Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28− T-suppressor cells

Sindhi, Rakesh; Manavalan, John S.; Magill, Amy; Suciu‐Foca, Nicole; Zeevi, A.

doi:10.1016/j.humimm.2004.05.017

Cited by 34 publications

(21 citation statements)

References 10 publications

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“…The ability of hMSCs to protect allografts from rejection could be mediated by targeting the effector function of alloreactive T cells. Because the CD8 receptor plays a crucial role during activation of CD8 T cells (Couedel et al, 1999;Gao and Jakobsen, 2000;Holler and Kranz, 2003), and as the CD8+CD282 cells could be protective for the graft (Coley et al, 2009;Colovai et al, 2003;Sindhi et al, 2005), we propose that the beneficial effects of hMSCs observed in the therapeutic context of transplantation occur through the inhibition of CD8 expression and costimulatory molecules. Conversely, this mechanism could explain why MSCs could promote cancer growth (Muehlberg et al, 2009;Prantl et al, 2010).…”

Section: Physiological Relevance Of the Inhibitory Effect Of Hmscs Onmentioning

confidence: 96%

“…The appearance of regulatory CD8 + CD28 2 T suppressor cells is associated with a reduced need for maintenance of immunosuppression in pediatric liver-intestine transplant recipients (Sindhi et al, 2005), as well as in adult-to-adult living donor liver transplantation (Lin et al, 2009). Studies in heart transplant patients indicate that CD8 + CD28 2 T suppressor cells upregulate the inhibitory receptors ILT-3 and ILT-4 on APCs (Chang et al, 2002).…”

Section: Physiological Relevance Of the Inhibitory Effect Of Hmscs Onmentioning

confidence: 99%

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Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Hof-Nahor¹,

Leshansky²,

Shivtiel³

et al. 2012

Journal of Cell Science

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SummaryThe mechanisms underlying the immunomodulatory effects of mesenchymal stem cells (MSCs) have been investigated under extreme conditions of strong T cell activation, which induces the rapid death of activated lymphocytes. The objective of this study was to investigate these mechanisms in the absence of additional polyclonal activation. In co-cultures of peripheral mononuclear blood cells with human MSCs (hereafter referred to as hMSCs), we observed a striking decrease in the level of CD8 expression on CD8+ cells, together with decreased expression of CD28 and CD44, and impaired production of IFN-gamma and Granzyme B. This effect was specific to hMSCs, because it was not observed with several other cell lines. Downregulation of CD8 expression required CD14+ monocytes to be in direct contact with the CD8+ cells, whereas the effects of hMSCs on the CD14+ cells were essentially mediated by soluble factors. The CD14+ monocytes exhibited a tolerogenic pattern when co-cultured with hMSCs, with a clear decrease in CD80 and CD86 co-stimulatory molecules, and an increase in the inhibitory receptors ILT-3 and ILT-4. CD8+ cells that were preconditioned by MSCs had similar effects on monocytes and were able to inhibit lymphocyte proliferation. Injection of hMSCs in humanized NSG mice showed similar trends, in particular decreased levels of CD44 and CD28 in human immune cells. Our study demonstrates a new immunomodulation mechanism of action of hMSCs through the modulation of CD8+ cells towards a non-cytotoxic and/or suppressive phenotype. This mechanism of action has to be taken into account in clinical trials, where it should be beneficial in grafts and autoimmune diseases, but potentially detrimental in malignant diseases.

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Section: Physiological Relevance Of the Inhibitory Effect Of Hmscs Onmentioning

confidence: 96%

Section: Physiological Relevance Of the Inhibitory Effect Of Hmscs Onmentioning

confidence: 99%

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Hof-Nahor¹,

Leshansky²,

Shivtiel³

et al. 2012

Journal of Cell Science

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“…We hypothesised proposed to represent an immune regulatory phenotype [9][10][11]. We therefore examined whether these cells might be capable of regulating immune effector cells.…”

Section: Allo-specific Regulatory T Cellsmentioning

confidence: 99%

“…We therefore examined whether these cells might be capable of regulating immune effector cells. Using the system described by Sindhi et al [11], we purified CD8 + CD28 − T cells from PIL and co-incubated them overnight with CD40L-activated monocytes expressing either donor or third party HLA class I antigens. We then examined expression of the co-stimulatory molecule CD86 and the inhibitory molecule ILT-3 on the monocytes.…”

Section: Allo-specific Regulatory T Cellsmentioning

confidence: 99%

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Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

et al. 2008

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Aims/hypothesis Simultaneous kidney-pancreas transplantation is an established treatment for patients with type 1 diabetes and end-stage renal failure, even though restored beta cell function may become affected by recurrent islet autoimmunity or graft rejection. We characterised infiltrating lymphocytes isolated from a pancreatic graft with normal endocrine function in a kidney-pancreas recipient with type 1 diabetes. Methods The pancreas graft was removed due to recurrent graft pancreatitis of unknown cause. Pancreas-infiltrating lymphocytes and peripheral blood mononuclear cells (PBMC) were isolated and characterised phenotypically and functionally.Results Compared with PBMC, pancreas-infiltrating lymphocytes exhibited a distinct activation/memory phenotype and T cell receptor profile that were indicative of selective infiltration of the pancreas. Islet autoreactive CD8 + T cells could be detected in the pancreas and were increased in frequency compared with PBMC. Additionally, an augmentation of CD8 + CD28 − regulatory T cells was observed in the pancreas; these induced expression of the inhibitory receptor immunoglobulin-like transcript-3 on antigen-presenting cells in a donor HLA class I-specific manner. Conclusions/interpretation These data demonstrate the simultaneous presence of regulatory and effector T cells in the pancreas allograft of a recipient with type 1 diabetes. They also indicate that circulating islet autoreactive T cells may reflect immunological processes in pancreatic tissue, even though their frequency in the periphery may lead to underestimation of their presence in the pancreas. Additional specificities were also present in the pancreas that were undetectable in the circulation.Keywords Effector T cells . Pancreas transplantation . Regulatory T cells . Type 1 diabetesAbbreviations APC antigen presenting cell CCR7 chemokine (C-C motif) receptor 7 CDR3 complementarity-determining region 3 IMDM Iscove's Modified Dulbecco's Medium IGRP islet-specific glucose-6-phosphatase catalytic subunit-related protein ILT immunoglobulin-like transcript mAbs monoclonal antibodies MACS magnetic-activated cell-sorting Diabetologia (2009) 52:494-503

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CD8⁺ suppressor‐mediated regulation of human CD4⁺ T cell responses to glutamic acid decarboxylase 65

James¹,

Kwok²

2006

Eur J Immunol

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Although potentially autoreactive T cells are present even in healthy subjects, most individuals do not develop autoimmune disease. It has been well demonstrated that CD4 + CD25 + regulatory T cells play a significant role in controlling the expansion of autoreactive T cells in the periphery. However, some healthy individuals exhibit measurable responses to self peptide even in the presence of CD4 + CD25 + regulatory cells. This article describes the regulation of human CD4 + T cell responses to glutamic acid decarboxylase 65 (GAD65), an autoantigen implicated in type-1 diabetes, by autologous CD8 + suppressor T cells. In cells cultured from healthy individuals, the inclusion of autologous CD8 + T cells at physiological levels resulted in a dramatic decrease in the magnitude of in vitro CD4 + T cell responses to GAD65 peptide. Based on transwell experiments, the observed suppression was cell contact-dependent. However, antibody blocking studies indicated that suppression was mediated by IL-10. Cell fractionation studies suggested that CD8 + suppressor T cells originate from the CD45RA + CD27 -population. The suppression of CD4 + T cell responses to GAD65 in healthy individuals raises the possibility that CD8 + suppressor T cells play an important role in controlling potentially autoreactive T cells in the general population.

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Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28− T-suppressor cells

Cited by 34 publications

References 10 publications

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

CD8⁺ suppressor‐mediated regulation of human CD4⁺ T cell responses to glutamic acid decarboxylase 65

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Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28− T-suppressor cells

Cited by 34 publications

References 10 publications

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

CD8+ suppressor‐mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65

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CD8⁺ suppressor‐mediated regulation of human CD4⁺ T cell responses to glutamic acid decarboxylase 65