期刊
BLOOD
卷 117, 期 1, 页码 299-308出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-03-271940
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资金
- Damon Runyon-Rachleff Innovation Award
- American Society of Hematology
- University of Michigan
- Leukemia & Lymphoma Society
- National Institutes of Health [R01 CA102464, R01 AI047833]
- National Institutes of Health through the University of Michigan's Cancer Center [5P30CA46592]
- University of Pennsylvania's Cancer Center
- National Institute of Allergy and Infectious Diseases [T32A1007413]
- Grants-in-Aid for Scientific Research [22591063] Funding Source: KAKEN
Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4(+) and CD8(+) T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4(+) T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4(+) T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT. (Blood. 2011;117(1):299-308)
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