Bronchoalveolar Lavage Cell Immunophenotyping Facilitates Diagnosis of Lung Allograft Rejection

Greenland, John R.; Jewell, Nicholas P.; Gottschall, Marc; Trivedi, Neil N.; Kukreja, Jasleen; Hays, Steven R.; Singer, Jonathan P.; Golden, Jeff; Caughey, George H.

doi:10.1111/ajt.12630

Cited by 49 publications

(77 citation statements)

References 38 publications

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“…23 Chronic lung allograft dysfunction (CLAD) was defined according to established criteria as an unresolving 20% decline in FEV 1 or FVC lasting over 30 days 24 and determined from clinical records as previously described. 25,26 CLAD-free survival was quantified as years of freedom from CLAD or death.…”

Section: Clinical Data and Outcomesmentioning

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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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: Clinical Data and Outcomesmentioning

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 greater concentration of NK cells in bronchoalveolar lavage (BAL) fluid has been observed during acute cellular rejection, even though the NK cell percentage of total BAL lymphocytes decreased 43. In subjects with CLAD, NK cell peripheral blood frequencies were decreased, but these NK cells had a more activated phenotype 43. CLAD subjects also have higher numbers of NK cells in allograft transbronchial biopsy specimens 44.…”

Section: Introductionmentioning

confidence: 99%

Natural killer cells in lung transplantation

Calabrese

Lanier

Greenland

2018

Thorax

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Natural killer (NK) cells are innate lymphoid cells that have been increasingly recognised as important in lung allograft tolerance and immune defence. These cells evolved to recognise alterations in self through a diverse set of germline-encoded activating and inhibitory receptors and display a broad range of effector functions that play important roles in responding to infections, malignancies and allogeneic tissue. Here, we review NK cells, their diverse receptors and the mechanisms through which NK cells are postulated to mediate important lung transplant clinical outcomes. NK cells can promote tolerance, such as through the depletion of donor antigen-presenting cells. Alternatively, these cells can drive rejection through cytotoxic effects on allograft tissue recognised as ‘non-self’ or ‘stressed’, via killer cell immunoglobulin-like receptor (KIR) or NKG2D receptor ligation, respectively. NK cells likely mediate complement-independent antibody-mediated rejection of allografts though CD16A Fc receptor-dependent activation induced by graft-specific antibodies. Finally, NK cells play an important role in response to infections, particularly by mediating cytomegalovirus infection through the CD94/NKG2C receptor. Despite these sometimes-conflicting effects on allograft function, enumeration of NK cells may have an important role in diagnosing allograft dysfunction. While the effects of immunosuppression agents on NK cells may currently be largely unintentional, further understanding of NK cell biology in lung allograft recipients may allow these cells to serve as biomarkers of graft injury and as therapeutic targets.

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“…However, a study of 27 subjects found no correlation between PBMC Treg frequency and risk of acute lung allograft rejection 9 . Increased Treg frequencies in bronchoalveolar lavage (BAL) fluid and transbronchial biopsy tissue have been associated with acute cellular rejection 10,11 and increased regulatory T cell frequencies have been found in endomyocardial biopsies prior to the development of acute cardiac allograft rejection 12 . Further, studies to date have evaluated total rather than donor-reactive subsets of Treg, leaving the association between acute rejection and systemic donor-reactive Treg undefined.…”

Section: Introductionmentioning

confidence: 99%

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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Bronchoalveolar Lavage Cell Immunophenotyping Facilitates Diagnosis of Lung Allograft Rejection

Cited by 49 publications

References 38 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

Natural killer cells in lung transplantation

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

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