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Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients.

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.

SUBMITTER: Ashton-Chess J

PROVIDER: S-EPMC2678031 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients.

Ashton-Chess Joanna J Dugast Emilie E Colvin Robert B RB Giral Magali M Foucher Yohann Y Moreau Anne A Renaudin Karine K Braud Christophe C Devys Anne A Brouard Sophie S Soulillou Jean-Paul JP

Journal of the American Society of Nephrology : JASN 20090408 5

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 gran ...[more]

PMID: 19357258

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Project description:Background: We aimed to investigate the effects of intravenous immune globulin (IVIG) and rituximab desensitization treatment on kidney transplant rate and blood gene expression profiles by microrarrays. Methods: We enrolled patients with PRA levels >50% and on the deceased-donor waiting list for >5 years. Patients received IVIG (2.0 g/kg) on day 0 and 30; and rituximab (375 mg/m2) on day 15. The antibodies with mean fluorescence intensity (MFI) values > 5,000 were reported to UNET as unacceptable antigens. The gene expression profiles of blood samples collected in PAXGene tube were studied by Affymetrix HuGene 1.0 ST expression arrays. Results: 40 of the 415 patients (10%) on the waiting list were eligible for desensitization treatment and 11 completed the treatment. While 15 of the remaining 29 patients (52%) received a transplant without therapy, only 2 of the 11 desensitized patients (18%) received transplant during a median follow-up of 217 days. While there were no statistically significant difference in demographics, desensitized patients had higher cPRA values (97% vs. 77%, p=0.0005) and more number of unacceptable antigens (39 vs. 10, p=0.0001). There was no significant change in the mean number of unacceptable antigens (39 ± 22 versus 39 ± 23) or reduction in the mean MFI values (11,333 ± 3,133 vs 11,289 ± 3,386). Analysis of genes chosen as significantly differentially expressed revealed downregulation of genes involved in B cells and immune system (CD79a, B and T lymphocyte associated transcript, B cell scaffold protein, CD22, CXCR5, fas apoptotic inhibitory protein). Gene set enrichment analysis using Pathogenesis Based Transcripts created by Edmonton Group demonstrated significant downregulation of B cell associated (p=0.04) and immunoglobulin transcripts (p=0.03). Conclusion: Although, desensitization with IVIG and rituximab decreases the expression of B cell and immunoglobulin associated transcripts, it was not successful in increasing kidney transplant rate or in decreasing the number of unacceptable antigens. Total of 28 arrays included in this study, which corresponding to 9 individuals with paired pre/post treatment samples and an additional 10 untreated control individuals. pair_analysis_normData.txt for paired analysis of pre/post treatment; ordinary_analysis_normData.txt for non-paired analysis include all samples, except for 38 Pax V0 and 56 Pax V1, which shows technicial bias and lowest array quality, hence removed from analysis.

Project description:BackgroundWe previously reported early on-treatment significant modulation in circulating regulatory T cell (Treg), myeloid derived suppressor cells (MDSC) and antigen-specific type I CD4+ and CD8+ T cells that correlated with clinical outcome in regionally advanced melanoma patients treated with neoadjuvant ipilimumab. Here, we investigated the long term immunologic impact of CTLA4 blockade.MethodsPatients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery. Blood specimens were collected at baseline and during treatment for up to 9 months. We tested immune responses at 3, 6, and 9 months utilizing multicolor flow cytometry. We compared frequencies of circulating Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1).ResultsLevels of Treg significantly increased when measured at 6 weeks following ipilimumab but returned to baseline by 3 months, with no significant difference in Treg levels between relapsed and relapse-free groups at 3, 6 or 9 months. However, lower baseline levels of circulating Treg (CD4+CD25hi+CD39+) were significantly associated with better relapse free survival (RFS) (p = 0.04). Levels of circulating monocytic HLA-DR+/loCD14+ MDSC were lower at baseline in the relapse-free group and further decreased at 6 weeks, though the differences did not reach statistical significance including measurements at 3, 6 or 9 months. We detected evidence of type I (interferon-γ producing), activated (CD69+) CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly boosted at 6 weeks and persisted at 3, 6 and 9 months following the initiation of ipilimumab.ConclusionsLower Treg levels at baseline are significantly associated with RFS and increased Treg frequency after CTLA4 blockade was only transient. Lower MDSC was also associated with RFS and MDSC levels were further decreased after ipilimumab. Tumor specific effector immune responses are boosted with CTLA4 blockade and tend to be durable. Trial registration ClinicalTrials.gov Identifier: NCT00972933.

Dataset Information

Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients.

Publications

Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients.

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