The Impact of Memory T Cells on Rejection and the Induction of Tolerance

Brook, Matthew O.; Wood, Kathryn J.; Jones, Nick D.

doi:10.1097/01.tp.0000226082.17507.da

Cited by 97 publications

(78 citation statements)

References 108 publications

(82 reference statements)

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“…Therefore, we further examined the potential role of IDO in suppressing the ability of the immune system to generate effector memory cells. Memory T cells generated by exposure to an alloantigen are believed to be a barrier to maintaining allograft survival (29). Compared with Tn, Tem responded more rapidly to lower concentrations of antigen, and were less dependent upon costimulation.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Iken

Liu²,

Liu³

et al. 2012

Am J Respir Cell Mol Biol

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The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan into kynurenine metabolites that suppress effector T-cell function. In this study, we investigated IDO and its metabolite, 3-hydroxyanthranilic acid (3HAA), in regulating lung allograft rejection, using a murine orthotopic lung transplant model with a major mismatch (BALB/c donor and C57BL6 recipient). IDO was overexpressed in murine donor lungs, using an established nonviral (polyethylenimine carrier)-based gene transfer approach, whereas 3HAA was delivered daily via intraperitoneal injection. Increased IDO expression or its metabolite, 3HAA, resulted in a remarkable therapeutic effect with near normal lung function and little acute rejection, approximately A1, compared with A3 in untreated allografts (grading based on International Society for Heart and Lung Transplantation guidelines). We found that a high IDO environment for 7 days in lung allografts resulted in impaired T-cell activation, the production of multiple effector cytokines (IL-2, IL-4, IL-5, IL-6, IFN-g, TNF-a, IL-12, and IL-13), and the generation of effector memory T cells (CD62L lo CD44 hi phenotype). In isolated murine splenocytes, we observed that IDO/3HAA impaired T-cell receptor (TCR)-mediated T-cell activation, and more importantly, a decrease of intracellular calcium, phospholipase C-g1 phosphorylation, and mitochondrial mass was evident. This work further illustrates the potential role of a high IDO environment in lung transplantation, and that the high IDO environment directly impairs TCR activation via the disruption of calcium signaling.Keywords: 3-hydroxyanthranilic acid; lung allograft rejection; nonviral gene transfer Lung transplantation is a well-accepted therapy for patients with endstage lung disease that is not amenable to other medical or surgical therapies. Unfortunately, acute cellular rejection (ACR) is a common complication in lung transplant recipients, despite current immunosuppressive protocols (1). ACR is problematic because it is the major risk factor for the development of bronchiolitis obliterans, believed to be the manifestation of chronic rejection, and ACR necessitates the augmentation of immune suppression, leading to increased mortality and morbidity (2). The difficulties with bronchiolitis obliterans and frequent rejections result in relatively poor outcomes for lung transplantation, compared with the transplants of other solid organs (1).Indoleamine 2,3-dioxygenase (IDO) is an inducible enzyme that promotes tryptophan (Trp) catabolism, and has been shown to involve immune modulating activities (3). By increasing IDO activity, an environment is generated with reduced Trp and an increase in its metabolic products, resulting in the modification of dendritic cell function and the inhibition of T-cell activation and proliferation. Consistent with this concept, our laboratory previously showed that an increase in IDO within rat lung allografts resulted in less rejection, transplant-mediated injury, and impaired CD8 cell function (4-6).In the pre...

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Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Iken

Liu²,

Liu³

et al. 2012

Am J Respir Cell Mol Biol

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“…Most infiltrating T cells in coronary arteries from patients with CAV express the phenotype of T mem cells, suggesting that these cells may play an important role in the development of CAV [67]. OX40 (CD134) is a member of the tumor necrosis factor receptor (TNFR) superfamily.The OX40-OX40L signaling pathway has been found to play a key role in the survival and homeostasis of T mem cells [68].…”

Section: Future Trendsmentioning

confidence: 99%

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Gupta¹

2014

Cardiol Pharmacol

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Cardiac allograft vasculopathy (CAV) of heart transplants is responsible for up to one-third of deaths at 5 years following cardiac transplantation. Risk factors for CAV include both traditional risk factors and immune factors. Drugs used for prevention and treatment of CAV include statins, calcium channel blockers and immunosuppressive agents. This review discusses the currently available drugs for CAV, the evidence behind their use, and future targets of therapy.

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“…A high level of cross-reactivity against allo-HLA molecules is therefore an essential feature of the virus-specific memory TCR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). This allo-HLA cross-reactivity by virus-specific T cells can be reproducibly detected in vitro.…”

mentioning

confidence: 92%

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

D’Orsogna

Heuvel

Meer-Prins

et al. 2012

The Journal of Immunology

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Viral infection is a major cause of morbidity and mortality, and there are few therapeutic options available to augment a virus-specific T cell response. Although allo-HLA cross-reactivity from virus-specific memory T cells is common, it is unclear whether priming with specific allogeneic cells could conversely elicit a viral peptide/self-HLA restricted cytotoxic T cell response in humans. First, we used the previously described allo-HLA-B*44:02 cross-reactivity of EBV peptide/HLA-B8 restricted T cells, to determine whether allogeneic HLA stimulation can elicit a cytolytic immune response against EBV. HLA-B8+ HLA-B44− EBV-seropositive PBMCs were stimulated with either HLA-B*44:02+ or HLA-B*44:03+ mismatched irradiated PBMCs in a 7–10 d MLR. The allo-HLA stimulated responder cells were then evaluated for cytotoxicity using EBV peptide loaded autologous target cells and unloaded HLA-B8+ EBV LCL target cells. PBMCs from EBV-seropositive donors gained EBV-specific cytolytic effector function following specific allo-HLA stimulation. Finally, we also elicited cytolytic CMV-specific responses using specific allogeneic cell stimulation, to confirm that this technique can be used to elicit viral peptide/self-HLA restricted responses even from nonpublic TCR responses. Allogeneic cell stimulation used as a cell therapy may be a potential tool to augment an antiviral T cell response in patients with EBV or CMV infection.

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The Impact of Memory T Cells on Rejection and the Induction of Tolerance

Cited by 97 publications

References 108 publications

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Indoleamine 2,3-Dioxygenase and Metabolites Protect Murine Lung Allografts and Impair the Calcium Mobilization of T Cells

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

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