Lung function early after lung transplantation is correlated with the frequency of regulatory T cells

Nakagiri, Tomoyuki; Warnecke, G.; Avşar, M.; Thissen, S.; Kruse, B.; Kühn, Christian; Ziehme, P.; Knöfel, Ann-Kathrin; Madrahimov, N.; Okumura, Meinoshin; Sawa, Yoshiki; Gottlieb, Jens; Simon, Andrè; Haverich, Axel; Strüber, Martin

doi:10.1007/s00595-011-0087-3

Cited by 16 publications

(17 citation statements)

References 28 publications

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“…The same investigator group also identified CD4 + invariant natural killer cells to be central in the development of ischemia reperfusion injury after hilar ligation, highlighting the importance of T cells in the development and regulation of lung injury 24 . In a recent study by Strüber et al, higher levels of CD25 + CD4 + CD152 + and CD25 + CD4 + Foxp3 + T cells within 3 weeks of lung transplant were correlated with higher forced expiratory volume in 1 second (FEV1) 25 . Furthermore, CD25 + CD4 + T regulatory cells have been shown to decrease the development of obliterative airways disease lesion in a mouse model of bronchiolitis obliterans syndrome (BOS), a leading cause of chronic lung allograft dysfunction after lung transplantation 26 .…”

Section: Discussionmentioning

confidence: 95%

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

Diamond

Cantu

Porteous

et al. 2017

American Journal of Transplantation

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Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 hours of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

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Section: Discussionmentioning

confidence: 95%

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

Diamond

Cantu

Porteous

et al. 2017

American Journal of Transplantation

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“…(E) Divided cells were quantified by CFSE expression into 7 adjacent intensity gates (C1-C7). Each intensity gate has a width of 2 8 ln 2/ln 10 = 77.1 relative fluorescence intensity units. The set of gates are positioned such that the C2 gate contains <1% of total cells for negative control (stimulated with media alone).…”

Section: Discussionmentioning

confidence: 99%

“…CFSE intensity was determined using a 10-color Navios flow cytometer (Beckman Coulter, Brea, CA), using the gating strategy shown in Figure S1. To quantify fluorescence intensity, cells were counted across 7 two-fold-dilution gates using cutoff values spaced at 2 8 ln 1/ln 10 relative fluorescence intensity units (because the Navios cytometer encodes each 10-fold change in intensity with 8-bits). To control for variability in CFSE labeling, these dilution cutoffs were set such that for the media alone controls, just <1% of cells were in the first dilution gate, which is labeled C2 in Figure S1E.…”

Section: Methodsmentioning

confidence: 99%

“…While these data suggest that Treg deficits enhance acute cellular rejection in mice, the data from humans are less clear. A study of 18 lung transplant recipients reported a trend towards decreased peripheral blood mononuclear cell (PBMC)-derived Treg frequency at 3 months in subjects with diminished lung function 8 . However, a study of 27 subjects found no correlation between PBMC Treg frequency and risk of acute lung allograft rejection 9 .…”

Section: Introductionmentioning

confidence: 99%

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Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts

et al. 2016

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Background Acute cellular rejection is a major cause of morbidity following lung transplantation. Because regulatory T cells (Treg) limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4+ (Tconv) and CD8+ T cells during acute cellular rejection. Methods To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell (PBMC) specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4+ Tconv, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T cell frequencies with acute cellular rejection pathology. Results An average of 16.5±9.0% of pretransplantation PBMC Treg were donor-reactive, compared with 3.8%±2.9% of CD4+ Tconv and 3.4±2.6% of CD8+ T cells. These values were largely unchanged following transplantation. Donor-reactive CD4+ Tconv and CD8+ T cell frequencies both increased 1.5-fold (95% CI 1.3-1.6, P <0.001 and 95% CI 1.2-1.6, P = 0.007, respectively) during A2-grade rejection compared with no rejection. Surprisingly, donor-reactive Treg frequencies increased by 1.7-fold (95% CI 1.4-1.8, P <0.001). Conclusions Contrary to prediction, overall proportions of donor-reactive Treg are similar before and after transplantation and increase during A2-grade rejection. This suggests how A2 rejection can be self-limiting. The observed increases over high baseline proportions in donor-reactive Treg were insufficient to prevent acute lung allograft rejection.

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“…Additionally, administration of inducible Tregs can induce lung allograft tolerance through the suppression Th17-mediated responses 56 . In human lung grafts the number of Foxp3 + Tregs correlates with a better prognosis, fewer episodes of AR, and better pulmonary function after transplantation 57–59 . The quantity of Tregs in transbronchial biopsies positively correlates with the degree of AR after lung transplantation, suggesting that Tregs are actively recruited to sites of AR and may play a role in downregulating inflammation 57,58 .…”

Section: Mechanisms Of Allorecognitionmentioning

confidence: 99%

Mechanisms of graft rejection after lung transplantation

Hsiao¹,

Scozzi

Gauthier³

et al. 2017

Current Opinion in Organ Transplantation

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Purpose of review To date, outcomes after lung transplantation are far worse than after transplantation of other solid organs. New insights into mechanisms that contribute to graft rejection and tolerance after lung transplantation remain of great interest. This review examines the recent literature on the role of innate and adaptive immunity in shaping the fate of lung grafts. Recent findings Innate and adaptive immune cells orchestrate allograft rejection after transplantation. Innate immune cells such as neutrophils are recruited to the lung graft early after reperfusion and subsequently promote allograft rejection. While it is widely recognized that CD4+ T lymphocytes in concert with CD8+ T cells promote graft rejection, regulatory Foxp3+ CD4+ T, central memory CD8+ T cells and natural killer cells can facilitate tolerance. Summary This review highlights interactions between innate and adaptive immune pathways and how they contribute to lung allograft rejection. These findings lay a foundation for the design of new therapeutic strategies that target both innate and adaptive immune responses.

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Lung function early after lung transplantation is correlated with the frequency of regulatory T cells

Abstract: The frequency of Treg cells was positively correlated with good lung function in the early period after lung transplantation.

Cited by 16 publications

References 28 publications

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts

Mechanisms of graft rejection after lung transplantation

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