Soluble lymphotoxin is an important effector molecule in GVHD and GVL.
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 (LTalpha3), 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 LTalpha 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 LTalpha3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LTalpha is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LTalpha- 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/LTalpha 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 LTalpha3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR.
Markey
Kate A
KA
Queensland Institute of Medical Research, Brisbane, Australia.
Burman
Angela C
AC
Banovic
Tatjana
T
Kuns
Rachel D
RD
Raffelt
Neil C
NC
Rowe
Vanessa
V
Olver
Stuart D
SD
Don
Alistair L J
AL
Morris
Edward S
ES
Pettit
Allison R
AR
Wilson
Yana A
YA
Robb
Renee J
RJ
Randall
Louise M
LM
Korner
Heinrich
H
Engwerda
Christian R
CR
Clouston
Andrew D
AD
Macdonald
Kelli P A
KP
Hill
Geoffrey R
GR
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000276:immunology*; D051379:Mice; D055503:Protein Multimerization; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000276:immunology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000276:immunology
D018836:Inflammation Mediators; D008233:Lymphotoxin-alpha; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha