Expression Profiling and the Clinical Course of Systemic Vasculitis

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Systemic vasculitis (AASV), caused when the immune system attacks the body, is a severe disease with a high risk of renal failure and premature death. As it is hard to predict how the disease will progress or respond to toxic immune suppressive therapy, such treatment may be used excessively, risking side effects such as infection and cancer. Clinicians, bioinformaticians, and immunologists have teamed up in Cambridge to study patients with vasculitis using modern technology to detect patterns of gene expression in blood cells. These patterns will be integrated with clinical information, providing new ways to measure disease activity and predict response to treatment. New tests thus generated may enable targeting of therapy to people who most need it, improving treatment effectiveness and reducing toxicity.

Technical Summary

Autoimmune diseases are major public health problems that affect 8-10% of the adult population. They have variable clinical features and often demonstrate unpredictable responses to therapy. ANCA-associated systemic vasculitis (AASV) is one such autoimmune disease, characterised by vascular inflammation and often severe tissue damage, with an incidence of 40/million/year. The optimal choice and length of treatment regimens is not known and no good markers predict therapeutic response or disease flare. There is therefore an urgent need to develop methods to predict the need for, and duration of, treatment in patients with AASV. Such ?biomarkers? might also provide an early definition of remission allowing truncation of treatment, or herald relapse allowing pre-emptive, briefer or less toxic therapy.

The Cambridge / Hinxton Centre for Translational Research in Autoimmune Disease (CHiC TRIAD) is a group of clinicians, bioinformaticians, and immunologists formed with the aim of integrating both clinical and microarray data in a cross-sectional and prospective fashion using state-of-the-art bioinformatics. Similar approaches have proven to be successful in the field of oncology, where microarray-based diagnostics are already entering clinical practice. We will study AASV before, during and after therapy with both conventional treatment and novel biological therapies. Microarray assays using purified leucocyte subsets will produce expression data which will be integrated with clinical, serological and immunological data using existing and novel informatics tools. This unique resource will allow us to define patterns of gene expression that will predict responses to treatment and that will also uncover novel ways of determining disease activity and of predicting drug toxicity. Tests generated from these findings will improve patient outcome by leading to better targeted therapy, with significant and beneficial effects on drug-related toxicity and treatment efficacy. In the longer term these techniques should be useful in the management of other autoimmune diseases.

Publications

10 25 50
 
Description BHF Project Grant
Amount £565,333 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Distiguished Innovator Pilot Grant
Amount $300,000 (USD)
Organisation Lupus Research Institute 
Sector Charity/Non Profit
Country United States
Start 12/2013 
End 11/2015
 
Description Evelyn Trust, Project Grant
Amount £86,981 (GBP)
Organisation The Evelyn Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description MRC Clinical Research Fellowship
Amount £242,463 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description MRC Clinical Research Fellowship
Amount £250,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description MRC Programme Grant
Amount £1,052,088 (GBP)
Funding ID MR/L019027/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2014 
End 09/2019
 
Description NACC Project Grant
Amount £81,981 (GBP)
Organisation National Association for Colitis and Crohn’s Disease (NACC) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Investigator Award
Amount £1,600,000 (GBP)
Funding ID 200871/Z/16/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Senior Investigator Award
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 07/2021
 
Description Wellcome Trust Project Grant
Amount £49,650 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Translation Award
Amount £516,647 (GBP)
Funding ID 099450/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 05/2015
 
Title eQTL Analysis 
Description eQTL analysis of multiple cell types in health and disease. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact This technique led to two publications. 
 
Title gene expression analysis of purified leucocyte subsets 
Description The analysis of gene expression of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMCs 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This approach provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease. 
 
Title Biomarkers for inflammatory bowel disease 
Description Patent describes a test for predicting disease outcome in IBD. 
IP Reference US20180010189 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact Too early.
 
Title DETECTION OF T CELL EXHAUSTION OR LACK OF T CELL COSTIMULATION AND USES THEREOF 
Description The application relates to methods of assessing whether an individual has an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype, and the use of such methods in determining an individual's risk of autoimmune disease progression, progression of a chronic infection, not responding to a treatment for a chronic infection, not mounting an effective immune response to vaccination, infection-associated immunopathology, transplant rejection, or cancer progression. The application also relates to in vitro methods for assessing whether CD8+ and CD4+ T cells in a sample have an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype, and for identifying a substance capable of inducing an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype in an individual, as well as a kit for assessing whether an individual has an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype or whether an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype is present in a sample of CD8+ and CD4+ T cells. 
IP Reference WO2016185182 
Protection Patent application published
Year Protection Granted 2016
Licensed Yes
Impact Too early
 
Title METHODS FOR PREDICTING AUTOIMMUNE DISEASE RISK 
Description Patent describes a method for predicting whether patients with autoimmune disease will follow a quiescent or severe disease course. 
IP Reference EP2389582 
Protection Patent granted
Year Protection Granted 2011
Licensed Yes
Impact Too early.
 
Company Name Predictimmune Ltd 
Description PredictImmune is developing pioneering tools for guiding treatment options in immune-mediated inflammatory diseases with the first product addressing Inflammatory Bowel Disease (both Crohn's disease and ulcerative colitis). The test, based on a simple whole-blood quantitative PCR assay, predicts long-term disease outcome at diagnosis prior to treatment, stratifying patients into those likely to follow either a quiescent or frequently relapsing course and informing clinical management. 
Year Established 2017 
Impact Too early.
Website http://www.predictimmune.com