A Novel Biomarker of Immune Function and Initial Experience in a Transplant Population
2014; Wolters Kluwer; Volume: 97; Issue: 8 Linguagem: Inglês
10.1097/tp.0000000000000078
ISSN1534-6080
AutoresSiddharth Sood, Diana Cundall, Lijia Yu, Misato Miyamasu, Jefferey S Boyle, Sim Yee Ong, Paul Gow, Robert Jones, Peter Angus, Kumar Visvanathan, Adam Testro,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoLong-term side effects of immunosuppression contribute to significant morbidity after liver transplantation. It is thought that 40% to 70% of posttransplant mortality and morbidity may be drug related (1, 2). An objective marker of immune function would allow individualization of therapy based on a patient's unique immune response and fundamentally alter posttransplant management. We describe preliminary results of a novel whole-blood immune function biomarker QuantiFERON Monitor (QFM, previously CST007; Cellestis Ltd, Melbourne, Victoria, Australia) that measures interferon (IFN)-gamma production in plasma after incubation of heparinized whole blood with innate (R848) and adaptive (CD3) stimulants. QFM was evaluated in 212 healthy controls, a subgroup of 30 age- and sex-matched controls, 30 patients awaiting liver transplant (pretransplant), 66 values in 18 early posttransplant patients at various time points (median time posttransplant=31 days), and 11 late posttransplant patients (2,290 days). Whole blood was stimulated using the QFM stimulant. Samples were incubated for 16 to 24 hr at 37°C, then plasma harvested for ELISA measurement of IFNγ (IU/mL). Higher values reflect a more robust immune response. Groups were compared using Dunn multiple comparison test. Linear regression analysis was used to examine any association between the assay and age, gender, and immunosuppression levels. This study had ethics approval. The mean IFNγ production was 555.2 IU/mL in healthy controls, and 614.6 IU/mL in age- and sex-matched controls. Separately, age and gender did not significantly impact QFM results. Mean IFNγ production from both pretransplant (IFNγ=89.3 IU/mL) and early posttransplant patients (IFNγ=3.76 IU/mL) was significantly lower than matched controls (P<0.001, Fig. 1). QFM values appeared to increase as time progressed posttransplant.FIGURE 1: QFM in immunosuppressed populations.As expected, there was a restoration of immune function in the late posttransplant patients (IFNγ of 256.1 IU/mL), which was significantly greater than early posttransplant patients (P<0.05). Importantly, tacrolimus and cyclosporin levels were not significantly associated with QFM values (r2=0.02, P=0.35 and r2=0.16, P=0.09, respectively). Current monitoring after organ transplantation relies on the combination of therapeutic drug levels and nonspecific biochemical changes, which likely occur after the rejection process is established. In particular, drug concentrations of the commonly used calcineurin inhibitors are employed to guide medication dosing posttransplant despite being an inadequate surrogate for efficacy (3). Furthermore, the U.S. Food and Drug Administration (FDA) have advised that no suitable therapeutic ranges exist, hence levels should not be used alone to adjust drug dosing (4). One alternative immune function test (ImmuKnow; Cylex, Columbia, MD) has been cleared by the U.S. FDA, but only evaluates the adaptive immune response (5) and is not in widespread use. A recent meta-analysis has suggested a potential sensitivity for detecting rejection in liver transplant patients of only 0.11 (95% CI: 0.01–0.33) and specificity of 0.94 (95% CI: 0.91–0.95) (6). Importantly, evidence suggests the innate immune system plays a central role in rejection and allorecognition in a range of solid organs after transplantation (7–10). The poor sensitivity of ImmuKnow may in part be secondary to its inability to measure innate immune responses. QFM was developed to provide an objective marker of net immune function. The use of two ligands showed synergy between the innate and adaptive immune system with results using co-stimulation superior than single stimulants. Clinical results in this initial patient population follow what one would expect clinically and demonstrate that QFM can distinguish between immunosuppressed populations. In particular, early posttransplant patients had significantly lower QFM values than healthy controls and late posttransplant patients. Furthermore, QFM appears to appropriately increment as time passes correlating well with the progressive reduction in immunosuppression. An ideal immune function test should be accessible, rapid, provide a marker of net immunity, not be affected by age or gender, and provide a warning of impending clinical events. To date, QFM appears to satisfy many of these criteria. The test is performed on whole blood with minimal laboratory processing as it is based on the same platform as the widely available QuantiFERON Gold assay. Results are available next day and the dual stimulation with innate and adaptive ligands confers a significant advantage over single-stimulant assays. Based on early data, QFM may provide an important advance in the management of patients after transplantation. Clearly, its widespread use will depend on the assay's ability to correlate with clinical events. We reveal the first documented use of QFM in a clinical population, and based on this data a prospective longitudinal study evaluating QFM with clinical events in a post-liver transplant population is ongoing. Siddharth Sood 1 Diana Cundall2 Lijia Yu2 Misato Miyamasu2 Jefferey S Boyle2 Sim Y Ong1 Paul J Gow1 Robert M Jones1 Peter WAngus1 Kumar Visvanathan3 Adam G Testro1 1Liver Transplant Unit Victoria Austin Health, University of Melbourne Melbourne, Australia 2Cellestis Ltd, Melbourne Australia 3Innate Immunity Laboratory St. Vincent's Hospital, University of Melbourne Melbourne, Australia
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