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

Greenland, John R.; Wong, Charissa M.; Ahuja, Rahul; Wang, Angelia S.; Uchida, C.; Golden, Jeffrey A.; Hays, Steven R.; Leard, Lorriana E.; Rajalingam, Raja; Singer, Jonathan P.; Kukreja, Jasleen; Wolters, Paul J.; Caughey, George H.; Tang, Qizhi

doi:10.1097/tp.0000000000001191

Cited by 15 publications

(21 citation statements)

References 37 publications

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“…17 Maintenance of immunosuppressant therapy included tacrolimus, prednisone, and mycophenolate mofetil. 17 Maintenance of immunosuppressant therapy included tacrolimus, prednisone, and mycophenolate mofetil.…”

Section: Study Population and Standard Therapiesmentioning

confidence: 99%

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Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Calabrese

Florez

Dewey

et al. 2018

Clinical Transplantation

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Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

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Section: Study Population and Standard Therapiesmentioning

confidence: 99%

“…for approximately 20% of the lung transplant recipients based on surgeons' preferences. 17 Maintenance of immunosuppressant therapy included tacrolimus, prednisone, and mycophenolate mofetil.…”

mentioning

confidence: 99%

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Calabrese

Florez

Dewey

et al. 2018

Clinical Transplantation

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“…A recent study finds that donor-reactive Treg is minimally impacted in lung transplant patients after basiliximab induction 53 . Treg normally express low levels of the IL-7 receptor α chain CD127 54,55 .…”

Section: Impact Of Approved Immunosuppressive Drugs On Tregmentioning

confidence: 99%

Impact of Immune-Modulatory Drugs on Regulatory T Cell

2016

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Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4+FOXP3+ regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens.

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“…One might speculate that IFNy+ Treg are induced when they are needed. A recent publication reports that, contrary to expectation, overall proportions of donor-reactive Treg are similar before and after lung transplantation and increase during acute A2 cellular rejection of lung allografts, suggesting a mechanism how A2 rejection might be self-limiting [25]. The authors noted that the observed increases over baseline donor-reactive Treg were insufficient to prevent acute lung allograft rejection [25].…”

Section: Discussionmentioning

confidence: 98%

Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function

et al. 2017

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BackgroundThere is circumstantial evidence that IFNy+ Treg might have clinical relevance in transplantation. IFNy+ Treg express IFNy receptors and are induced by IFNy. In the present study we investigated in kidney transplant recipients with good long-term stable graft function the absolute cell counts of IFNy+ Treg subsets and whether their expression of Foxp3 is stable or transient.MethodHelios expression determined by eight-color-fluorescence flow cytometry and methylation status of the Foxp3 Treg specific demethylation region (TSDR) served as indicators for stability of Foxp3 expression. Methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations originating from peripheral blood using high resolution melt analysis. A total of 136 transplant recipients and 52 healthy controls were studied.ResultsProportions of IFNy+ Treg were similar in patients and healthy controls (0.05% and 0.04% of all CD4+ lymphocytes; p = n.s.). Patients also had similar absolute counts of IFNy producing Helios+ and Helios- Treg (p = n.s.). Most of the IFNy+ and IFNy- Treg in transplant recipients had a methylated Foxp3 TSDR, however, there was a sizeable proportion of IFNy+ and IFNy- Treg with demethylated Foxp3 TSDR. Male and female patients showed more frequently methylated IFNy+ and IFNy- Treg than male and female controls (all p<0.05).ConclusionsKidney transplant recipients with good long-term stable graft function have similar levels of IFNy+ Treg as healthy controls. IFNy+ and IFNy- Treg subsets in patients consist of cells with stable and cells with transient Foxp3 expression; however, patients showed more frequently methylated IFNy+ and IFNy- Treg than controls. The data show increased levels of Treg subsets with stable as well as transient Foxp3 expression in patients with stable allograft acceptance compared to healthy controls.

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

Cited by 15 publications

References 37 publications

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Impact of Immune-Modulatory Drugs on Regulatory T Cell

Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function

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