Monitoring pharmacologically induced immunosuppression by immune repertoire sequencing to detect acute allograft rejection in heart transplant patients: a proof-of-concept diagnostic accuracy study.

Christopher Vollmers,Garrett Cohen,Helen Luikart,Lolita Penland,Calvin Strehl,Iwijn De Vlaminck,Stephen R Quake,Kiran K Khush,Hannah A Valantine,Andrew H Beck

doi:10.1371/journal.pmed.1001890

Christopher Vollmers, Garrett Cohen + Show 8 more

Open Access

https://doi.org/10.1371/journal.pmed.1001890

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Journal: PLoS Medicin	Publication Date: Oct 14, 2015
Citations: 52	License type: CC BY 4.0

Affiliation: Stanford University, Howard Hughes Medical Institute

Abstract

BackgroundIt remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.Methods and FindingsIn this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.ConclusionsIf confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.

Highlights

An enduring challenge in immunology is the lack of quantitative measurements of immune strength
Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression, as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% and a specificity of 82.0%
The immune repertoire sequence data have been deposited in the Sequence Read Archive (PRJNA260905). In this proof-of-concept study, we analyzed 130 blood samples from 12 patients who underwent pharmacological immunosuppression to prevent allograft rejection after heart transplantation. These individuals were a subset of a larger prospective cohort study [13] and were selected to represent patients with and without acute rejection events who were otherwise free of severe infections or other immune-related disorders

Summary

Introduction

An enduring challenge in immunology is the lack of quantitative measurements of immune strength. In view of the lack of more predictive assays, pharmacological immunosuppressive therapy, e.g., in the context of post-organ-transplant therapy, is guided mainly by dosage and measurement of the concentration of immunosuppressive drugs in blood. While in some cases therapeutic drug levels (e.g., trough or C0 levels of tacrolimus) can be monitored, these levels are more reflective of toxicity than therapeutic efficacy This approach does not account for individual differences in the response to immunosuppressive drugs, and frequently gives rise to complications related to over- or under-immunosuppression. The organ recipient may not survive transplantation surgery, and sometimes the transplanted organ fails to work in its new owner Another major risk for patients who receive an allograft (an organ from another person) is acute rejection. The chances of rejection can be minimized by “matching” the antigens on the donated organ to those on recipient’s organs and by giving the recipient immunosuppressive drugs such as prednisone and tacrolimus

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