-
Richard Danger,
Chloé Paul, Magali Giral,
Amélie Lavault,
Yohann Foucher,
Nicolas Degauque,
Annaïck Pallier,
Maxim Durand,
Stéphanie Castagnet,
Jean-Paul Duong Van Huyen,
Michel Delahousse,
Karine Renaudin,
Jean-Paul Soulillou,
Sophie Brouard
[show abstract]
[hide abstract]
ABSTRACT: In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR) to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC) of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056). Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.
PLoS ONE 01/2013; 8(4):e60702. · 4.09 Impact Factor
-
Patrick Miqueu,
Nicolas Degauque,
Marina Guillet, Magali Giral,
Catherine Ruiz,
Annaïck Pallier,
Cécile Braudeau,
Gwenaëlle Roussey-Kesler,
Joanna Ashton-Chess,
Jean-Christophe Doré, [......],
Anthony N Warrens,
Michel Goldman,
Hans-Dieter Volk,
Uwe Janssen,
Kathryn J Wood,
Robert I Lechler,
Dominique Bertrand,
Véronique Sébille,
Jean-Paul Soulillou,
Sophie Brouard
-
[show abstract]
[hide abstract]
ABSTRACT: Pathogenesis of antibody (Ab) responses to transplant are yet not well defined. This study aimed to detect and to analyze posttransplant circulating allo-Abs reacting toward graft endothelial cells (ECs) using primary EC cultures prospectively isolated from the transplant donor at the time of transplantation.
This study shows a retrospective analysis performed using a dedicated EC crossmatch (ECXM) assay that we developed for the experimental assessment of donor-specific EC-reactive Abs. Donor-specific ECXM was performed by flow cytometry on posttransplant sera (n=256) from an historical cohort of 22 kidney allograft recipients.
In this study, we show that 27.3% (6/22) of recipients have a positive ECXM that strictly correlates (100%, 6/6) with the presence of anti-human leukocyte antigen (HLA) Abs posttransplantation. ECXM identifies both donor-specific Abs (DSA; 50%) and non-DSA (50%) reactive to EC. DSA and non-DSA are mostly IgG1 and exhibit peak titers ranging from 1/8 to 1/1024. ECXM indicates that DSA correspond to anti-HLA class II Abs; this immunization is late (M3-M60) but persistent (still detected at M60). In contrast, non-DSA are non-HLA-type Abs reacting with third-party EC and reflecting an early but transient immunization (ended at M3-M12). Our findings demonstrate selective regulatory pathways initiated by anti-HLA class II and non-DSA in graft EC reflected by CCR4 and interleukin 1β up-regulation, respectively.
We provide evidence that circulating Abs in HLA-sensitized transplant recipients include both DSA and non-HLA/non-DSA able to bind to graft EC and induce specific gene transcription.
Transplantation 02/2012; 93(3):257-64. · 4.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Achieving drug-free tolerance or successfully using only small doses of immunosuppression is a major goal in organ transplantation. To investigate the potential mechanisms by which some kidney transplant recipients can achieve operational tolerance, we compared the expression profiles of microRNA in peripheral blood mononuclear cells of operationally tolerant patients with those of stable patients treated with conventional immunosuppression. B cells from operationally tolerant patients overexpressed miR-142-3p. The expression of miR-142-3p was stable over time and was not modulated by immunosuppression. In Raji B cells, overexpression of miR-142-3p modulated nearly 1000 genes related to the immune response of B cells, including potential miR-142-3p targets and molecules previously identified in the blood of operationally tolerant patients. Furthermore, our results suggested that a negative feedback loop involving TGF-β signaling and miR-142-3p expression in B cells may contribute to the maintenance of tolerance. In summary, miR-142-3p expression in peripheral blood mononuclear cells correlates with operational tolerance. Whether upregulation of miR-142-3p modulates inflammatory responses to promote tolerance or is a result of this tolerance state requires further study.
Journal of the American Society of Nephrology 01/2012; 23(4):597-606. · 9.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The determination of a cut-off value for a continuous prognostic test is an important problem, which is statistically challenging and practically important for risk assessment. We propose in this paper a method to estimate the optimal cut-off from this type of longitudinal data with censored failure times. The principle is to combine the prognostic error rates of false positives and false negatives with a cost function, which has the advantages to be statistically convenient and to be directly associated with the decision-making. Simulations were performed and the results demonstrate the interest of our approach compared to a reference method. The method is also illustrated by predicting the long-term survival of kidney transplant recipients from the 1-year creatinine clearance.
The International Journal of Biostatistics 01/2012; 8(1). · 1.28 Impact Factor
-
Katy Trébern-Launay,
Yohann Foucher, Magali Giral,
Christophe Legendre,
Henri Kreis,
Michèle Kessler,
Marc Ladrière,
Nassim Kamar,
Lionel Rostaing,
Valérie Garrigue,
Georges Mourad,
Emmanuel Morelon,
Jean-Paul Soulillou,
Jacques Dantal
[show abstract]
[hide abstract]
ABSTRACT: Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate.
To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (N = 3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization.
We showed that STR have a higher risk of graft failure than FTR (HR = 2.18, p = 0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HR = 1.01, p = 0.9675) or steroid-resistant ARE (HR = 1.27, p = 0.4087).
The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally.
PLoS ONE 01/2012; 7(10):e47915. · 4.09 Impact Factor
-
Sophie Brouard,
Alice Le Bars,
Alexandre Dufay,
Morgane Gosselin,
Yohann Foucher,
Marina Guillet,
Anne Cesbron-Gautier,
Eric Thervet,
Christophe Legendre,
Emilie Dugast,
Annaick Pallier,
Cécile Guillot-Gueguen,
Laetitia Lagoutte,
Gwenaelle Evanno, Magali Giral,
Jean-Paul Soulillou
[show abstract]
[hide abstract]
ABSTRACT: Despite their utility, immunosuppressive treatments have numerous side effects, including infectious complications, malignancies and metabolic disorders, all of which contribute to long-term graft loss. In addition to the development of new pharmaceutical products with reduced toxicity and more comfortable modes of administration, tailoring immunosuppression according to the immune status of each patient would represent a significant breakthrough. Gene expression profiling has been shown to be a clinically relevant monitoring tool. In this paper, we have assessed the overall long-term kidney transplant outcome and attempted to identify operationally tolerant-like patients among recipients with stable clinical status at least 5 years post-transplantation. We thus measured a combination of noninvasive blood biomarkers of operational tolerance in a cohort of 144 stable patients and showed that only 3.5% exhibited a gene expression profile of operational tolerance, suggesting that such a profile can be detected under immunosuppressive therapy but that its frequency is low in kidney transplant recipients when compared with liver transplant recipients. We suggest that a rational approach to patient selection, based on a combination of clinical and biological characteristics, may help to provide a safer method for identification of patients potentially suitable for immunosuppressive drug weaning procedures.
Transplant International 04/2011; 24(6):536-47. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Large analyses have demonstrated that pre-emptive kidney transplantation (PKT) leads to significant improvements in patient and graft survival when compared with transplantation performed after a period of dialysis. We analysed 1585 patients who received a first renal transplantation from a deceased donor between 2000 and 2004 in four French transplantation centres. The objective was to compare the characteristics of the deceased donor transplantations with or without previous dialysis and to evaluate the impact of PKT and length of dialysis on patient and graft outcomes. Mean age of recipients was 48.1 ± 13.4 years, 62% were men, and 118 (7.4%) of them received a pre-emptive transplantation. For the nonpre-emptive patients, mean time on pretransplant dialysis was 3.4 ± 3.2 years. Pretransplant factors independently related to pre-emptive transplantation were year of transplantation, centre and recipients characteristics: gender, diabetes history, blood group and donor age. Patients with pretransplant dialysis were three times more likely to have delayed graft function than pre-emptive transplant patients, and were 10 times more likely to receive post-transplant dialysis. Five-year patient survival was 92.9%. Five-year graft survival was 89.0%. Neither pre-emptive transplantation nor time on dialysis was significantly associated with patient and/or graft survival.
Transplant International 03/2011; 24(3):266-75. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Successful kidney transplant management throughout the graft lifespan depends on adequate diagnosis (i.e., recognition of a particular type of graft rejection or injury) and prognosis (i.e., predicting future events or outcome). The currently used methods (mainly graft histology, immunosuppressive drug level monitoring, measurement of renal function, and DSA) have proven highly useful on a population level by indicating good or bad outcome, but are difficult to translate into meaningful tests for individual patients. There is thus a need for diagnostic and predictive tests that add value by being more informative to each patient, more powerful, addressing more specific questions or providing less invasive interventions. Gene expression profiling using microarrays or quantitative PCR has become a benchmark in research into novel and informative monitoring assays for transplantation. A wealth of gene expression studies are reported in the literature spanning two decades. There is now a need for clinical validation so that such tests can become standardized and approved for widespread integration into the standard of care to improve outcome for kidney transplant recipients.
Transplantation 01/2011; 91(7):691-6. · 4.00 Impact Factor
-
Maud Racapé,
Jean-Paul Duong Van Huyen,
Richard Danger, Magali Giral,
Françoise Bleicher,
Yohann Foucher,
Annaïck Pallier,
Paul Pilet,
Petra Tafelmeyer,
Joanna Ashton-Chess,
Emilie Dugast,
Ségolène Pettré,
Béatrice Charreau,
Jean-Paul Soulillou,
Sophie Brouard
[show abstract]
[hide abstract]
ABSTRACT: The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.
We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.
In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance.
PLoS ONE 01/2011; 6(5):e19321. · 4.09 Impact Factor
-
Yohann Foucher,
Pascal Daguin,
Ahmed Akl,
Michèle Kessler,
Marc Ladrière,
Christophe Legendre,
Henri Kreis,
Lionel Rostaing,
Nassim Kamar,
Georges Mourad,
Valérie Garrigue,
François Bayle,
Bruno H de Ligny,
Mathias Büchler,
Carole Meier,
Jean P Daurès,
Jean-Paul Soulillou, Magali Giral
[show abstract]
[hide abstract]
ABSTRACT: Determining early surrogate markers of long-term graft outcome is important for optimal medical management. In order to identify such markers, we used clinical information from a cross-validated French database (Données Informatisées et VAlidées en Transplantation) of 2169 kidney transplant recipients to construct a composite score 1 year after transplantation. This Kidney Transplant Failure Score took into account a series of eight accepted pre- and post-transplant risk factors of graft loss, and was subsequently evaluated for its ability to predict graft failure at 8 years. This algorithm outperformed the traditional surrogates of serum creatinine and the estimated graft filtration rate, with an area under the receiver-operator characteristic curve of 0.78. Validation on an independent database of 317 graft recipients had the same predictive capacity. Our algorithm was also able to stratify patients into two groups according to their risk: a high-risk group of 81 patients with 25% graft failure and a low-risk group of 236 patients with an 8% failure rate. Thus, although this clinical composite score predicts long-term graft survival, it needs validation in different patient groups throughout the world.
Kidney International 12/2010; 78(12):1288-94. · 6.61 Impact Factor
-
Patrick Miqueu,
Nicolas Degauque,
Marina Guillet, Magali Giral,
Catherine Ruiz,
Annaïck Pallier,
Cécile Braudeau,
Gwenaëlle Roussey-Kesler,
Joanna Ashton-Chess,
Jean-Christophe Doré, [......],
Anthony N Warrens,
Michel Goldman,
Hans-Dieter Volk,
Uwe Janssen,
Kathryn J Wood,
Robert I Lechler,
Dominique Bertrand,
Véronique Sébille,
Jean-Paul Soulillou,
Sophie Brouard
[show abstract]
[hide abstract]
ABSTRACT: The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8(+) /CD4(+) T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation.
European Journal of Immunology 11/2010; 40(11):3280-90. · 5.10 Impact Factor
-
Annaick Pallier,
Sophie Hillion,
Richard Danger, Magali Giral,
Maud Racapé,
Nicolas Degauque,
Emilie Dugast,
Joanna Ashton-Chess,
Ségolène Pettré,
Juan José Lozano,
Régis Bataille,
Anne Devys,
Anne Cesbron-Gautier,
Cécile Braudeau,
Catherine Larrose,
Jean-Paul Soulillou,
Sophie Brouard
[show abstract]
[hide abstract]
ABSTRACT: Several transplant patients maintain stable kidney graft function in the absence of immunosuppression. Here we compared the characteristics of their peripheral B cells to that of others who had stable graft function but were under pharmacologic immunosuppression, to patients with chronic rejection and to healthy volunteers. In drug-free long-term graft function (DF) there was a significant increase in both absolute cell number and frequency of total B cells; particularly activated, memory and early memory B cells. These increased B-cell numbers were associated with a significantly enriched transcriptional B-cell profile. Costimulatory/migratory molecules (B7-2/CD80, CD40, and CD62L) were upregulated in B cells; particularly in memory CD19(+)IgD(-)CD38(+/-)CD27(+) B cells in these patients. Their purified B cells, however, responded normally to a polyclonal stimulation and did not have cytokine polarization. This phenotype was associated with the following specific characteristics which include an inhibitory signal (decreased FcgammaRIIA/FcgammaRIIB ratio); a preventive signal of hyperactive B-cell response (an increase in BANK1, which negatively modulates CD40-mediated AKT activation); an increased number of B cells expressing CD1d and CD5; an increased BAFF-R/BAFF ratio that could explain why these patients have more peripheral B cells; and a specific autoantibody profile. Thus, our findings show that patients with DF have a particular blood B-cell phenotype that may contribute to the maintenance of long-term graft function.
Kidney International 09/2010; 78(5):503-13. · 6.61 Impact Factor
-
Pallier A,
Hillion S,
Danger R, Giral M,
Racapé M,
Degauque N,
Dugast E,
Ashton-Chess J,
Pettré S,
Lozano JJ,
Bataille R,
Devys A,
Cesbron-Gautier A,
Braudeau C,
Larrose C,
Soulillou JP,
Brouard S
[show abstract]
[hide abstract]
ABSTRACT: Several transplant patients maintain stable kidney graft function in the absence of immunosuppression. Here we compared the characteristics of their peripheral B cells to that of others who had stable graft function but were under pharmacologic immunosuppression, to patients with chronic rejection and to healthy volunteers. In drug-free long-term graft function (DF) there was a significant increase in both absolute cell number and frequency of total B cells; particularly activated, memory and early memory B cells. These increased B-cell numbers were associated with a significantly enriched transcriptional B-cell profile. Costimulatory/migratory molecules (B7-2/CD80, CD40, and CD62L) were upregulated in B cells; particularly in memory CD19+IgD−CD38+/−CD27+ B cells in these patients. Their purified B cells, however, responded normally to a polyclonal stimulation and did not have cytokine polarization. This phenotype was associated with the following specific characteristics which include an inhibitory signal (decreased FcγRIIA/FcγRIIB ratio); a preventive signal of hyperactive B-cell response (an increase in BANK1, which negatively modulates CD40-mediated AKT activation); an increased number of B cells expressing CD1d and CD5; an increased BAFF-R/BAFF ratio that could explain why these patients have more peripheral B cells; and a specific autoantibody profile. Thus, our findings show that patients with DF have a particular blood B-cell phenotype that may contribute to the maintenance of long-term graft function.Keywords: B cells; cell surface molecules; human; tolerance; transplantation
Kidney International 06/2010; 78(5):503-513. · 6.61 Impact Factor
-
Magali Giral,
Yohann Foucher,
Georges Karam,
Yann Labrune,
Michelle Kessler,
Bruno Hurault de Ligny,
Mathias Büchler,
François Bayle,
Carole Meyer,
Nathalie Trehet,
Pascal Daguin,
Karine Renaudin,
Anne Moreau,
Jean Paul Soulillou
[show abstract]
[hide abstract]
ABSTRACT: Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (<2.3 g/kg; P<0.0001). In this low KwRw ratio group, the graft filtration rate remained stable between 6 months and 7 years but then decreased at a mean rate of 3.17 ml/min per yr (P<0.0001). In addition, low KwRw ratios conferred greater risk for proteinuria, more antihypertensive drugs, and segmental or global glomerulosclerosis. Moreover, a KwRw ratio<2.3 g/kg associated with a 55% increased risk for transplant failure by 2 years of follow-up. In conclusion, incompatibility between graft and recipient weight is an independent predictor of long-term graft survival, suggesting that avoiding kidney and recipient weight incompatibility may improve late clinical outcome after kidney transplantation.
Journal of the American Society of Nephrology 06/2010; 21(6):1022-9. · 9.66 Impact Factor
-
Pervinder Sagoo,
Esperanza Perucha,
Birgit Sawitzki,
Stefan Tomiuk,
David A Stephens,
Patrick Miqueu,
Stephanie Chapman,
Ligia Craciun,
Ruhena Sergeant,
Sophie Brouard, [......],
Michel Goldman,
Kathryn J Wood,
Kenneth Newell,
Vicki Seyfert-Margolis,
Anthony N Warrens,
Uwe Janssen,
Hans-Dieter Volk,
Jean-Paul Soulillou,
Maria P Hernandez-Fuentes,
Robert I Lechler
[show abstract]
[hide abstract]
ABSTRACT: Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
The Journal of clinical investigation 06/2010; 120(6):1848-61. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We followed up 550 primary kidney transplant recipients in an observational retrospective cohort to evaluate the impact of three consecutive cytomegalovirus (CMV) prevention strategies. In period 1 (1996-2000; n = 190), no anti-CMV prophylaxis was given; in period 2 (2000-2004; n = 173), 6-month valacyclovir was given and in period 3 (>2004; n = 187), 6-month valganciclovir was given. Cytomegalovirus disease significantly decreased from 33.2% in period 1 to 13.9% in period 2 and to 8.6% in period 3; onset was significantly prolonged with valganciclovir (228 days) compared with valacyclovir (93 days) and with no prophylaxis (33 days). After Cox regression adjustments, both valganciclovir and valacyclovir were similarly protective factors for CMV disease. Cytomegalovirus diseases encountered in both valacyclovir and valganciclovir groups were primary infections (79.2 and 93.8% respectively) as compared with a significant low number (39.7%) in the nonprophylaxis group. Two cases of valganciclovir resistance were recorded in the valganciclovir group and no resistance was seen with valacyclovir. A significantly reduced incidence of other herpes viruses was only observed with valganciclovir. Valganciclovir was better tolerated than valacyclovir and this long-term prophylaxis was applicable to 85% of patients. Longer follow-up of valganciclovir or valacyclovir prophylaxis is still required to appreciate its impact on graft and patient survivals, as well as other indirect effects, in the mycophenolate mofetil and calcineurin inhibitor immunosuppressive era.
Transplant International 03/2010; 23(9):897-906. · 2.92 Impact Factor
-
Joanna Ashton-Chess,
Hoa Le Mai,
Vojislav Jovanovic,
Karine Renaudin,
Yohann Foucher, Magali Giral,
Anne Moreau,
Emilie Dugast,
Michael Mengel,
Maud Racapé,
Richard Danger,
Claire Usal,
Helga Smit,
Marina Guillet,
Wilfried Gwinner,
Ludmilla Le Berre,
Jacques Dantal,
Jean-Paul Soulillou,
Sophie Brouard
[show abstract]
[hide abstract]
ABSTRACT: Chronic active antibody-mediated rejection is a form of late rejection with a poor prognosis. To identify specific markers of this, we analyzed several microarray studies in the literature and performed mRNA profiling of 65 biopsies and 165 blood samples of a large cohort of renal transplant patients with precisely characterized pathologies. Immunoproteasome beta subunit 10 was found to be specifically increased in the graft and blood samples during chronic active antibody-mediated rejection and was also significantly increased in rat cardiac allografts undergoing acute rejection as well as chronic active antibody-mediated rejection. This syndrome is characterized by chronic transplant vasculopathy associated with diffuse C4d staining and circulating donor-specific antibodies. Using this animal model, we found that administration of the proteasome inhibitor, Bortezomib, delayed acute rejection and attenuated the humoral response in both the acute phase and established state of this syndrome in a dose-dependent manner. Following treatment with this reagent, donor-specific antibodies and C4d deposition were reduced. These studies highlight the role of the proteasome in chronic rejection and identify this molecule as a marker of this syndrome.
Kidney International 02/2010; 77(10):880-90. · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Despite great improvements in renal allograft survival over the last 3 decades, long-term graft loss, particularly through antibody-mediated rejection, remains the bane of kidney transplantation. Interindividual patient variation means that a given immunosuppressive regimen may be inadequate in certain patients and excessive in others. Currently, there is no way of personalizing such treatments. We believe that this may be made possible by evaluating the degree of immunologic "risk" in a transplant recipient. Such immunological risk assessment would enable those patients at low risk to be at least partially or totally weaned from immunosuppression, whereas those at high risk could benefit from an increase or adjustment in their immunosuppression. Here, we outline our own group's efforts in the identification of peripheral blood biomarkers of high- and low-immunologic risk in relationship to the current literature on the subject.
Transplantation 06/2009; 87(9 Suppl):S95-9. · 4.00 Impact Factor
-
Joanna Ashton-Chess,
Emilie Dugast,
Robert B Colvin, Magali Giral,
Yohann Foucher,
Anne Moreau,
Karine Renaudin,
Christophe Braud,
Anne Devys,
Sophie Brouard,
Jean-Paul Soulillou
[show abstract]
[hide abstract]
ABSTRACT: Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3+ cells seem to be an inherent component of acute rejection (AR) in human recipients of renal transplants. The balance between regulatory cells and effector/cytotoxic cells may determine graft outcome; this balance has not been described for chronic allograft injury. We investigated the expression of key regulatory, effector, and cytotoxic transcripts (i.e., FOXP3, T-bet, and granzyme B, respectively) in the grafts and peripheral blood of long-term-surviving renal transplant patients. We found that, whereas neither intragraft nor peripheral blood FOXP3 or T-bet mRNA could distinguish between rejection and nonrejection status, granzyme B (GrzB) mRNA could: It was significantly increased in the graft and significantly decreased in the peripheral blood of patients with chronic antibody-mediated rejection (CAMR). Quantifying peripheral blood GrzB mRNA demonstrated potential to aid in the noninvasive diagnosis of CAMR. In summary, these data affirm GrzB as a marker not only for AR but also for CAMR. In addition, we identified several previously unreported clinical or demographic factors influencing regulatory/effector/cytotoxic profiles in the peripheral blood, highlighting the necessity to consider confounding variables when considering the use of potential biomarkers, such as FOXP3, for diagnosis or prognosis in kidney transplantation.
Journal of the American Society of Nephrology 05/2009; 20(5):1113-22. · 9.66 Impact Factor
