To date, stem cell transplantation (SCT) remains the preferred treatment option for the majority of blood cancers. Chemotherapy/radiation during conditioning (in preparation for the SCT) 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. We have published extensively using pre-clinical models of stem cell transplantation. Most recently, we demonstrated that mucosal associated invariant T cells (MAIT cells), known to bind bacterial metabolites leading to cell activation, protected against intestinal acute GVHD. The specific aim of this project is to further investigate the host innate immune response and its interaction with intestinal microbiota. This project is not limited to, but will involve, extensive animal work, flow cytometry, immunological assays and microbiological techniques, and is best suited for a PhD candidate.
Dr Varelias’ Selected Key Publications:
1. 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. 128(5):1919-1936 (2018). *Joint first authors.
2. 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. 129(15):2172-2185 (2017).
3. 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. 125(15):2435-44 (2015).
4. Kennedy GA*, Varelias A*, Vuckovic S, Le Texier L, Gartlan KH, Zhang P, Thomas G, Anderson L, Boyle G, Cloonan N, Leach J, Sturgeon E, Avery J, Olver SD, Lor M, Misra AK, Hutchins C, Morton AJ, Durrant STS, Subramoniapillai E, Butler JP, Curley CI, MacDonald KPA, Tey SK and Hill GR.
Addition of IL-6 inhibition to standard GVHD prophylaxis after allogeneic stem cell transplantation: a phase I/II trial. Lancet Oncol. 15(13):1451-9 (2014). *Joint first authors.
5. Koyama M, Kuns RD, Olver SD, Raffelt NC, Wilson YA, Don AL, Lineburg KE, Cheong M, Robb RJ, Markey KA, Varelias A, Malissen B, Hämmerling GJ, Clouston AD, Engwerda CR, Bhat P,
MacDonald KP and Hill GR. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med. 18(1):135-42 (2012).