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

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

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 3

Notch1 inactivation in T cells is sufficient to protect mice from lethal GVHD.

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Notch1 inactivation in T cells is sufficient to protect mice from letha...
Irradiated BALB/c mice (9 Gy) were infused with TCD BM and WT, DNMAML, or Notch1f/f Cd4-Cre+ (N1 KO) spleen B6 T cells. Isotype control or anti-Notch2 antibodies (5 mg/kg) were administered i.p. twice weekly. (A) Survival after transplantation and (B) clinical GVHD score showing protection from lethal GVHD in groups transplanted with DNMAML or Notch1 KO T cells, irrespective of Notch2 blockade (P < 0.0001 for TCD BM, DNMAML, Notch1 KO groups vs. WT isotype and WT anti-Notch2) (n = 8/group). Cross indicates death of all mice by the indicated time point. Preserved in vivo proliferation (C) and expansion (D) of DNMAML and Notch1 KO CD4+ and CD8+ T cells. Donor-derived H2Kb+H2Kd–CFSE-labeled T cells were tracked in the spleen at day 5 after transplantation. DNMAML-GFP was present in the same channel as CFSE fluorescence. (E) Increased expansion of DNMAML and Notch1 KO T cells at days 14 and 21 after transplantation. Graphs show the number of donor-derived H2Kb+H2Kd– CD4+ or CD8+ T cells in the spleen. (F) Increased percentage and absolute numbers of donor FoxP3+ Tregs upon DNMAML expression or Notch1 inactivation. Representative flow cytometry plots are shown, including a sample stained with isotype control antibodies. Bar graphs represent mean ± SD. **P < 0.01; *P < 0.05.