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Kennedy Trust Prize Studentships

  • Project No: KTPS-Clinical-8
  • Intake: 2021 KTPS

PROJECT OUTLINE

Patients with intestinal Failure (where the gut cannot provide adequate nutrition) require parenteral nutrition, which can lead to devastating complications and the need for intestinal transplantation (ITx). However, ITx has a high rate of rejection and poor survival (1). Previous studies have demonstrated the dynamics of donor and recipient T cell populations in following ITx, with implications both for graft rejection and for understanding tissue residency (2-4). However, much less is understood about B cell dynamics following ITx, the intestinal microbiota, and how secretory IgA from those B cell populations sculpts the microbiota post-transplant. Similarly, microbiota perturbations are seen in small bowel transplantation, with some evidence suggesting a role in rejection, including a decrease Firmicutes and Lactobacillales species seen in transplant recipients with rejection (5). However few studies have explored casual relationships of microbiota changes and intestinal graft rejection and other pathologies.

This project will investigate the intestinal microbiota and mucosal T and B/plasma cell dynamics, in a unique cohort of adult ITx recipients. It will employ multi-omic approaches to study the mucosal, luminal, and IgA-opsonised intestinal microbiota, as well as the dynamics, phenotype, transcriptome, and localisation of mucosal T/B/plasma cells. Donor- and recipient-derived lymphocyte populations will be distinguished using Class I HLA mismatches between donor and recipient. This will provide a general characterization of the intestinal microbiota following ITx, as well as T and B/plasma cell dynamics within the graft, and interactions between them, mediated via secretory IgA.

The outcome of this study will be to gain insights into fundamental questions about B/plasma cell residency, and the establishment of the humoral immune response to the new microbiota in the transplanted intestine.

KEYWORDS

  • Microbiome
  • Adaptive immunity
  • Intestine transplant

TRAINING OPPORTUNITIES

The Kennedy Institute is a world-renowned research facility supporting basic and clinical research. It is also home to the Oxford Centre for Microbiome Studies, which provides access to state-of-the-art microbiome research facilities. The successful candidate will also be part of the Oxford Translational Gastroenterology Unit (TGU) within the Nuffield Department of Medicine. Oxford is one of only two adult intestinal transplant centres in the UK, and the TGU laboratory research group has extensive experience working with intestinal-derived immune cells. Over the past two years TGU has set up close working relationships between the transplant service and laboratory, including consenting most patients in this transplantation cohort to the Oxford GI Illnesses Biobank(REC Ref: 16/YH/0247). The intestinal biopsy samples were used to study the dynamics of T cell residency in intestinal transplantation, optimizing the use of HLA-allele congenic cell tracking, spectral flow cytometry, chip cytometry, and single-cell RNA sequencing of intestine-derived T cell populations, with the work now in press.

In addition to being part of these cutting-edge research facilities, the successful candidate will have the opportunity to interact with the wider University of Oxford via a college association, and the opportunity to network and present their work at national and international meetings.

REFERENCES 

  1. Smith JM, Skeans MA, Horslen SP, Edwards EB, Harper AM, Snyder JJ, Israni AK, Kasiske BL (2017) OPTN/SRTR 2015 Annual Data Report: Intestine. Am J Transplant, 17:1, 252-285.
  2. Michael E.B. FitzPatrick, Nicholas M. Provine, Lucy C. Garner, Kate Powell, Ali Amini, Sophie Irwin, Helen Ferry, Tim Ambrose, Peter Friend, Georgios Vrakas, Srikanth Reddy, Elizabeth Soilleux, Paul Klenerman, Philip J. Allan. Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets. Cell reports, in press.
  3. Zuber, J., B. Shonts, S.P. Lau, A. Obradovic, J. Fu, S. Yang, M. Lambert, S. Coley, J. Weiner, J. Thome, S. DeWolf, D.L. Farber, Y. Shen, S. Caillat-Zucman, G. Bhagat, A. Griesemer, M. Martinez, T. Kato, and M. Sykes (2016) Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Science Immunology, 1, eaah3732–eaah3732.
  4. Zuber, J., S. Rosen, B. Shonts, B. Sprangers, T.M. Savage, S. Richman, S. Yang, S.P. Lau, S. DeWolf, D. Farber, G. Vlad, E. Zorn, W. Wong, J. Emond, B. Levin, M. Martinez, T. Kato, and M. Sykes (2015) Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD. American Journal of Transplantation, 15, 2691–2703.
  5. Oh PL, Martínez I, Sun Y, Walter J, Peterson DA, Mercer DF (2012) Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am J Transplant, 12, 753-62. 

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