Noninvasive Diagnosis of Cellular and Antibody-Mediated Rejection by Perforin and Granzyme B in Renal Allografts

Veale, Jeffrey L.; Liang, Leonard W.; Zhang, Qiuheng; Gjertson, David W.; Du, Ziyun; Bloomquist, Erik; Jia, Juan; Qian, Lei; Wilkinson, Alan H.; Danovitch, Gabriel M.; Pham, Phuong‐Thu T.; Rosenthal, J. Thomas; Lassman, Charles; Braun, Jonathan; Reed, Elaine F.; Gritsch, H. Albin

doi:10.1016/j.humimm.2006.07.006

Cited by 49 publications

(45 citation statements)

References 33 publications

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“…For this molecule, measuring the mRNA appeared more sensitive than measuring the protein. We additionally show for the first time that, in contrast to acute rejection where GrzB is increased in the PBMC, 16,17,26 during CAMR GrzB is significantly decreased. Furthermore, ROC analysis revealed that measuring GrzB mRNA may have potential as a decision-making tool in clinical practice to diagnose CAMR in a minimally invasive manner.…”

Section: Discussionmentioning

confidence: 65%

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Ashton‐Chess

Dugast²,

Colvin³

et al. 2009

Journal of the American Society of Nephrology

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Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3ϩ 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.

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Section: Discussionmentioning

confidence: 65%

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Ashton‐Chess

Dugast²,

Colvin³

et al. 2009

Journal of the American Society of Nephrology

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“…31 Moreover, this study focused on chronic injury, but TRIB1 could also be increased in acute rejection. TRIB1 differs from the other minimally invasive biomarkers of transplant rejection described to date that are of T/NK cell origin, [7][8][9]32 in that it is expressed primarily by APC as well as EC. As such, our findings point toward a possible but as yet unconfirmed role for APC in this pathology.…”

Section: Discussionmentioning

confidence: 98%

“…Such an approach has proved successful in the case of acute cellular rejection, for which urine levels of Granzyme B and FOXP3 transcripts have been shown to have diagnostic and prognostic value. [7][8][9] In the case of late graft injury, attention has been paid to genome-wide profiling in the search for biomarkers. 10 -14 Although such studies have thrown light onto the gene pathways concerned, the analyses were performed on graft biopsies, meaning that the genes identified might not be applicable to a noninvasive approach.…”

mentioning

confidence: 99%

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Ashton‐Chess

Giral

Mengel³

et al. 2008

Journal of the American Society of Nephrology

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Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue biomarker of chronic antibody-mediated rejection, an active immune-mediated form of chronic allograft failure associated with a poor prognosis. TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity. TRIB1 was also upregulated in a rodent model of chronic cardiac vasculopathy, suggesting that this biomarker may be useful in other solid-organ transplants and across species. It was determined that TRIB1 is expressed primarily by antigen-presenting cells and activated endothelial cells. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-mediated allograft failure.

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“…Similar effects have also been observed in solid organ transplantation. Gr (and also perforin) levels were elevated during acute early cardiac rejection, 15,16 acute pancreas rejection, 17 kidney allograft rejection, [18][19][20] acute liver rejection, 21 acute lung rejection 22,23 and ongoing islet allograft loss. 24 Recent data suggest that molecular monitoring of GrB/perforin gene expression might be used along with clinical criteria to detect presymptomatic acute rejection after intestinal transplantation.…”

Section: Discussionmentioning

confidence: 99%

Granzymes A and B serum levels in allo-SCT

Kircher

Schumacher

Nachbaur

2008

Bone Marrow Transplant

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Activated cytotoxic T lymphocytes and natural killer cells, which are involved in the pathogenesis of GVHD and viral infections after SCT produce granzymes (Grs). This study performed an ELISA in the serum of 86 patients at various time points before and after Allo-SCT to investigate GrA and GrB levels as potential markers for these serious complications. The increase in Gr levels from the day of transplantation until the appearance of the complication was highly predictive. If GrA increased to three times its pretransplant level, the cumulative incidence of developing acute GVHD was 73% and for CMV infection 68%, in comparison with 45 and 35%, respectively, for patients without these complications. A strong increase in GrA level correlated with clinical severity of acute GVHD. No correlation was observed with early relapse or long-term overall survival. In addition to clinical parameters, a strong increase in GrA levels was identified as an independent marker for the occurrence of acute GVHD as well as for CMV infection. Similar effects were observed with GrB. In conclusion, Gr protein levels can also be used as a marker for complications after Allo-SCT.

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Noninvasive Diagnosis of Cellular and Antibody-Mediated Rejection by Perforin and Granzyme B in Renal Allografts

Cited by 49 publications

References 33 publications

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Regulatory, Effector, and Cytotoxic T Cell Profiles in Long-Term Kidney Transplant Patients

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Granzymes A and B serum levels in allo-SCT

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