Predominant Th1 and Cytotoxic Phenotype in Biopsies from Renal Transplant Recipients with Transplant Glomerulopathy

Homs, Sébastien; Mansour, Hicham; Desvaux, Dominique; Diet, Carine; Hazan, Marc; Büchler, Matthias; Lebranchu, Yvon; Buob, David; Badoual, Cécile; Matignon, Marie; Audard, Vincent; Lang, Philippe; Grimbert, Philippe

doi:10.1111/j.1600-6143.2009.02596.x

Cited by 48 publications

(38 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 This profile was associated with transcript coding for granzyme B (GZM-B) in the graft. [9][10][11] Similar observations made in the blood of CAMR patients reported a restricted TCR Vb repertoire, an increase in IFN-g, GZM-B, and perforin-1 (PERF-1) transcripts, and an increase in CD8 T cells. [12][13][14] These observations suggest that alteration in the TCR Vb repertoire of CD8 T cells may be associated with kidney dysfunction.…”

supporting

confidence: 61%

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Yap

Boeffard

Clave

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

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 Vb 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 Vb diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA + CCR7 2 CD27 2 CD28 2 ) 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-a and IFN-g. 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.

show abstract

supporting

confidence: 61%

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Yap

Boeffard

Clave

et al. 2014

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…We then can hypothesize that such peripheral expansions, and particularly in patients with chronic rejection, could be related to dominant indirect [3] or direct [30] alloimmune responses against the graft. The role of T cells and especially CD8 1 T cells had been likely undermined in the process of chronic rejection, whereas several studies confirmed the presence of CD8 1 T cells infiltrate in the graft [31][32][33]. Moreover, we have shown that blood of animals (as reported here in patients) with chronic rejection exhibited strong alteration of the CD8 1 T-cell repertoire [34].…”

Section: Discussionmentioning

confidence: 55%

Analysis of the peripheral T‐cell repertoire in kidney transplant patients

et al. 2010

View full text Add to dashboard Cite

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 1 /CD4 1 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. 3280 IntroductionTo prevent graft rejection following kidney transplantation, recipients take lifelong immunosuppression. Despite continuous improvements in such treatments, the half-life of a kidney graft has not increased significantly in the past two decades [1]. Manifest by a decrease in renal function that is associated with specific histological lesions [2], chronic rejection remains the major problem of late allograft loss [3]. The identification of biomarkers predictive of chronic rejection in patients with a stable graft function would therefore be a valuable tool in patient management [4][5][6]. In contrast to the patients who develop chronic rejection, rare cases exist of kidney recipients who tolerate their graft despite discontinuation of immunosuppression [7].Operational tolerance and suspicious chronic Ab-mediated rejection are clinical and immunological situations, representing the two opposing endpoints for patients with stable kidney graft function. Indeed, because T cells have been shown to be involved in both chronic rejection and tolerance [8], we have explored the T-cell repertoire in a cohort of patients with stable kidney graft function. We have previously shown, in a small cohort of patients, that both drug-free operationally tolerant patients (TOL patients) and patients with the ''suspicious'' form of chronic rejection (CHR patients) display a TCR repertoire that differs from healthy, nontransplanted individuals [9][10][11]. In this article, we revisit the relationship between peripheral T-cell repertoire and clinical status, using a new statistical method to analyze the TCR repertoires presented as TcLandscape (TcL) data. We show that, despite being selected accordin...

show abstract

“…Our results showed increased expression of QCAT but not of GRIT, DSAST, ENDAT, or NKAT, suggesting cytotoxic T cellmediated but not antibody-mediated chronic injury. Homs et al reported increased expression of IFN-g, T-bet (a marker for Th1 CD4 T cells), and granzyme B (a CD8 marker) in TGP biopsy specimens, suggesting an active T cell-mediated inflammatory and cytotoxic process in the pathogenesis of TGP (11). Several other studies have also recognized that an increased cellular immune response involving T cells and monocytes is associated with the development of TGP (12)(13)(14).…”

Section: Discussionmentioning

confidence: 94%

“…TGP is reported to be associated with donor-specific antibody (DSA), especially class II DSA (5,8), but histologic evidence of TGP may be seen without C4d and DSA (9). Increased chemokine (CXCL9 and CXCL10) and chemokine receptor (CXCR3) expression by glomerular leukocytes, which is associated with effector T cell activation (10) and other T cell-mediated inflammatory or cytotoxic processes (11)(12)(13)(14), have been demonstrated in TGP biopsy specimens. Nonimmune mechanisms may also be associated with TGP, as suggested by a recent report of hepatitis C virus infection (36%) and thrombotic microangiopathy (32%) in 25 patients with TGP (15).…”

Section: Introductionmentioning

confidence: 99%

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

Hayde

Bao

Pullman

et al. 2013

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SummaryBackground This study investigated the mechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays.Design, Setting, Participants, & Measurements This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d2 TGP, 25 DSA2/C4d2 TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays.Results The mean sum score of glomerulitis and peritubular capillaritis increased from 0.2860.78 in IFTA specimens to 0.7560.85 in DSA2/C4d2 TGP specimens, 1.7161.49 in DSA+/C4d2/TGP specimens, and 2.1161.74 in CAMR specimens (P,0.001). During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d2 TGP specimens (14.3%), and DSA2/C4d2 TGP specimens (16%) (P=0.01). With use of microarrays, comparison of the gene expression profiles of DSA2/C4d2 TGP specimens with glomerulitis + peritubular capillaritis scores . 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT). However, both CAMR and DSA+/C4d2 TGP specimens had higher expression of not only QCAT but also IFN-g and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens.Conclusions These results suggested that DSA+/C4d2 TGP biopsy specimens may be classified as CAMR. In contrast, DSA2/C4d2 TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.

show abstract

Predominant Th1 and Cytotoxic Phenotype in Biopsies from Renal Transplant Recipients with Transplant Glomerulopathy

Cited by 48 publications

References 20 publications

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients

Analysis of the peripheral T‐cell repertoire in kidney transplant patients

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

Contact Info

Product

Resources

About