T Regulatory cells and the outcome of bone marrow transplantation: understanding variation in circulating Tregs
Allogenic haematopoietic stem cell transplantation (HSCT or bone marrow transplantation) using grafts from HLA-matched sibling or unrelated donors is widely used as a curative treatment in haematological malignancies. However, it carries up to 40% transplant related mortality due to infection and graft versus host disease.
We have shown that the proportion of CD4+ CD25+ Foxp3++ T regulatory cells/CD4 cells in the HSCT graft has a profound effect of the outcome of transplantation. Those receiving grafts with the highest quartile of Tregs/CD4 cells have 60% 5-year survival compared with 40% 5yr survival for those receiving the lowest quartile of Tregs/CD4 cells (Danby et al, 2016). These results are consistent with and indeed strengthened by a meta-analysis of Treg/CD3 ratios in allografts and transplantation outcome (Fisher et al, 2017).
These results show the clear potential to select grafts with high Treg/CD4 cells ratios to improve HSCT outcome and we are testing if this is feasible with Dr Colin Brown (Head of Immunogenetics, British Bone Marrow Registry, Colindale).
However, a more widely applicable method to enhance Treg numbers would be to understand the causes of natural variation in Treg numbers and how we can improve Treg/CD4 ratios in donors and so benefit patients. We have shown considerable variation in Treg/CD4 cell ratios in human volunteers (Lamikanra et al, 2017 and in preparation). Some of this variation is due to difference 25 (OH) vitamin D levels in our observational studies and in a randomised trial of vitamin D (Lamikanra et al, in preparation).
We have hypothesised that there is additional diversity in the proportion and function of Tregs in peripheral blood of donors due to biochemical, genetic and environmental differences (including the gut microbiome) and these differences determine the outcome of HSC transplantation. We have collaborated with Dr Gosia Trynka and the Sanger Institute and will have preliminary data from single cell RNA-Seq and eQTL studies of Tregs in 100 donors to allow further characterisation of variation in Treg phenotype and the genetic basis of this variation.
In this project, we will determine the number and diversity of Tregs in human volunteers at before and after mobilisation of haematopoietic stem cells and at different times of the day. We will relate the number and sub-types of Tregs to biochemical traits including vitamin D levels, short chain fatty acids, season and circadian rhythms, genetic traits and the gut microbiome.
These studies are supported by collaborations with Prof Fiona Powrie FRS at the Kennedy Institute, University of Oxford and Dr Gosia Trynka at Sanger Institute.
These studies will lead to novel translational methods can manipulate the number and type of T regulatory cells in donors to optimise the cellular composition of the HSCT graft and so improve the outcome for patients receiving these grafts.
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Astle et al., (2016) The allelic landscape of human blood cell trait variation and links to common complex disease, Cell, 167, 1415–1429.
Danby R, Zhang W, Rocha V, Peniket A, Roberts DJ. High proportions of regulatory T cells in peripheral blood stem cell grafts are associated with improved total lymphocyte, CD8+ T-cell and CD19+ cell recovery following allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplantation, 2016, 51(1):110-8. 106.
Lamikanra AA, Zhang W, Tsang HP, Morgan P, Smith D, Curnow E, Smythe J, Peniket A, Danby R, Roberts DJ. Measuring the resting naive sub-population of T-regulatory cells improves prediction of suppressive function of clinical grade T-regulatory products. Cytotherapy. 2017 19(3):440-443.
Fisher SA, Lamikanra A, Dorée C, Gration B, Tsang P, Danby RD, Roberts DJ. Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review. Br J Haematol. 2017 Feb;176(3):448-463. doi: 10.1111/bjh.14433
Howie D, Cobbold SP, Adams E, Bokum AT, Necula AS, Zhang W, Huang H, Roberts DJ, Thomas B, Hester SS, Vaux DJ, Betz AG, Waldmann H, Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight. 2017 Feb 9;2(3):e89160.