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Blockade of individual Notch ligands and receptors controls graft-versus-host disease
Ivy T. Tran, … , Christian W. Siebel, Ivan Maillard
Ivy T. Tran, … , Christian W. Siebel, Ivan Maillard
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1590-1604. https://doi.org/10.1172/JCI65477.
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Research Article Immunology Article has an altmetric score of 47

Blockade of individual Notch ligands and receptors controls graft-versus-host disease

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Abstract

Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer activity of the allogeneic graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells showed markedly decreased production of inflammatory cytokines, but normal in vivo proliferation, increased accumulation of regulatory T cells, and preserved anticancer effects. Here, we report that γ-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. Notch1 inhibition controlled GVHD, but led to treatment-limiting toxicity. In contrast, Delta-like1/4 inhibition blocked GVHD without limiting adverse effects while preserving substantial anticancer activity. Transient blockade in the peritransplant period provided durable protection. These findings open new perspectives for selective and safe targeting of individual Notch pathway components in GVHD and other T cell–mediated human disorders.

Authors

Ivy T. Tran, Ashley R. Sandy, Alexis J. Carulli, Christen Ebens, Jooho Chung, Gloria T. Shan, Vedran Radojcic, Ann Friedman, Thomas Gridley, Amy Shelton, Pavan Reddy, Linda C. Samuelson, Minhong Yan, Christian W. Siebel, Ivan Maillard

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Figure 4

Dominant role of Notch1 in intestinal regeneration after BM transplantation.

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Dominant role of Notch1 in intestinal regeneration after BM transplantat...
BALB/c mice were lethally irradiated (9 Gy) and transplanted with TCD B6 BM (5 × 106 cells). Monoclonal antibodies (5 mg/kg) were administered i.p. twice weekly. (A) H&E staining and anti-BrdU immunohistochemistry of ileum in mice treated with isotype control or combined anti-Notch1/Notch2 antibodies (day 4). BrdU was given i.p. 2 hours before euthanasia. The number of BrdU+ crypts was quantified in 6–10 crypts/mouse. Bar graphs represent mean ± SD (n = 3/group). **P < 0.01. (B) Rapid lethality in anti-Notch1/Notch2–treated mice, as seen with GSI treatment (Figure 1). Isotype control, n = 5; anti-Notch1/Notch2, n = 12. (C) H&E and anti-BrdU staining of ileum in mice treated with isotype control (day 5), anti-Notch1 (day 6), or anti-Notch2 antibodies (day 5). Bar graphs represent mean ± SD (n = 3/group). Scale bars: 100 μm. (D) Rapid lethality in anti-Notch1–treated mice, consistent with the major effects of Notch1 blockade on intestinal regeneration as seen in C. This was not the case with anti-Notch2 alone (see Figure 3A). Isotype control, n = 5; anti-Notch1, n = 6 mice/group.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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