Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection

Obata, Fumiya; Yoshida, Kazunari; Ohkubo, M; Ikeda, Yuki; Taoka, Yoshinori; Takeuchi, Yasuo; Shinohara, Nobukata; Endo, Takuro; Baba, Shirō

doi:10.1016/j.trim.2004.11.003

Cited by 40 publications

(31 citation statements)

References 17 publications

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“…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: Discussionsupporting

confidence: 49%

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

et al. 2010

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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...

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Section: Discussionsupporting

confidence: 49%

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

et al. 2010

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“…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.…”

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confidence: 62%

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

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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.

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“…A Th1 response is associated with transplant rejection, while a Th2 response may contribute to tolerance and stable graft survival (Wadia and Tambur, 2008). Expression of IFN-γ was found to be elevated in heart and kidney transplants of recipients during rejection (Saiura et al, 2001;Obata et al, 2005). However, others reported that the rejection was aggravated in the heart and kidney implants when the IFN-γ gene was knocked out (Halloran et al, 2001;Miura et al, 2003).…”

Section: Cd4mentioning

confidence: 99%

Th17 promotes acute rejection following liver transplantation in rats

Xie

Zhou

et al. 2010

J. Zhejiang Univ. Sci. B

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T help cell 17 (Th17), recently identified as a new subset of CD4 + T cells, has been implicated in autoimmune diseases, tumor immunity, and transplant rejection. To investigate the role of Th17 in acute hepatic rejection, a rat model of allogeneic liver transplantation (Dark Agouti (DA) to Brown Norway (BN)) was established and isogeneic liver transplantation (BN to BN) was used as controls in the study. The expression of Th17-related cytokines in the liver and peripheral blood was determined by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), or real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Strong expression of interleukin-17A (IL-17A), IL-6, transforming growth factor-β (TGF-β), IL-8, and myeloperoxidase (MPO) was observed in liver allografts. The ratios of Th17 to CD4 + lymphocytes in the liver and peripheral blood were dramatically increased in the allograft group compared with the control (P<0.01). Secreted IL-17 and IL-6 in liver homogenate and serum were significantly elevated in the allograft group, while secreted TGF-β was increased in liver homogenate and decreased in serum compared with the control (P<0.01). The messenger RNA (mRNA) levels of IL-17, IL-21, and IL-23 were enhanced in the allografts compared with the control (P<0.01). Correlation analysis showed significant correlations between IL-17 and IL-6 and TGF-β and between IL-17 and IL-21 and IL-23. The present study demonstrates that Th17 plays a role in promoting rat liver allograft rejection.

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Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection

Cited by 40 publications

References 17 publications

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

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

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

Th17 promotes acute rejection following liver transplantation in rats

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