunotherapy, such as type-1 diabetes.
Collapse
Affiliation(s)
- Mohamed B. Ezzelarab
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Angus W. Thomson
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
18
|
Alachkar H, Mutonga M, Kato T, Kalluri S, Kakuta Y, Uemura M, Imamura R, Nonomura N, Vujjini V, Alasfar S, Rabb H, Nakamura Y, Alachkar N. Quantitative characterization of T-cell repertoire and biomarkers in kidney transplant rejection. BMC Nephrol 2016; 17:181. [PMID: 27871261 PMCID: PMC5117555 DOI: 10.1186/s12882-016-0395-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 11/09/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND T-cell-mediated rejection (TCMR) remains a major cause of kidney allograft failure. The characterization of T-cell repertoire in different immunological disorders has emerged recently as a novel tool with significant implications. We herein sought to characterize T-cell repertoire using next generation sequencing to diagnose TCMR. METHODS In this prospective study, we analyzed samples from 50 kidney transplant recipients. We collected blood and kidney transplant biopsy samples at sequential time points before and post transplant. We used next generation sequencing to characterize T-cell receptor (TCR) repertoire by using illumina miSeq on cDNA synthesized from RNA extracted from six patients' samples. We also measured RNA expression levels of FOXP3, CD8, CD4, granzyme and perforin in blood samples from all 50 patients. RESULTS Seven patients developed TCMR during the first three months of the study. Out of six patients who had complete sets of blood and biopsy samples two had TCMR. We found an expansion of the TCR repertoire in blood at time of rejection when compared to that at pre-transplant or one-month post transplant. Patients with TCMR (n = 7) had significantly higher RNA expression levels of FOXP3, Perforin, Granzyme, CD4 and CD8 in blood samples than those with no TCMR (n = 43) (P = 0.02, P = 0.003, P = 0.002, P = 0.017, and P = 0.01, respectively). CONCLUSIONS Our study provides a potential utilization of TCR clone kinetics analysis in the diagnosis of TCMR. This approach may allow for the identification of the expanded T-cell clones associated with the rejection and lead to potential noninvasive diagnosis and targeted therapies of TCMR.
Collapse
Affiliation(s)
- Houda Alachkar
- School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
| | - Martin Mutonga
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Taigo Kato
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Sowjanya Kalluri
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Kendall regional medical center, Miami, FL, 33175, USA
| | - Yoichi Kakuta
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Motohide Uemura
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Vikas Vujjini
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Johns Hopkins Hospital, Baltimore, MD, 21287, USA
| | - Sami Alasfar
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Johns Hopkins Hospital, Baltimore, MD, 21287, USA
| | - Hamid Rabb
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Johns Hopkins Hospital, Baltimore, MD, 21287, USA
| | - Yusuke Nakamura
- Department of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Nada Alachkar
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Johns Hopkins Hospital, Baltimore, MD, 21287, USA
| |
Collapse
|
|
19
|
Dousdampanis P, Trigka K, Mouzaki A. Tregs and kidney: From diabetic nephropathy to renal transplantation. World J Transplant 2016; 6:556-63. [PMID: 27683634 PMCID: PMC5036125 DOI: 10.5500/wjt.v6.i3.556] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/14/2016] [Accepted: 07/29/2016] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation is recognised as the most effective treatment for patients with end-stage renal disease (ESRD). Kidney transplantation continues to face several challenges including long-term graft and patient survival, and the side effects of immunosuppressive therapy. The tendency in kidney transplantation is to avoid the side effects of immunosuppresants and induce immune tolerance. Regulatory T-cells (Tregs) contribute to self-tolerance, tolerance to alloantigen and transplant tolerance, mainly by suppressing the activation and function of reactive effector T-cells. Additionally, Tregs are implicated in the pathogenesis of diabetes, which is the leading cause of ESRD, suggesting that these cells play a role both in the pathogenesis of chronic kidney disease and the induction of transplant tolerance. Several strategies to achieve immunological tolerance to grafts have been tested experimentally, and include combinations of co-stimulatory blockade pathways, T-cell depletion, in vivo Treg-induction and/or infusion of ex-vivo expanded Tregs. However, a successful regimen that induces transplant tolerance is not yet available for clinical application. This review brings together certain key studies on the role of Tregs in ESRD, diabetes and kidney transplantation, only to emphasize that many more studies are needed to elucidate the clinical significance and the therapeutic applications of Tregs.
Collapse
|
|
20
|
Baroja-Mazo A, Revilla-Nuin B, Parrilla P, Martínez-Alarcón L, Ramírez P, Pons JA. Tolerance in liver transplantation: Biomarkers and clinical relevance. World J Gastroenterol 2016; 22:7676-91. [PMID: 27678350 PMCID: PMC5016367 DOI: 10.3748/wjg.v22.i34.7676] [Citation(s) in RCA: 20] [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: 04/28/2016] [Revised: 07/04/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.
Collapse
|
|
21
|
Bestard O, Cravedi P. Monitoring alloimmune response in kidney transplantation. J Nephrol 2016; 30:187-200. [PMID: 27245689 DOI: 10.1007/s40620-016-0320-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 05/15/2016] [Indexed: 01/22/2023]
Abstract
Currently, immunosuppressive therapy in kidney transplant recipients is generally performed by protocols and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients are likely to receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. Developing reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival. Emerging data indicate that many assays, likely used in panels rather than single assays, have potential to be diagnostic and predictive of short and also long-term outcome. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Of note, some prospective, randomized, multicenter biomarker-driven studies are currently on-going aiming at confirming such preliminary data. These works as well as other future studies are highly warranted to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.
Collapse
Affiliation(s)
- Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, IDIBELL, Barcelona, Spain
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Annenberg Building, New York, NY, 10029, USA.
| |
Collapse
|
|
22
|
Cho JH, Yoon YD, Jang HM, Kwon E, Jung HY, Choi JY, Park SH, Kim YL, Kim HK, Huh S, Won DI, Kim CD. Immunologic Monitoring of T-Lymphocyte Subsets and Hla-Dr-Positive Monocytes in Kidney Transplant Recipients: A Prospective, Observational Cohort Study. Medicine (Baltimore) 2015; 94:e1902. [PMID: 26554788 PMCID: PMC4915889 DOI: 10.1097/md.0000000000001902] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The clinical significance of circulating T-lymphocyte subsets and human leukocyte antigen (HLA)-DR-positive monocytes in the peripheral blood of kidney transplant recipients (KTRs) remains unclear. We examined the efficacy of enumerating these cells for the immunologic monitoring of KTRs.Blood samples were obtained before transplantation, 2 weeks after transplantation and at diagnosis, and 2 weeks after treating biopsy-proven acute cellular rejection and cytomegalovirus (CMV) infection. Serial flow cytometric analysis was performed using peripheral blood obtained from 123 patients to identify the frequencies of HLA-DR, CD3, CD4, CD8, and CD25 T-lymphocytes and HLA-DR-positive monocytes.Frequencies of CD4CD25/CD4 T cells, CD8CD25/CD8 T cells, and HLA-DR-positive monocytes were significantly lower at 2 weeks after transplantation than before transplantation (all P < 0.001). This decrease was not correlated with clinical parameters. The frequency of CD4CD25/CD4 T cells was significantly higher in KTRs with acute rejection than in KTRs at 2 weeks after transplantation (9.10% [range 4.30-25.6%] vs 5.10% [range 0.10-33.3%]; P = 0.024). However, no significant differences were observed between stable KTRs and KTRs with CMV infection. Analysis of the receiver operating characteristic curve adjusted by covariates showed that acute rejection could be predicted with 75.0% sensitivity and 68.4% specificity by setting the cutoff value of CD4CD25/CD4 T cell frequency as 5.8%.Circulating T-lymphocyte and monocyte subsets showed significant and consistent changes in their frequencies after immunosuppression. Of the various immune cells examined, circulating levels of CD4CD25 T cells might be a useful noninvasive immunologic indicator for detecting acute rejection.
Collapse
Affiliation(s)
- Jang-Hee Cho
- From the Department of Internal Medicine (J-HC, Y-DY, EK, H-YJ, J-YC, S-HP, Y-LK, C-DK); Department of Statistics (HMJ); Department of Surgery (H-KK, SH); and Department of Clinical Pathology, Kyungpook National University Hospital, Daegu, Korea (D-IW)
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Braza F, Durand M, Degauque N, Brouard S. Regulatory T Cells in Kidney Transplantation: New Directions? Am J Transplant 2015; 15:2288-300. [PMID: 26234373 DOI: 10.1111/ajt.13395] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 05/03/2015] [Accepted: 05/24/2015] [Indexed: 01/25/2023]
Abstract
The contribution of regulatory T cells in the maintenance of kidney graft survival is of major interest. Although many experimental models suggest a role in the induction of graft tolerance, reproducing these findings in clinic is less clear. While modulation of the regulatory T cell response is a promising therapeutic concept in transplantation, a better understanding of function, phenotype and biology is needed to be able to optimally exploit these cells in order to induce graft tolerance. With this in mind, we review here the current understanding of the phenotypic-functional delineation of Tregs and how Tregs can contribute to graft survival. We highlight their potential role in long-term graft survival and kidney operational tolerance. We also discuss the mechanisms needed for the molecular development of regulatory T cells: A combination of FOXP3 molecular partners, epigenetic, metabolic, and posttranslational modifications are necessary to generate well-functioning regulatory T cells and maintain their core identify. We discuss how an improved understanding of these mechanisms will permit the identification of new potent therapeutic strategies to improve kidney graft survival.
Collapse
Affiliation(s)
- F Braza
- Université, de Nantes, Faculté de Médecine, Nantes, F-44035, France.,INSERM, UMR 1064, Nantes, F-44093, France.,CHU de Nantes, ITUN, Nantes, F-44093, France
| | - M Durand
- Université, de Nantes, Faculté de Médecine, Nantes, F-44035, France.,INSERM, UMR 1064, Nantes, F-44093, France.,CHU de Nantes, ITUN, Nantes, F-44093, France
| | - N Degauque
- INSERM, UMR 1064, Nantes, F-44093, France.,CHU de Nantes, ITUN, Nantes, F-44093, France
| | - S Brouard
- INSERM, UMR 1064, Nantes, F-44093, France.,CHU de Nantes, ITUN, Nantes, F-44093, France
| |
Collapse
|
|
24
|
Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| |
Collapse
|
|
25
|
Mehrotra A, Leventhal J, Purroy C, Cravedi P. Monitoring T cell alloreactivity. Transplant Rev (Orlando) 2014; 29:53-9. [PMID: 25475045 DOI: 10.1016/j.trre.2014.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 10/03/2014] [Accepted: 11/09/2014] [Indexed: 01/06/2023]
Abstract
Currently, immunosuppressive therapy in kidney transplant recipients is center-specific, protocol-driven, and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. The individualization of immunosuppression requires the development of assays able to reliably quantify and/or predict the magnitude of the recipient's immune response toward the allograft. As alloreactive T cells are central mediators of allograft rejection, monitoring T cell alloreactivity has become a priority for the transplant community. Among available assays, flow cytometry based phenotyping, T cell proliferation, T cell cytokine secretion, and ATP release (ImmuKnow), have been the most thoroughly tested. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Future studies are required to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.
Collapse
Affiliation(s)
- Anita Mehrotra
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Jeremy Leventhal
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Carolina Purroy
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
| |
Collapse
|
|
26
|
van Doesum WB, Abdulahad WH, van Dijk MCRF, Dolff S, van Son WJ, Stegeman CA, Sanders JSF. Characterization of urinary CD4⁺ and CD8⁺ T cells in kidney transplantation patients with polyomavirus BK infection and allograft rejection. Transpl Infect Dis 2014; 16:733-43. [PMID: 25092256 DOI: 10.1111/tid.12273] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 04/19/2014] [Accepted: 05/05/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES The objective of this study was to characterize CD4(+) and CD8(+) T-cell populations in blood and urine of renal transplant patients with BK virus (BKV) infection or allograft rejection. MATERIALS AND METHODS Percentages and absolute numbers of CD4(+) and CD8(+) effector memory T-cell subtype (TEM ) and terminal differentiated T cells (TTD ) in renal transplant patients with BKV infection (n = 14), with an episode of allograft rejection (n = 9), and in uncomplicated renal transplant patients with a stable kidney function (n = 12) were measured and compared using 4-color fluorescence-activated cell sorting. Results were correlated with the number of CD4(+) and CD8(+) T cells in renal biopsies. RESULTS In patients with allograft rejection, the number of urinary CD4(+) TEM and CD8(+) TEM cells was significantly increased compared to patients with BKV infection or patients without complications. Positive correlation was found between the number of CD4(+) and CD8(+) cells in the renal biopsies and the number of CD4(+) and CD8(+) cells in urine. In patients with rejection, after 2 months of immunosuppressive therapy, a reduction in urinary CD8(+) TEM cells was found. CONCLUSIONS CD4(+) TEM and CD8(+) TEM cells in urine could be a marker to distinguish allograft rejection from BKV-associated nephropathy and to monitor therapy effectiveness in renal transplant patients with allograft rejection.
Collapse
Affiliation(s)
- W B van Doesum
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Limited efficacy of immunosuppressive drugs on CD8+ T cell-mediated and natural killer cell-mediated lysis of human renal tubular epithelial cells. Transplantation 2014; 97:1110-8. [PMID: 24704664 DOI: 10.1097/tp.0000000000000108] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although CD8+ T cell-mediated and natural killer (NK) cell-mediated cytotoxicity against renal tubular epithelial cells (TECs) plays a crucial role during rejection, the degree of inhibition of these lytic immune responses by immunosuppressive drugs is unknown. We investigated the CD8 T-cell and NK cell responses induced by TECs in vitro and questioned how these processes are affected by immunosuppressive drugs. METHODS Donor-derived TECs were co-cultured with recipient peripheral blood monocyte cells. Proliferation of CD8+ T cells and NK cell subsets was assessed using PKH dilution assay. CD107a degranulation and europium release assay were performed to explore CD8+-mediated and NK cell-mediated TEC lysis. Experiments were conducted in the absence or presence of tacrolimus (10 ng/mL), everolimus (10 ng/mL), and prednisolone (200 ng/mL). RESULTS Tubular epithelial cells induce significant CD8+ T-cell and NK cell proliferation. All immunosuppressive drugs significantly inhibited TEC-induced CD8+ T-cell proliferation. Interestingly, prednisolone was the most powerful inhibitor of NK cell proliferation. CD8-mediated and NK cell-mediated early lytic responses were marked by strong degranulation after an encounter of unstimulated TECs, represented by a high cell surface expression of CD107a. However, with the use of interferon-γ-activated and tumor necrosis factor-α-activated TECs, the NK degranulation response was significantly reduced and CD8 degranulation response was even more enhanced (P<0.05). Tubular epithelial cell-induced CD8 degranulation and CD8-mediated TEC lysis were preferentially inhibited by tacrolimus and prednisolone, and not by everolimus. Although tacrolimus showed the most inhibitory effect on the degranulation of NK cells, NK cell-mediated TEC lysis was efficiently inhibited by prednisolone (P<0.05). CONCLUSION Overall, our data point to a limited efficacy of immunosuppressive drugs on CD8+ T cell-mediated and NK cell-mediated lysis of human renal TECs.
Collapse
|
|
28
|
Yap M, Boeffard F, Clave E, Pallier A, Danger R, Giral M, Dantal J, Foucher Y, Guillot-Gueguen C, Toubert A, Soulillou JP, Brouard S, Degauque N. Expansion of highly differentiated cytotoxic terminally differentiated effector memory CD8+ T cells in a subset of clinically stable kidney transplant recipients: a potential marker for late graft dysfunction. J Am Soc Nephrol 2014; 25:1856-68. [PMID: 24652799 DOI: 10.1681/asn.2013080848] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vβ repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vβ diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.
Collapse
Affiliation(s)
- Michelle Yap
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Françoise Boeffard
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Emmanuel Clave
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 940, Paris, France; and
| | - Annaick Pallier
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Richard Danger
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Magali Giral
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Jacques Dantal
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Yohann Foucher
- Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Université de Nantes, Equipe d'Accueil 4275 and Labex Transplantex, Nantes, France
| | - Cécile Guillot-Gueguen
- Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France
| | - Antoine Toubert
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 940, Paris, France; and
| | - Jean-Paul Soulillou
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
| | - Sophie Brouard
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - Nicolas Degauque
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| |
Collapse
|
|
29
|
Substantial proliferation of human renal tubular epithelial cell-reactive CD4+CD28null memory T cells, which is resistant to tacrolimus and everolimus. Transplantation 2014; 97:47-55. [PMID: 24157471 DOI: 10.1097/01.tp.0000435697.31148.b2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND In spite of maintenance treatment with immunosuppressive drugs, tubulitis still occurs and can lead to structural kidney graft damage. We hypothesize that human renal tubular epithelial cells (TECs) trigger selective proliferation of recipient T-cell subsets with variable sensitivity to immunosuppressive drugs. METHODS Recipient peripheral blood mononuclear cells were cocultured with donor-derived TECs for 7 days. The proliferation of the total CD4 T-cell pool was assessed. Next, we analyzed which CD4 T-cell subset proliferated and how this response was affected by tacrolimus, everolimus, prednisolone, and mycophenolic acid (MPA) in clinically relevant concentrations. RESULTS CD4 T-cell proliferation upon TEC encounter was mainly executed by memory T cells. Interestingly, 38%±7% of the proliferating CD4 T-cell pool showed a CD28 phenotype. These proliferating CD4CD28 memory T cells produced high levels of interferon-γ, tumor necrosis factor-α, and the cytolitic protease granzyme B. TEC-reactive CD4 T-cell proliferation was significantly suppressed by tacrolimus, everolimus, prednisolone, and MPA (P<0.05). Surprisingly and in contrast to prednisolone and MPA, neither tacrolimus nor everolimus could inhibit the CD4CD28 T-cell proliferative response. CONCLUSION Our data show substantial proliferation of TEC-reactive CD4CD28 memory T cells, which are resistant to tacrolimus and everolimus. This phenomenon might play an important mechanistic role during cellular rejection under full immunosuppression.
Collapse
|
|
30
|
Dugast E, Chesneau M, Soulillou JP, Brouard S. Biomarkers and possible mechanisms of operational tolerance in kidney transplant patients. Immunol Rev 2014; 258:208-17. [DOI: 10.1111/imr.12156] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Emilie Dugast
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
| | - Mélanie Chesneau
- INSERM UMR 1064; Nantes France
- Université de Nantes; Nantes France
| | - Jean-Paul Soulillou
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
- CHU de Nantes; Nantes France
- Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
- CHU de Nantes; Nantes France
- Université de Nantes; Nantes France
| |
Collapse
|
|
31
|
The diagnostic value of transcription factors T-bet/GATA3 ratio in predicting antibody-mediated rejection. Clin Dev Immunol 2013; 2013:460316. [PMID: 24235972 PMCID: PMC3819890 DOI: 10.1155/2013/460316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 09/19/2013] [Accepted: 09/19/2013] [Indexed: 01/27/2023]
Abstract
Background. Previous data showed that the predominance of intraglomerular T-bet or GATA3 is correlated with different mechanisms of rejection, suggesting that the ratio of T-bet/GATA3 might be used to distinguish antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR). Methods. We compared the intraglomerular T-bet/GATA3 ratio in ABMR and TCMR. The intragraft expression of T-bet and GATA3 was studied via immunohistochemistry. The correlation of the diagnosis of AMR with the ratio of T-bet/GATA3 was examined. Results. Both intraglomerular T-bet- and GATA3-expressing cells were increased during acute rejection. T-bet/GATA3>1 was strongly correlated with ABMR (93.3% versus 18.2%). The incidence of positive HLA-I/II antibodies and glomerulitis is significantly higher in T-bet/GATA3>1 group (P < 0.001, 0.013, resp.). The scores of peritubular capillary inflammation and glomerulitis were also higher in T-bet/GATA3>1 group (P = 0.052, P < 0.001, resp.). Nevertheless, T-bet/GATA3>1 is also correlated with C4d-negative ABMR and resistance to steroid treatment. Compared with C4d deposition, T-bet/GATA3>1 had a slight lower (90% versus 100%) specificity but a much higher (87.5% versus 68.8%) sensitivity. Conclusion. Our data suggested that intraglomerular predominance of T-bet over GATA3 might be used as diagnosis maker of ABMR in addition to C4d, especially in C4d-negative cases.
Collapse
|
|
32
|
Abstract
Organ transplantation appears today to be the best alternative to replace the loss of vital organs induced by various diseases. Transplants can, however, also be rejected by the recipient. In this review, we provide an overview of the mechanisms and the cells/molecules involved in acute and chronic rejections. T cells and B cells mainly control the antigen-specific rejection and act either as effector, regulatory, or memory cells. On the other hand, nonspecific cells such as endothelial cells, NK cells, macrophages, or polymorphonuclear cells are also crucial actors of transplant rejection. Last, beyond cells, the high contribution of antibodies, chemokines, and complement molecules in graft rejection is discussed in this article. The understanding of the different components involved in graft rejection is essential as some of them are used in the clinic as biomarkers to detect and quantify the level of rejection.
Collapse
Affiliation(s)
- Aurélie Moreau
- INSERM UMR 1064, Center for Research in Transplantation and Immunology-ITUN, CHU de Nantes 44093, France
| | | | | | | |
Collapse
|
|
33
|
Lim DG, Park YH, Kim SE, Jeong SH, Kim SC. Diagnostic value of tolerance-related gene expression measured in the recipient alloantigen-reactive T cell fraction. Clin Immunol 2013; 148:219-26. [PMID: 23778261 DOI: 10.1016/j.clim.2013.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 04/17/2013] [Accepted: 05/19/2013] [Indexed: 10/26/2022]
Abstract
The efficient development of tolerance-inducing therapies and safe reduction of immunosuppression should be supported by early diagnosis and prediction of tolerance in transplantation. Using mouse models of donor-specific tolerance to allogeneic skin and islet grafts we tested whether measurement of tolerance-related gene expression in their alloantigen-reactive peripheral T cell fraction efficiently reflected the tolerance status of recipients. We found that Foxp3, Nrn1, and Klrg1 were preferentially expressed in conditions of tolerance compared with rejection or unmanipulated controls if their expression is measured in CD69(+) T cells prepared from coculture of recipient peripheral T cells and donor antigen-presenting cells. The same pattern of gene expression was observed in recipients grafted with either skin or islets, recipients of different genetic origins, and even those taking immunosuppressive drugs. These findings suggest that the expression of tolerance-related genes in the alloantigen-reactive T cell fraction could be used to detect tolerance in the clinic.
Collapse
Affiliation(s)
- Dong-Gyun Lim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | | | | | | |
Collapse
|
|
34
|
Regulatory T-cell subset analysis and profile of interleukin (IL)-10, IL-17 and interferon-gamma cytokine-producing cells in kidney allograft recipients with donor cells infusion. Clin Exp Nephrol 2013; 16:636-46. [PMID: 22314659 DOI: 10.1007/s10157-012-0591-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Accepted: 01/09/2012] [Indexed: 12/27/2022]
Abstract
BACKGROUND This pilot study aimed to assess whether the perioperative infusion of donor bone marrow cells (DBMC) in renal allograft recipients can affect the appearance of peripheral regulatory T-cell subsets and the profile of cytokine-producing cells [interferon-gamma (IFN-γ), interleukin (IL)-17 and IL-10] 2 years after transplantation. METHODS Fresh blood samples were collected from 14 kidney recipients who received infusion and from 13 kidney recipients without infusion who served as controls at the end of the second post-transplantation year. Initially the percentages of CD4(+)CD25(+)FoxP3(+) T cells and CD3(+)CD8(+)CD28(-) T cells were quantified using flowcytometry. Thereafter, the frequencies of IL-10-, IL-17- and IFN-γ-producing cells were determined separately using the ELISPOT technique with peptides corresponding to mismatched donor HLA-DR molecules and phytohemagglutinin (PHA). RESULTS The mean numbers of IFN-γ- and IL-17-producing cells in response to PHA were lower in infused patients than in controls (P = 0.02 and P = 0.18, respectively); however, an increased frequency of IL-10-producing cells was observed compared to controls (P = 0.07). Furthermore, the ratio of IL-10/IFN-γ-producing cells was significantly higher in the DBMC-infused group versus controls (P = 0.01). There was a negative correlation between the percentage of CD3(+)CD8(+)CD28(-)T cells and IL-17-producing cells in the infused group (r = -0.539, P = 0.04). The mean levels and the frequency of microchimerism within the first post-transplantation year were also significantly higher in infused patients than in controls (P = 0.007 and P = 0.001, respectively). CONCLUSION Our findings suggest that DBMC infusion could partially stimulate the regulatory mechanisms against alloimmune responses in kidney allograft recipients
Collapse
|
|
35
|
Schaier M, Seissler N, Becker LE, Schaefer SM, Schmitt E, Meuer S, Hug F, Sommerer C, Waldherr R, Zeier M, Steinborn A. The extent of HLA-DR expression on HLA-DR+Tregs allows the identification of patients with clinically relevant borderline rejection. Transpl Int 2013; 26:290-9. [DOI: 10.1111/tri.12032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Revised: 05/21/2012] [Accepted: 11/12/2012] [Indexed: 01/08/2023]
Affiliation(s)
| | | | | | | | - Edgar Schmitt
- Institute of Immunology; University of Mainz; Germany
| | - Stefan Meuer
- Institute of Immunology; University of Heidelberg; Germany
| | - Friederike Hug
- Department of Nephrology; University of Heidelberg; Germany
| | | | | | - Martin Zeier
- Department of Nephrology; University of Heidelberg; Germany
| | - Andrea Steinborn
- Department of Obstetrics and Gynecology; University of Heidelberg; Germany
| |
Collapse
|
|
36
|
Zuber J, Grimbert P, Blancho G, Thaunat O, Durrbach A, Baron C, Lebranchu Y. Prognostic significance of graft Foxp3 expression in renal transplant recipients: a critical review and attempt to reconcile discrepancies. Nephrol Dial Transplant 2012; 28:1100-11. [PMID: 23262436 DOI: 10.1093/ndt/gfs570] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.
Collapse
Affiliation(s)
- Julien Zuber
- Department of Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Akimova T, Kamath BM, Goebel JW, Meyers KEC, Rand EB, Hawkins A, Levine MH, Bucuvalas JC, Hancock WW. Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients. Am J Transplant 2012; 12:3449-61. [PMID: 22994804 PMCID: PMC3513508 DOI: 10.1111/j.1600-6143.2012.04269.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
Collapse
Affiliation(s)
- Tatiana Akimova
- Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, and University of Toronto, Canada
| | - Jens W. Goebel
- Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Kevin E. C. Meyers
- Department of Pediatrics, Division of Nephrology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia
| | - Elizabeth B. Rand
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Andre Hawkins
- Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Matthew H. Levine
- Department of Surgery, Division of Transplant Surgery, Hospital of the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA
| | - John C. Bucuvalas
- Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Wayne W. Hancock
- Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA,Corresponding author: Wayne W. Hancock,
| |
Collapse
|
|
38
|
Cellular Infiltrates and NFκB Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance. Transplantation 2012; 94:729-37. [DOI: 10.1097/tp.0b013e31826032be] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
39
|
Schlickeiser S, Sawitzki B. Peripheral biomarkers for individualizing immunosuppression in transplantation - Regulatory T cells. Clin Chim Acta 2012; 413:1406-13. [DOI: 10.1016/j.cca.2012.02.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 02/10/2012] [Accepted: 02/10/2012] [Indexed: 01/08/2023]
|
|
40
|
Sun Q, Zhang M, Xie K, Li X, Zeng C, Zhou M, Liu Z. Endothelial injury in transplant glomerulopathy is correlated with transcription factor T-bet expression. Kidney Int 2012; 82:321-9. [DOI: 10.1038/ki.2012.112] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
41
|
Abstract
Alloantibodies clearly cause acute antibody mediated rejection, and all available evidence supports their pathogenic etiology in the development of chronic alloantibody mediated rejection (CAMR). But the slow evolution of this disease, the on-going immunosuppression, the variations in titer of alloantibodies, and variation in antigenic targets all complicate identifying which dynamic factors are most important clinically and pathologically. This review highlights the pathological factors related to the diagnosis of CAMR, the time course and natural history of this disease. What is known about CAMR pathogenesis is discussed including alloantibodies, the role of complement, gene activation, and Fc effector cell function. Therapy, which is problematic for this disease, is also discussed, including on-going and potential therapies and their limitations.
Collapse
Affiliation(s)
- R. Neal Smith
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
42
|
Abstract
BACKGROUND Subclinical rejection and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies are associated with outcome. We study the relationship between histologic lesions in early protocol biopsies and histologic diagnoses in late biopsies for cause. MATERIALS AND METHODS Renal transplants with a protocol biopsy performed within the first 6 months posttransplant between 1988 and 2006 were reviewed. Biopsies were evaluated according to Banff criteria, and C4d staining was available in biopsies for cause. RESULTS Of the 517 renal transplants with a protocol biopsy, 109 had a subsequent biopsy for cause which showed the following histological diagnoses: chronic humoral rejection (CHR) (n=44), IF/TA (n=42), recurrence of the primary disease (n=11), de novo glomerulonephritis (n=7), T-cell-mediated rejection (n=4), and polyoma virus nephropathy (n=1). The proportion of retransplants (15.9% vs. 2.3%, P=0.058) and the prevalence of subclinical rejection were higher in patients with CHR than in patients with IF/TA (52.3% vs. 28.6%, P=0.0253). Demographic donor and recipient characteristics and clinical data at the time of protocol biopsy were not different between groups. Logistic regression analysis showed that subclinical rejection (relative risk, 2.52; 95% confidence interval, 1.1-6.3; P=0.047) but not retransplantation (relative risk, 6.7; 95% confidence interval, 0.8-58.8; P=0.085) was associated with CHR. CONCLUSION Subclinical rejection in early protocol biopsies is associated with late appearance of CHR.
Collapse
|
|
43
|
Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical role of the renal transplant biopsy. Nat Rev Nephrol 2012; 8:110-21. [PMID: 22231130 DOI: 10.1038/nrneph.2011.213] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Percutaneous needle core biopsy is the definitive procedure by which essential diagnostic and prognostic information on acute and chronic renal allograft dysfunction is obtained. The diagnostic value of the information so obtained has endured for over three decades and has proven crucially important in shaping strategies for therapeutic intervention. This Review provides a broad outline of the utility of performing kidney graft biopsies after transplantation, highlighting the relevance of biopsy findings in the immediate and early post-transplant period (from days to weeks after implantation), the first post-transplant year, and the late period (beyond the first year). We focus on how biopsy findings change over time, and the wide variety of pathological features that characterize the major clinical diagnoses facing the clinician. This article also includes a discussion of acute cellular and humoral rejection, the toxic effects of calcineurin inhibitors, and the widely varying etiologies and characteristics of chronic lesions. Emerging technologies based on gene expression analyses and proteomics, the in situ detection of functionally relevant molecules, and new bioinformatic approaches that hold the promise of improving diagnostic precision and developing new, refined molecular pathways for therapeutic intervention are also presented.
Collapse
Affiliation(s)
- Winfred W Williams
- Transplant Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. wwwilliams@ partners.org
| | | | | | | |
Collapse
|
|
44
|
Gheith OAA. Gene expression profiling in organ transplantation. Int J Nephrol 2011; 2011:180201. [PMID: 21845224 PMCID: PMC3154482 DOI: 10.4061/2011/180201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 06/22/2011] [Indexed: 11/20/2022] Open
Abstract
Aim of Review. Huge effort is being made among the transplant community investigating novel biomarkers that enable transplant clinicians to identify patients at risk for allograft rejection or those who will develop tolerance so that immunosuppression could be safely minimized or even ideally withdrawn. Despite the important advances achieved in the identification of several potential biomarkers of tolerance, rejection, or both, validation and demonstration of their clinical utility still needs to be tested, which will need international cooperative networks. It is important to note that the reproducibility of differently expressed genes might be affected by many factors such as gene ranking and selection methods, inherent differences between types, and the choice of thresholds. However, because microarray analyses are expensive and time consuming and their statistical evaluation is often very difficult, gene expression analysis using the RTPCR method is nowadays recommended. Conclusions. In the field of organ transplantation, gene-expression-based decision might help in improving patient and graft outcome and there are a multitude of studies showing that gene-expression profiling is feasible.
Collapse
|
|
45
|
Batal I, Azzi J, El-Haddad N, Riella LV, Lunz JG, Zeevi A, Sasatomi E, Basu A, Tan H, Shapiro R, Randhawa P. Immunohistochemical markers of tissue injury in biopsies with transplant glomerulitis. Hum Pathol 2011; 43:69-80. [PMID: 21777946 DOI: 10.1016/j.humpath.2011.04.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2011] [Revised: 04/02/2011] [Accepted: 04/08/2011] [Indexed: 11/28/2022]
Abstract
Transplant glomerulitis is associated with suboptimal graft function. To understand its pathogenesis and to assess the parameters of potential prognostic value, we immunostained 25 paraffin-embedded allograft biopsies showing glomerulitis for markers of complement activation (C4d), cytotoxicity (Granzyme-B), apoptosis (Bcl-XL, Bcl-2, and Fas-L), and endothelial injury (von Willebrand factor). Staining was semiquantitatively assessed in different anatomical compartments, and comparison was made with 40 control allograft biopsies without glomerulitis. Biopsies with glomerulitis had more frequent incidence of "mixed" T-cell and antibody-mediated rejection compared with controls [8/25 (32%) versus 4/40 (10%), P = .046]. Furthermore, they had higher glomerular capillary-C4d scores (1.9 ± 1.1 versus 1.2 ± 1.2, P = .015), which tended to persist when biopsies showing transplant glomerulopathy were excluded. Higher glomerular capillary-C4d scores were observed in samples with versus without donor-specific antibody (2.5 ± 0.9 versus 1.2 ± 1.2, P = .01). Compared with controls, biopsies with glomerulitis had more intraglomerular (4.8 ± 4.5 versus 0.9± 0.8 cells/glomerulus, P < .001) and interstitial mainly peritubular capillary (6.1 ± 4.1 versus 3.2 ± 3.4 cells/hpf, P = .002) Granzyme-B(+) leukocytes. Higher mesangial-von Willebrand factor scores were noted in the glomerulitis group (1.8 ± 1.0 versus 0.8 ± 0.8, P = .003) and correlated with the percentage of inflamed glomeruli (r = 0.54, P < .001). Interstitial-von Willebrand factor was associated with a higher peritubular capillaritis score (interstitial-von Willebrand factor: 1.6 ± 1.2 versus no interstitial-von Willebrand factor: 0.6 ± 0.9, P = .02). Glomerular capillary-Bcl-XL was not associated with accommodation. Finally, no difference in Bcl-2 or Fas-L was observed upon comparing glomerulitis to controls. In conclusion, glomerular injury in transplant glomerulitis appears to be mediated by complement activation and cellular cytotoxicity. Mesangial- or interstitial-von Willebrand factor identified cases with more severe microcirculation injury.
Collapse
Affiliation(s)
- Ibrahim Batal
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
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
|
|
47
|
Shan J, Guo Y, Luo L, Lu J, Li C, Zhang C, Huang Y, Feng L, Wu W, Long D, Li S, Li Y. Do CD4+ Foxp3+ Treg cells correlate with transplant outcomes: a systematic review on recipients of solid organ transplantation. Cell Immunol 2011; 270:5-12. [PMID: 21640985 DOI: 10.1016/j.cellimm.2011.05.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 04/12/2011] [Accepted: 05/06/2011] [Indexed: 02/05/2023]
Abstract
Regulatory T cells (Tregs) are considered to be critical for the induction of transplant tolerance. Tregs counts were measured in blood, biopsy and urine sample after transplantation in many studies. Although not unanimous, some studies have suggested that Tregs is associated with better outcome and can also serve as an immune marker to predict the individual risk of rejection and identify tolerant patients. In this study, we systematically reviewed the correlation between Tregs and transplant outcomes, identifying if Tregs can predict transplant rejection and tolerance. A total of 22 articles were included and assessed, the results showed that Tregs in recipients are helpful to maintain a stable graft function, reduce acute/chronic rejection rate. And the Tregs in graft and urine, rather than in PBL, may have a better diagnostic value for transplant outcomes. However, since the low quality of included studies, results may be influenced by bias. More high quality studies with bigger sample size are still needed in future.
Collapse
Affiliation(s)
- Juan Shan
- Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan Province, PR China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Spatial differences in the presence of FOXP3+ and GranzymeB+ T cells between the intra- and extravascular compartments in renal allograft vasculopathy. PLoS One 2011; 6:e18656. [PMID: 21494640 PMCID: PMC3071842 DOI: 10.1371/journal.pone.0018656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Accepted: 03/15/2011] [Indexed: 11/25/2022] Open
Abstract
Background Allograft vasculopathy (AV) and native atherosclerosis (NA) share the presence of a T-cell mediated inflammatory response, but differ in overall plaque morphology and growth rate. We studied the distribution and frequency of regulatory- and cytotoxic T cells in the arterial intima lesions in both conditions. Methodology/Principal Findings The study is based on vessels of 15 explanted human renal allografts with AV and 10 carotid artery plaques obtained at surgery. Distribution and frequency of cytotoxic- and regulatory T cells, as identified by the expression of Granzyme B (GrB) and FOXP3 was established in NA and AV. Furthermore, we compared the distribution of these cells in AV with the perivascular, interstitial renal tissue using immunohistochemistry. The total number of T cells was much higher in AV than in NA lesions (711±135 and 37±8 CD3/mm2 respectively, p<0.005, mean, ± SEM). Total numbers of FOXP3+ regulatory cells were also significantly increased in AV (36±10 and 0.9±0.3 FOXP3+/mm2 p<0.05), but relative numbers, expressed as a percentage of the total number of CD3+ T cells ((FOXP3+/CD3+) ×100), were not significantly different (4.6%±0.9 and 2.7%±0.6). GrB+ cells were rare in NA, but significantly increased numbers of GrB+ cells were found in AV lesions (85±24 and 0.2±0.1 GrB+/mm2, p<0.05). Perivascular tissues in the allografts showed a higher relative frequency of FOXP3+ cells than adjacent intimal lesions (14.0%±2.7 and 4.6%±0.9, respectively, p<0.05), but a lower frequency of GrB+ cytotoxic T cells (16.1%±2.7 and 22.6%±3.6, p<0.05). Conclusions Similar to NA, AV is characterized by a low frequency of intimal FOXP3+ regulatory T cells. Moreover, significant spatial differences exist in the distribution of functional T cell subsets between the intra- and extravascular micro-environments of the graft.
Collapse
|
|
49
|
Sun Q, Cheng D, Zhang M, He Q, Chen Z, Liu Z. Predominance of intraglomerular T-bet or GATA3 may determine mechanism of transplant rejection. J Am Soc Nephrol 2011; 22:246-52. [PMID: 21289214 DOI: 10.1681/asn.2010050471] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The transcription factors T-bet and GATA3 determine the differentiation of helper T cells into Th1 or Th2 cells, respectively. An altered ratio of their relative expression promotes the pathogenesis of certain immunological diseases, but whether this may also contribute to the pathogenesis of antibody-mediated rejection (ABMR) versus T cell-mediated rejection (TCMR) is unknown. Here, we characterized the intragraft expression of T-bet and GATA3 and determined the correlation of their levels with the presence of typical lesions of ABMR and TCMR. We found a predominant intraglomerular expression of T-bet in patients with ABMR, which was distinct from that in patients with TCMR. In ABMR, interstitial T-bet expression was typically located in peritubular capillaries, although the overall quantity of interstitial T-bet was less than that observed in TCMR. The expression of intraglomerular T-bet correlated with infiltration of CD4+ and CD8+ lymphocytes, which express T-bet, as well as intraglomerular CD68+ monocyte/macrophages, which do not express T-bet. The predominance of intraglomerular T-bet expression relative to GATA3 expression associated with poor response to treatment with bolus steroid. In summary, predominance of intraglomerular T-bet expression correlates with antibody-mediated rejection and resistance to steroid treatment.
Collapse
Affiliation(s)
- Qiquan Sun
- Research Institute of Nephrology, Jinling Hospital, 305 East Zhong Shan Road, Nanjing 210002, China
| | | | | | | | | | | |
Collapse
|
|
50
|
Colvin RB, Hirohashi T, Farris AB, Minnei F, Collins AB, Smith RN. Emerging role of B cells in chronic allograft dysfunction. Kidney Int 2011:S13-7. [PMID: 21116310 DOI: 10.1038/ki.2010.436] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss.
Collapse
Affiliation(s)
- Robert B Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
| | | | | | | | | | | |
Collapse
|