To date, stem cell transplantation (SCT) remains the preferred treatment option for the majority of blood cancers. Chemotherapy/radiation during conditioning damages intestinal epithelium resulting in systemic exposure to microbial products normally sequestered in the intestinal lumen, in addition to a marked cytokine release. We have demonstrated that these microbial products and cytokines modulate graft-versus-host disease (GVHD) and thereby transplant outcome. Numerous approaches in the clinic targeting intestinal microbiota to harness GVHD such as gut decontaminating antibiotics, introduction of beneficial bacteria or targeting anaerobic bacteria have been attempted but these have shown varied effects. A greater understanding of the cellular and molecular mechanisms underlying these approaches will inform of new strategies that could be adopted to protect against unrestrained immune activation and GVHD. Recently, we demonstrated that mucosal associated invariant T (MAIT) cells, activated in response to engagement with microbial-derived riboflavin derivatives loaded onto MR1 ligands, protected against intestinal acute GVHD.
The overall aim of this project is to further investigate the host innate immune response and its interaction with intestinal microbiota during homeostasis and in acute GVHD.
Approaches / Techniques to be utilised
This project is not limited to, but will involve, extensive animal work, flow cytometry, immunological assays, molecular and microbiological techniques.
References / Key papers
Varelias A, Gartlan KH, Kreijveld E, Olver SD, Lor M, Kuns RD, Lineburg KE, Teal BE, Raffelt N, Cheong M, Alexander KA, Koyama M, Markey KA, Sturgeon E, Leach J, Reddy P, Kennedy GA, Yanik G, Blazar BR, Tey S-K, Clouston AD, MacDonald KPA, Cooke KR and Hill GR. Lung parenchyma–derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation. Blood. 2015. 125(15):2435-44.
Varelias A, Ormerod KL, Bunting MD, Koyama M, Gartlan KH, Kuns RD, Lachner N, Locke KR, Lim CY, Henden AS, Zhang P, Clouston AD, Hasnain SZ, McGuckin MA, Bruce R Blazar, MacDonald KPA, Hugenholtz P and Hill GR. Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood. 2017. 129(15):2172-2185.
Varelias A*, Bunting MD*, Ormerod KL, Koyama M, Olver SD, Straube J, Kuns RD, Robb RJ, Henden AS, Cooper L, Lachner N, Gartlan KH, Lantz O, Kjer-Nielsen L, Mak JYW, Fairlie DP, Clouston AD, McCluskey J, Rossjohn J, Lane SW, Hugenholtz P and Hill GR. Recipient Mucosal-Associated Invariant T Cells control GVHD within the colon. J Clin Invest. 2018. 128(5):1919-1936. *Joint first authors.
Martins JP, Andoniou CE, Fleming P, Kuns RD, Schuster IS, Voigt V, Daly S, Varelias A, Tey SK, Degli-Esposti MA, Hill GR. Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation. Science. 2019. 363(6424):288-293.