Targeting GLUT1 to control autoreactive T cells post islet transplantation

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Abstract Summary

Background

Islet transplantation in patients with type 1 diabetes can be associated to re-activation of quiescent autoreactive T cells and standard immuno-suppression has limited capacity to control autoimmunity recurrence. Once activated, autoreactive T cells upregulate the glucose transporter GLUT1 in the context of metabolic re-programming for activation and proliferation. 

 

Methods

We determined by flow cytometry whether GLUT1 is upregulated in autoreactive T cells post islet transplantation and how we can interfere with GLUT1 to control autoreactive T cells post islet transplantation.

 

Results

 

In autoreactive resting T cells pre islet transplantation, GLUT1 is expressed at low levels, predominantly in T cell subsets with a memory phenotype such as Tscm and Tcm. Post islet transplantation, GLUT1 is upregulated in GAD65 specific CD8+ T cells in approximately 30% of subjects. GLUT1 positive T cells also express markers of proliferation (Ki67) and activation (CD25). Therefore, we tested WZB117, a small molecule that acta s selective inhibitor of GLUT1, for its ability to suppress the response of GAD65 specific CD8+ T cells. We show that WZB117 can inhibit the glucose uptake of activated T cells and reduce proliferation. Activation of GAD65 specific T cells in the presence of WZB117 leads to expression of exhaustion markers PD1, LAG3 and TIM3. GAD65 specific T cells activated in the presence of WZB117 showed also an impaired secondary response to GAD65 stimulation. Interestingly, T cells that are not stimulated with the antigen are not affected by WZB117 treatment. Islet transplantation represent an ideal model to test GLUT1 blockade as it is possible to identify a time window for autoreactive T cell activation in a way that GLUT1 blockade would selectively affect autoreactive (and possibly alloreactive) T cells in a short course treatment.

Submission ID :
IDS9080
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Abstract Topics
IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute

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KEY DATES

Event dates:
Thursday 25 October - Monday 29 October 2018

Abstract submission deadline:
Monday 14 May 2018

Abstract notification:
July 2018

Early registration deadline:
Monday 3 September 2018

Registration deadline:
Monday 15 October 2018

Contact
British Society for Immunology
+44 (0)20 3019 5901
congress@immunology.org