Background
The understanding of the immune pathogenesis of Multiple Sclerosis (MS) is incomplete. There is lack of clarity regarding why some patients have aggressive disease and there no reliable biomarkers to delineate this at patient’s individual level. Autologous haematopoietic stem cell transplantation (aHSCT) is being increasingly used as an intensive one-off treatment for such patients after having been demonstrated to be highly effective at inducing long term remission and may be more effective than disease modifying treatment (DMT). The treatment is not however without risk meaning patient selection is paramount. Despite its success, some patients respond less well to aHSCT and the reasons for this are unknown. The mechanism of action of aHSCT has not been completely defined and there is limited knowledge of the reconstitution of the immune system in the blood and cerebrospinal fluid CSF. Initially the immune system is depleted with a conditioning (chemotherapy) regimen before it then regenerates with a higher level of immune tolerance that lasts well beyond recovery of absolute lymphocyte numbers. The gut microbiome plays a significant role in homeostasis of the immune system and alterations are likely to play an important role in the disease process. The response to the re-vaccination in the 12 months following stem cell transplantation is reduced although the mechanism of this impaired response has not yet been delineated. Utilising techniques (scRNA-seq and 16S rRNA sequencing of stool) which have been used sparingly in MS patients previously, a deeper understanding of the changes to the immune system which occur in aggressive RRMS is expected. The response to both aHSCT and DMT may yield additional biomarkers to help predict response to treatment.
Study hypothesis:
Delineation of the immune profile of peripheral blood, CSF, peripherally obtained stem cells and the microbiome before and after aHSCT or high efficacy DMT in patients with active relapsing remitting MS will provide mechanistic insight into disease mechanisms and control and form the basis for biomarker development thereby enabling earlier diagnosis, prognostication and treatment guidance.
Specific aims:
Longitudinally characterise the immune system of patients undergoing aHSCT and compare this to patients receiving DMT.
Objectives
1. Quantitatively and qualitatively characterise the immune profile of stem cells, blood, CSF and the microbiome pre and post treatment of 15 patients undergoing aHSCT or DMT for MS.
2. Phenotype profiling of stem cells, cells in blood and CSF using multi-parameter flow cytometry.
3. Profile the gut microbiome using 16S rRNA sequencing and flow cytometric analysis.
4. Perform single cell RNA sequencing (scRNA-Seq) on paired CSF and blood pre and post treatment.
5. Profiling of T cell receptor and B cell receptor repertoire diversity and clonality
6. Assess the immunogenicity of a routine vaccination programme following aHSCT.
Training
You will join a team of several postdocs, PhD students and technicians and will benefit from their support and expertise. The supervisory team within Sheffield Institute for Translational Neuroscience and Nottingham Trent University (led by Professor Rutella) are ideally placed to offer the training and support required
Entry Requirements:
Candidates must have a first or upper second-class honours degree or significant research experience.
How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Please clearly state the prospective main supervisor in the respective box and select Neuroscience as the department.
Enquiries:
Interested candidates should in the first instance contact Professor Majid ([Email Address Removed])
Start date:
October 2023
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