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Mapping the induction of allo-immune effector cells in haematopoietic stem cell transplantation

Fully funded PhD studentship in immunology / stem cell therapy available for 3 years starting Sept-Dec 2018.  

Haematopoietic stem cell transplantation (bone marrow transplantation) is the only curative therapy for many haematological malignancies, bone marrow failure syndromes and immune system disorders.  The success of this treatment depends critically upon the activation of donor T cells and myeloid cells by antigenic differences between the donor and recipient (allo-immunity).  A donor versus leukaemia immune effect acts as a form of cellular therapy that can lead to long term cure. However, excessive activation of the donor immune system can lead to graft versus host disease, a relatively common and sometimes fatal complication.  The project aims to map key transcriptional regulators that govern the development of allo-reactive cells following stem cell transplantation. The ultimate goal will be to identify new molecular targets that can used to manipulate allo-immune responses and thus to improve the safety and efficacy of transplantation.

 

Recent studies from the group indicate that multiple lineages of donor CD4 T cells, CD8 T cells and monocyte-derived macrophages are elicited during stem cell transplantation but the genesis of these effector cells is not well understood.  It is not known whether allo-immune T cells develop from naïve T cells or cross-reactive memory T cells responding either directly or indirectly to antigenic stimuli.  The role of myeloid cells is also poorly defined and may be required in lymphoid tissues or at the sites of allo-immune responses in the tissues and bone marrow.

 

Single cell RNAseq using the 10X system now enables us to map the induction of allo-reactive effector phenotypes and usage of T cell antigen receptors at single cell resolution.  A seminal publication illustrates that 10X data resolves peripheral blood cell lineages and that genomic variation can be used to distinguish between donor and recipient in transplantation (DOI: 10.1038/ncomms14049).  Using a combination of in vitro HLA-matched mixed leukocyte reactions from donor-recipient pairs and mononuclear cells and single cell suspensions isolated from the skin and bone marrow of stem cell transplant recipients, the research student will map the transcriptional regulation of donor cells during the induction of an allo-immune response and identify transcription factors that control the differentiation of effector phenotypes.

 

The project provides a top-class opportunity for a motivated and able student to tackle the fundamental problem of human allo-reactivity using state of the art technology, supported by the most research-active BMT programme in the UK.  Training will begin in conventional cellular immunology and progress to the cutting edge of immune response analysis using single cell transcriptome profiling.  

 

The supervisory team has an excellent track record in the areas of BMT and immunology.  Prof Collin is Director of BMT at Newcastle upon Tyne Hospitals and has maintained a leading role in GVHD-related research.  Dr Laurence (Clinical lecturer / NURF) is also a BMT physician and one of the 100 top-cited immunologists in the world with expertise in T cell signalling and Treg biology.  Dr Armanath (NURF) is an expert in GVHD modelling, Treg and innate lymphoid cell biology.  This team is supported by Dr Clare Lendrem for BMT database support and statistical analysis and by Dr Venetia Bigley and doctoral student Anna Resteu in the analysis of single cell data.