Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation

Background: Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods: A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: 7 TCMR, 10 ABMR, and 1 mixed rejection. The second validation set included 8 quiescence and 11 rejections: 7 TCMR, 2 ABMR, and 2 mixed. AlloSure donor derived cell-free DNA was also evaluated. Results: AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median 9.49, IQR 7.68-11.53) and rejection (median 13.09, IQR 11.25-15.28), p < 0.001. In the second validation set, the cohorts were statistically different (p = 0.028) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC 0.894). Conclusion: Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunological activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.

Download Full-text

A Peripheral Blood Gene Expression Signature for Subclinical Acute Rejection and Associated Long-Term Graft Injury.

Transplantation Journal ◽

10.1097/00007890-201407151-00658 ◽

2014 ◽

Vol 98 ◽

pp. 223

Author(s):

M. Menon ◽

W. Zhang ◽

Z. Yi ◽

C. Wei ◽

C. Woytovich ◽

...

Keyword(s):

Gene Expression ◽

Acute Rejection ◽

Peripheral Blood ◽

Gene Expression Signature ◽

Blood Gene Expression ◽

Expression Signature ◽

Peripheral Blood Gene Expression

Download Full-text

A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents

Allergy ◽

10.1111/all.14314 ◽

2020 ◽

Vol 75 (12) ◽

pp. 3248-3260 ◽

Cited By ~ 6

Author(s):

Nathanaël Lemonnier ◽

Erik Melén ◽

Yale Jiang ◽

Stéphane Joly ◽

Camille Ménard ◽

...

Keyword(s):

Gene Expression ◽

Children And Adolescents ◽

Whole Blood ◽

Gene Expression Signature ◽

Blood Gene Expression ◽

Expression Signature

Download Full-text

Whole blood gene expression signature in patients with obstructive sleep apnea and effect of continuous positive airway pressure treatment

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2021.103746 ◽

2021 ◽

pp. 103746

Author(s):

Eva Christensson ◽

Souren Mkrtchian ◽

Anette Ebberyd ◽

Åsa Österlund Modalen ◽

Karl A. Franklin ◽

...

Keyword(s):

Gene Expression ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Continuous Positive Airway Pressure ◽

Airway Pressure ◽

Positive Airway Pressure ◽

Gene Expression Signature ◽

Pressure Treatment ◽

Blood Gene Expression ◽

Obstructive Sleep

Download Full-text

Interferon-Inducible Blood Gene Expression Signature in COPD Patients with CT Airway Disease Phenotypes

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a4052 ◽

2019 ◽

Author(s):

J.H. Yun ◽

S. Lee ◽

R. Chase ◽

M.M. Parker ◽

A. Saferali ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Signature ◽

Airway Disease ◽

Blood Gene Expression ◽

Expression Signature ◽

Disease Phenotypes ◽

Copd Patients

Download Full-text

A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

Blood ◽

10.1182/blood-2009-03-210732 ◽

2010 ◽

Vol 115 (2) ◽

pp. 315-325 ◽

Cited By ~ 85

Author(s):

Shannon K. McWeeney ◽

Lucy C. Pemberton ◽

Marc M. Loriaux ◽

Kristina Vartanian ◽

Stephanie G. Willis ◽

...

Keyword(s):

Gene Expression ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Gene Expression Signature ◽

Cytogenetic Response ◽

Expression Array ◽

Cd34 Cells ◽

Risk Patients ◽

Validation Set

Abstract In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34+ cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph+ metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated β-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity.

Download Full-text

IRF8 Governs Tumor-Associated Macrophage Control of T Cell Exhaustion

10.1101/2020.03.12.989731 ◽

2020 ◽

Author(s):

Briana G. Nixon ◽

Fengshen Kuo ◽

Ming Liu ◽

Kristelle Capistrano ◽

Mytrang Do ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Gene Expression Signature ◽

T Cell Exhaustion ◽

Human Renal Cell Carcinoma ◽

Cell Exhaustion ◽

Tumor Associated Macrophage ◽

Expression Program ◽

State Of Exhaustion

SummaryTumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion. How T cell exhaustion is elicited in the tumor remains poorly understood. Here we show that tumor-associated macrophages (TAMs) present cancer cell antigen and induce CTL exhaustion through a gene expression program dependent on the transcription factor interferon regulatory factor-8 (IRF8). In a transgenic model of murine breast cancer, CTL priming was supported by IRF8-dependent dendritic cells; yet, CTL exhaustion required TAM expression of IRF8, and its ablation suppressed tumor growth. An analysis of the highly immune-infiltrated human renal cell carcinoma tumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. The IRF8 signature co-segregated with T cell exhaustion markers and was negatively associated with long-term patient survival. Thus, CTL exhaustion is promoted by TAMs via IRF8, and this crosstalk may be disrupted in TAM-targeted therapies.

Download Full-text