Identifying biomarkers of aggressive multiple sclerosis

Our 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 are no reliable biomarkers to delineate this at patient’s individual level. Autologous haematopoietic stem cell transplantation (HSCT) 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. The treatment is not however without risk, meaning patient selection is paramount. Despite its success, some patients respond less well to HSCT and the reasons for this are unknown. 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 the recovery of absolute lymphocyte numbers. The mechanism of action of HSCT has not been thoroughly defined, and there is limited knowledge of the reconstitution of the immune system, and its dynamics, in the blood and cerebrospinal fluid (CSF) of patients with MS.

This is a truly unique opportunity for the successful candidate to work alongside established academics with the aim to delineate the immune profile of peripheral blood and cerebrospinal fluid specimens obtained from patients with active relapsing remitting multiple sclerosis (MS) before and after autologous haematopoietic stem cell transplantation (HSCT) or high efficacy disease modifying treatment (DMT). These studies will provide crucial insight into disease mechanisms and control and they will inform biomarker development thereby enabling earlier diagnosis and better prognostication.

The post-graduate researcher will have access to state-of-the-art omics platforms (spectral flow cytometry, single-cell RNA sequencing) and will collect transcriptomic, proteomic, and functional data from primary patient samples (blood,  cerebrospinal fluid and haemopoietic stem cells). They will leverage advanced computational biology pipelines to integrate this information with clinical data, and to generate knowledge that is expected to advance the field.

The post-graduate researcher will be based in Nottingham Trent University’s John van Geest Cancer Research Centre and is expected to work very closely with and to receive training from the supervisory team within Sheffield Institute for Translational Neuroscience.

References

Lindsay JO, Hind D, Swaby L, et al. Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterology & Hepatology 2024; 9(4): 333-345.

Rutella S, Vadakekolathu J, Mazziotta F, et al. Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia. Journal of Clinical Investigation 2022; 132 (21): e159579. DOI: 10.1172/JCI159579.

Kalincik T, Sharmin S, Roos I, et al. Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry 2024; 95 (8): 775-783.

Vadakekolathu J, Minden MD, Hood T, et al. Immune landscapes predict therapeutic resistance, immunotherapy response and clinical outcomes in acute myeloid leukemia. Science Translational Medicine 2020; 12 (Issue 546): eaaz0463.

Brittain G, Roldan E, Alexander T, Saccardi R, Snowden JA, Sharrack B, Greco R. The Role of Chimeric Antigen Receptor T-Cell Therapy in Immune-Mediated Neurological Diseases. Annals of Neurology 2024; 96(3): 441-452.

Entrants must have solid foundational knowledge of immunology and how the immune response is subverted in individuals who have inflammatory diseases. Some background knowledge of bioinformatics and biostatistics is desirable.

This is a match fund project supported by the Sheffield Institute for Translational Neuroscience