OR41 Transcriptome analysis of immunity related genes as early predictor of graft versus host disease

Abstract

Background Graft versus host disease (GVHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT) as 10–15% HCT recipients die and 25% suffer long-term due to GVHD. Effective but toxic prophylaxes for GVHD (e.g., anti-thymocyte globulin) exist that can be given preemptively to patients with high risk of GVHD. The major barrier to this ’preemptive therapy’ is the lack of sensitive and specific assays that can identify patients at high risk of GVHD. Since allo-immune responses generated through recognition of host antigens by donor T cells culminate into GVHD, we performed the transcriptome analysis of 594 genes with immunity related functions at different posttransplant time points to predict ensuing GVHD. Methods A total of 147 RNA specimens from 65 first allo-HCT recipients were analyzed. RNA was extracted from cryopreserved PBMNCs collected at one week (n = 22), one month (n = 65) and two months (n = 60) post transplantation. Transcriptome analysis for 594 human genes with immunity related functions and 15 internal reference genes was performed using Nanostring based gene expression CodeSet profiling. Empirical Bayes statistics, receiver operating characteristic ( ROC ) and principle component analyses were performed to identify gene expression pattern predictive of GVHD. Results A ’GVHD transcript signature’ comprising of highly upregulated 6 genes with T cell related pro-inflammatory functions were identified at one month after HCT in patients with clinically significant GVHD (median day of onset = 100 days). The genes identified were CD27 (AUC = 0.93; p = 3.4X10 −8 ); B- and T-lymphocyte attenuator, BTLA (AUC = 0.92; p = 3.4X10 −8 ), Inducible T-cell Co-stimulator, ICOS (AUC = 0.90; p = 3.5X10 −7 ), CD5 (AUC = 0.87; p = 8.5X10 −7 ), CD3D (AUC = 0.88; p = 8.8X10 −7 ) and CD28 (AUC = 0.91; p = 9.9X10 −7 ). The GVHD transcript panel predicted clinically significant GVHD with sensitivity of 85% and specificity of 95%. Conclusions Early posttransplant transcript profile of genes with T cell related pro-inflammatory functions has a prominent impact on the occurrence of GVHD. The identified ‘6-genes GVHD transcript signature’ is highly sensitive and specific in early identification of patients at high risk of developing GVHD and could pave the way to precision HCT medicine.