Autoimmunity after alemtuzumab: a human model to study the role of regulatory T cells in lymphopenia associated autoimmunity. (360G-Wellcome-105924_Z_14_A)
The association between lymphopenia and autoimmunity is well recognised, but poorly understood. MS patients treated with the highly effective, recently licensed, lymphocyte-depleting antibody alemtuzumab offer a rare opportunity to study this phenomenon as: 30% develop autoimmune thyroid disease, 1% ITP and 20% asymptomatic autoantibodies after treatment. We previously reported increased CD4+CD25hiFoxP3+ Tregs after alemtuzumab (similar expansions are seen in other lymphopenic settings). Her e, by immunophenotyping, TCR-sequencing, TREC analysis, FoxP3 methylation and isoform analysis, RNAseq and functional assays, I will explore the hypotheses that autoimmunity occurs because these cells are: 1. Not Tregs but activated Tconv2. 2. Defective, incapable of suppressing Th2 auto-antibody responses, due to being clonally restricted, exhausted or skewed towards a Th1 Treg phenotype. 3. Plastic - generating autoimmune effector cells via the loss of FoxP3. 4. Or, the defect may lie wit h other FoxP3- regulatory cells, e.g. the newly reported CD52hi population. This work may directly benefit MS patients; once the post-alemtuzumab Treg population is understood it may be possible to augment their function, e.g. with IL-2 or rapamycin. It also has the potential to advance our understanding of human autoimmunity, and may benefit people with other forms of lymphopenia-associated autoimmunity.
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Grant Details
Amount Awarded | 25000 |
Applicant Surname | Jones |
Approval Committee | Clinical Interview Committee |
Award Date | 2014-11-13T00:00:00+00:00 |
Financial Year | 2014/15 |
Grant Programme: Title | Intermediate Clinical Fellowship |
Internal ID | 105924/Z/14/A |
Lead Applicant | Dr Joanne Jones |
Partnership Value | 25000 |
Planned Dates: End Date | 2020-02-29T00:00:00+00:00 |
Planned Dates: Start Date | 2015-02-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Alasdair Coles |