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469 Novel Nomogram of the Immune Response After Heart Transplantation Thursday, Apr 10, 2014, 10:00 AM - 7:15 PM M. Bakir1, T. Khuu2, M. Cadeiras1, N. Wisniewski1, V. M. Groysberg1, G. Bondar1, E. Depasquale1, J. Fuentes2, L. Rangel2, J. Zhang3, E. F. Reed3, M. C. Deng1. 1Cardiology, UCLA, Los Angeles, CA,2Heart & Lung Transplant, UCLA, Los Angeles, CA, 3Path & Lab Med-Immunogenetics Cntr, UCLA, Los Angeles, CA, Purpose: Technological advances in heart transplantation continue to evolve. We now have the possibility of conducting multi-parametric immune monitoring. While individual parameters are contributory, none of them are free from limitations and none have been evaluated in relation to each other as of yet. We hypothesize that a nomogram of the ideal immune response could be developed for the management of heart transplant immune modulation utilizing a combination of multiple individual parameters. Methods: We retrospectively collected data from 69 adult heart transplant recipients between January 2010 to May 2013 who had been followed with a comprehensive immune monitoring panel consisting of brain natriuretic peptide (BNP), anti-HLA Class I and II antibodies, AlloMap molecular expression testing, and Cylex immune function test. This data was evaluated in the context of immunosuppression management over time, along with rejection and survival outcomes. Results: Heatmap clustering of the data mimics clinical practice patterns. We see that immunosuppression, BNP, and prednisone dose are expectedly reduced over time. Concurrently, more activated immune monitoring pattern emerges as immunosuppression decreases. While limited by sample size and the retrospective nature of the data set, visualization within a cluster heatmap suggests that a nomogram of the expected response to immunosuppression minimization can be outlined (Image 1). Correlation with rejection outcomes was not possible due to low incidence. Conclusion: Development of a nomogram for various risk groups will allow individualization of immunosuppression management by contrasting individual data to population parameters. Developing a nomogram of the normal immune response is currently possible within the current era of immune monitoring and will be further benefit from incorporation of new markers including proteomics, metabolomics, multiplex cytokine and T-cell immunophenotyping, and gene expression profiling currently evolving in our labs.
Abstract:
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=a9cec8cf-2ddd-4918-97f96ab8e4a6c6f4&cKey=c56a4d3a-6cf8-4d04-8e8a-ef8a427a797f&mKey=%7b9D7C7E85-822F-4273-9A11EB7E2A6FFBC5%7d
633 Differential Mitochondrial Gene Expression in Patients Undergoing MCSD Implantation Friday, Apr 11, 2014, 10:00 AM - 6:30 PM E. Chang, M. Cadeiras, C. Chan, G. Bondar, N. Wisniewski, M. Bakir, J. Chittoor, T. Khuu, M. Deng.Medicine/Cardiology, UCLA, Los Angeles, CA, Purpose: The main cause of death of high risk INTERMACS patients with Advanced Heart Failure (AdHF) is the immune related MultiOrgan Dysfunction Syndrome (MOD). Mitochondrial dysfunction in the context of severe energy depletion and detrimental organ damage via oxidative stress has emerged as a key contributor to pathogenesis of MOD, which correlates with the poor survival of these patients. We hypothesized that a more severe mitochondrial dysfunction develops in more advanced heart failure before and after MCSD implantation. Methods: We collected peripheral blood mononuclear cell (PBMC) samples from 8 AdHF patients with mean age of 5325 years-old undergoing MCSD implantation between August 2012-2013. Time dependent gene expression of 3 patients in INTERMACS 3 at the time of MCSD implantation was compared to 5 patients in INTERMACS 1-2. Samples were collected 1 day before surgery, and days 1, 3, 5 and 8 postoperatively. Purified mRNA was subjected to whole-genome next gen. sequencing (NGS). Two-way ANOVA with Benjamini-Hochberg correction was used to identify differentially expressed genes.Genes with fold change of 1.5 were hierarchically clustered. Biological significance of clusters was assessed by gene ontology (GO) enrichment and pathway analysis. Results: Out of 1519 genes in the (mitochondrial) GO category, 303 genes (q-value 1.05E-08) were observed to be differentially expressed between the low and high risk group. Within the mitochondrial respiratory chain category, differentially expressed genes including OXA1L, SOD2, and NDUFA1 in the high risk group were higher in magnitude compared with the low risk group (Figure 1). Conclusion: Severity-dependent differential PBMC-mitochondrial gene expression was observed in AdHF patients. Since mitochondrial dysfunction after MCSD surgery is linked to major inflammatory response mechanisms of infection, further examination of the temporal alterations in the mitochondrial gene expression by PBMC gene expression is warranted.
Abstract:
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Presentation Abstract
86 NGS PBMC Transcriptome Analysis Identifies More Pronounced Activation of the Inflammatory Response in Advanced INTERMACS Class Before MCSD Implantation Friday, Apr 11, 2014, 4:15 PM - 4:30 PM G. Bondar1, M. Cadeiras1, N. Wisniewski1, E. Chang1, M. Bakir1, J. Chittoor1, J. Maque1, K. Dong1, C. Y. Chan2, Y. D. Korin3, P. Ping2, E. F. Reed2, M. Deng1. 1Medicine/Cardiology, UCLA, Los Angeles, CA, 2Physiology and Medicine/Cardiology, Proteomics Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 3Pathology and Laboratory Medicine/ Immunogenetic Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, Purpose: The main cause of death of high risk INTERMACS patients with Advanced Heart Failure (AdHF) is the immune related MultiOrgan Dysfunction Syndrome (MODS). However, prognostic information based on immune system function in relationship to INTERMACS class prior to MCSD-implantation is virtually nonexistent. We hypothesized that pre-MCSD peripheral blood mononuclear cell (PBMC) gene expression profiling (GEP) by next-generation sequencing (NGS) identifies a subgroup of patients with higher risk of post MCSD MODS. Methods: PBMC samples from 8 AdHF patients (5325 years old) undergoing MCSD implantation included in the prospective MultiOrgan Dysfunction Expression (MOD-E) profiling study between August 2012 - 2013. Obtained 1 day before surgery, and at days 1, 3, 5 and 8 postoperatively were collected for 3 INTERMACS level 3 patients (n=3) and 5 patients (n=5) INTERMACS level 1-2. Purified mRNA was subjected to whole-genome NGS analysis. Differentially expressed genes where identified by Two-way ANOVA and Benjamini-Hochberg correction. Only those with fold change of at least 1.5 were included in the analysis. Hierarchically clustering was used for visualization. Biological significance was assessed by gene ontology and pathway analysis. Results: Compared to INTERMACS level 3, patients in the higher risk categories had dramatic differences in their gene expression profiles before and across all 5 time points (Figure 1). Over 3100 different genes were identified and mechanistically linked to the systemic inflammatory response by their biological significance. Gene ontology and pathway analysis revealed significant enrichment of immune related categories and pathways. Conclusion: In AdhF patient facing MCSD-implantation, NGS-based PBMC GEP correlates with clinical severity as assessed by INTERMACS class prior to as well as early after MCSD-implantation and may be further develop to assist in improved patient selection.
Abstract:
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=a5fd6f51-1ded-414d-ae2538b3a2242708&cKey=8ae9a3cb-8a94-44aa-9269-ba83c8e93712&mKey=9d7c7e85-822f-4273-9a11eb7e2a6ffbc5