Soluble lymphotoxin is an important effector molecule in GVHD and GVL

Abstract

Tumor necrosis factor (TNF) is a key cytokine in the effector phase of graftversus-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␣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␣ 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␣3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LT␣ is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LT␣-and TNFdeficient 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␣ 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␣3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR. (Blood. 2010;115: 122-132)

Immune-Mediated Mechanisms of Parasite Tissue Sequestration during Experimental Cerebral Malaria

“…1 d prior to PbAluc infection. TNF and LTa blockade was performed by administering TNFR2-Ig (Enbrel; Amgen, Thousand Oaks, CA), a fusion protein that has been shown previously to inhibit the functional activity of both murine TNF and soluble LTa homotrimers (53). A total of 0.2 mg TNFR2-Ig was administered i.p.…”

Immune insufficiency during GVHD is due to defective antigen presentation within dendritic cell subsets

“…11 All recipient mice were transplanted and irradiated on day 0, with irradiation doses as follows: BALB/c, 900 cGy; B6D2F1, 1100 cGy; and B6 and bm1.Act-mOVA, 1000 cGy. BALB/c mice were transplanted with 10 7 T cell-depleted (TCD) BM cells from B6 (allogeneic) or BALB/c (syngeneic) donors, with or without the addition of 0.2 ϫ 10 6 CD3 ϩ T cells, or CD4 or CD8 MACS-purified T cells.…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…This includes an important role of LT signaling in the acceptance of donor stem cells, controlling cuprizone-induced demyelination, the progression of experimental autoimmune encephalomyelitis and the control of lipid metabolism or liver regeneration Lo et al, 2007;Plant et al, 2007;Markey et al, 2009;Ruddell et al, 2009;Tumanov et al, 2009). Studies with different mouse models revealed a role of LTbR signaling in atherosclerosis development (Schreyer et al, 2002;Grabner et al, 2009) and an involvement of LTbR signaling was discovered in the pathogenesis of RA (Fava et al, 2003).…”