Soluble lymphotoxin is an important effector molecule in GVHD and GVL

Kate Markey, Angela Burman, Tatjana Banovic, Rachel Kuns, Neil Raffelt, Vanessa Rowe, Stuart Olver, Alistair Don, Edward Morris, Allison Pettit, Yana Wilson, Renee Robb, Louise Randall, Heinrich Körner, Christian Engwerda, Andrew Clouston, Kelli MacDonald, Geoffrey Hill

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    28 Citations (Scopus)

    Abstract

    Tumor necrosis factor (TNF) is a key cytokine in the effector phase of graft-versus-host disease (GVHD) after bone marrow transplantation, and TNF inhibitors have shown efficacy in clinical and experimental GVHD. TNF signals through the TNF receptors (TNFR), which also bind soluble lymphotoxin (LTα3), a TNF family member with a previously unexamined role in GVHD pathogenesis.We have used preclinical models to investigate the role of LT in GVHD.We confirm that grafts deficient in LTα have an attenuated capacity to induce GVHD equal to that seen when grafts lack TNF. This is not associated with other defects in cytokine production or T-cell function, suggesting that LTα3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LTα is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LTα - and TNF-deficient grafts. Further impairment in tumor clearance was seen using Tnf/Lta-/- donors, suggesting that these molecules play nonredundant roles in GVL. Importantly, donor TNF/LTα were only required for GVL where the recipient leukemia was susceptible to apoptosis via p55 TNFR signaling. These data suggest that antagonists neutralizing both TNF and LTα3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR.

    Original languageEnglish
    Pages (from-to)122-132
    Number of pages11
    JournalBlood
    Volume115,
    Issue number1
    DOIs
    Publication statusPublished - 7 Jan 2010

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  • Cite this

    Markey, K., Burman, A., Banovic, T., Kuns, R., Raffelt, N., Rowe, V., Olver, S., Don, A., Morris, E., Pettit, A., Wilson, Y., Robb, R., Randall, L., Körner, H., Engwerda, C., Clouston, A., MacDonald, K., & Hill, G. (2010). Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood, 115,(1), 122-132. https://doi.org/10.1182/blood-2009-01-199927