Soluble lymphotoxin is an important effector molecule in GVHD and GVL

Markey, KA, Burman, AC, Banovic, T, Kuns, RD, Raffelt, NC, Rowe, V, Olver, SD, Don, ALJ, Morris, ES, Pettit, AR, Wilson, YA, Robb, RJ, Randall, LM, Korner, H, Engwerda, CR, Clouston, AD, MacDonald, KPA and Hill, GR (2010) Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood, 115 1: 122-132. doi:10.1182/blood-2009-01-199927

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Author Markey, KA
Burman, AC
Banovic, T
Kuns, RD
Raffelt, NC
Rowe, V
Olver, SD
Don, ALJ
Morris, ES
Pettit, AR
Wilson, YA
Robb, RJ
Randall, LM
Korner, H
Engwerda, CR
Clouston, AD
MacDonald, KPA
Hill, GR
Title Soluble lymphotoxin is an important effector molecule in GVHD and GVL
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
Publication date 2010-01-07
Year available 2009
Sub-type Article (original research)
DOI 10.1182/blood-2009-01-199927
Volume 115
Issue 1
Start page 122
End page 132
Total pages 11
Place of publication United States
Publisher American Society of Hematology
Collection year 2010
Language eng
Subject C1
9201 Clinical Health (Organs, Diseases and Abnormal Conditions)
110702 Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
Formatted 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 (LT{alpha}3), 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 LT{alpha} 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 LT{alpha}3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LT{alpha} is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LT{alpha}- 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/LT{alpha} 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 LT{alpha}3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR.
Keyword Tumor-Necrosis-Factor
Versus-Host-Disease
Bone-Marrow-Transplantation
Factor-Alpha
TNF-Alpha
Gastrointestinal-Tract
Rheumatoid-Arthritis
Leukemia Responses
Lymphoid Organs
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Sun, 24 Jan 2010, 00:05:33 EST