Kenneth Smith, MD, PhD

Kenneth SmithKenneth Smith, MD, PhD

University of Cambridge
Cambridge, UK
2013

Title: Transcriptional Prediction of Outcome in SLE

The Study and What It Means to Patients

“We have discovered that lupus patients who develop more severe disease have a distinctive pattern of genes turned on in their white blood cells. My group will investigate whether this gene pattern can be used as a practical test for long-term lupus prognosis. Such a predictive test would allow for safer and more effective personalized treatment. We will also explore what causes this gene pattern, in the search for new treatment strategies.”

Summary

Like other autoimmune diseases, lupus behaves differently from person to person, with some people having an aggressive course while others have a more benign disease. When lupus develops doctors need to treat it “blind” – as they have no way of predicting which patients have naturally benign disease, requiring minimal treatment, and those who will require more intensive maintenance treatment. This is a major problem for patients and for the healthcare system.  It means that patients who need more intensive therapy may not get it early, or that excessive and unnecessary treatment might expose patients to significant side-effects.  Poorly targeted therapy also has a financial cost.

We have used “genomic” technology to measure the genes turned on in blood white cells in patients with lupus.  Analysing this genomic data using advanced computational techniques has resulted in the discovery of a biomarker that predicts outcome in four different conditions; lupus, Crohn’s disease, ulcerative colitis, and vasculitis. We will recruit a further cohort of patients to confirm that this biomarker is useful in lupus, paving the way for its introduction to the clinic as a test predicting outcome. We will also study what drives these gene activation changes, in the expectation we will uncover new immune pathways controlling lupus that might lead to new treatment avenues in the future.

Scientific Abstract

This project is built around recruitment of a well-characterised SLE patient cohort to be studied before and after treatment, which should replicate a CD8 T cell prognostic signature that we have previously described, allowing its adoption as a prognostic biomarker in the clinic. It will also allow us to begin to examine the biology underlying the signature in SLE, complementing work in other diseases and in particular examining the role played by interferon in determining long-term outcome through its effect on T cell exhaustion.  This might allow induction of exhaustion in defined patients through co-stimulation or interferon blockade.

Publication 2015

Dr. Smith and the Cambridge research team rapidly delivered the outstanding results published in the professional journal NatureHe and co-investigator Dr. Eoin McKinney uncovered that the more tired the CD8 T cells become, the less energy they have to attack the body. The exhausted T cell immune response, known to increase poor outcomes in certain viral infections, is now shown to produce just the opposite effect in inflammatory autoimmune disease, namely less severe disease progression with fewer relapses. 

Building on this breakthrough, Drs. Smith and McKinney will now pursue ways to predict the course of the disease and to direct treatment choices accordingly. The goal is to minimize medication side effects, lessen organ damage and slow down lupus progression. 

“We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion," said Dr. Kenneth Smith.

Key Publications

Nature. 2015 Jul 30;523(7562):612-6.  Epub 2015 Jun 29. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG.

Dr. Smith and the Cambridge research team have rapidly delivered the outstanding results just published in the prestigious professional journal Nature.

Novel Discovery Brings Personalized Lupus Treatment Much Closer
Dr. Smith and co-investigator Dr. Eoin McKinney uncovered that the more tired the CD8 T cells become, the less energy they have to attack the body. The exhausted T cell immune response, known to increase poor outcomes in certain viral infections, is now shown to produce just the opposite effect in inflammatory autoimmune disease, namely less severe disease progression with fewer relapses. 

Building on this breakthrough, Drs. Smith and McKinney will now pursue ways to predict the course of the disease and to direct treatment choices accordingly. The goal is to minimize medication side effects, lessen organ damage and slow down lupus progression. 

“We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion," said Dr. Kenneth Smith.

- See more at: http://www.lupusresearchinstitute.org/lupus-news/2015/07/09/lri%E2%80%93...

Dr. Smith and the Cambridge research team have rapidly delivered the outstanding results just published in the prestigious professional journal Nature.

Novel Discovery Brings Personalized Lupus Treatment Much Closer
Dr. Smith and co-investigator Dr. Eoin McKinney uncovered that the more tired the CD8 T cells become, the less energy they have to attack the body. The exhausted T cell immune response, known to increase poor outcomes in certain viral infections, is now shown to produce just the opposite effect in inflammatory autoimmune disease, namely less severe disease progression with fewer relapses. 

Building on this breakthrough, Drs. Smith and McKinney will now pursue ways to predict the course of the disease and to direct treatment choices accordingly. The goal is to minimize medication side effects, lessen organ damage and slow down lupus progression. 

“We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion," said Dr. Kenneth Smith.

- See more at: http://www.lupusresearchinstitute.org/lupus-news/2015/07/09/lri%E2%80%93...

Dr. Smith and the Cambridge research team have rapidly delivered the outstanding results just published in the prestigious professional journal Nature.

Novel Discovery Brings Personalized Lupus Treatment Much Closer
Dr. Smith and co-investigator Dr. Eoin McKinney uncovered that the more tired the CD8 T cells become, the less energy they have to attack the body. The exhausted T cell immune response, known to increase poor outcomes in certain viral infections, is now shown to produce just the opposite effect in inflammatory autoimmune disease, namely less severe disease progression with fewer relapses. 

Building on this breakthrough, Drs. Smith and McKinney will now pursue ways to predict the course of the disease and to direct treatment choices accordingly. The goal is to minimize medication side effects, lessen organ damage and slow down lupus progression. 

“We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion," said Dr. Kenneth Smith.

- See more at: http://www.lupusresearchinstitute.org/lupus-news/2015/07/09/lri%E2%80%93...

Dr. Smith and the Cambridge research team have rapidly delivered the outstanding results just published in the prestigious professional journal Nature.

Novel Discovery Brings Personalized Lupus Treatment Much Closer
Dr. Smith and co-investigator Dr. Eoin McKinney uncovered that the more tired the CD8 T cells become, the less energy they have to attack the body. The exhausted T cell immune response, known to increase poor outcomes in certain viral infections, is now shown to produce just the opposite effect in inflammatory autoimmune disease, namely less severe disease progression with fewer relapses. 

Building on this breakthrough, Drs. Smith and McKinney will now pursue ways to predict the course of the disease and to direct treatment choices accordingly. The goal is to minimize medication side effects, lessen organ damage and slow down lupus progression. 

“We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion," said Dr. Kenneth Smith.

- See more at: http://www.lupusresearchinstitute.org/lupus-news/2015/07/09/lri%E2%80%93...