Journal
JOURNAL OF IMMUNOLOGY
Volume 205, Issue 1, Pages 272-281Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2000054
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Funding
- National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH) [T32 AI125231]
- National Heart, Lung, and Blood Institute, NIH [T32 HL07899]
- NIAID, NIH [R21-AI116007, R01 AI136500, R21 AI105841]
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Acute graft-versus-host disease (GVHD) is a frequent complication of hematopoietic transplantation, yet patient risk stratification remains difficult, and prognostic biomarkers to guide early clinical interventions are lacking. We developed an approach to evaluate the potential of human T cells from hematopoietic grafts to produce GVHD. Nonconditioned NBSGW mice transplanted with titrated doses of human bone marrow developed GVHD that was characterized by widespread lymphocyte infiltration and organ pathology. Interestingly, GVHD was not an inevitable outcome in our system and was influenced by transplant dose, inflammatory status of the host, and type of graft. Mice that went on to develop GVHD showed signs of rapid proliferation in the human T cell population during the first 1-3 wk posttransplant and had elevated human IFN-gamma in plasma that correlated negatively with the expansion of the human hematopoietic compartment. Furthermore, these early T cell activation metrics were predictive of GVHD onset 3-6 wk before phenotypic pathology. These results reveal an early window of susceptibility for pathological T cell activation following hematopoietic transplantation that is not simply determined by transient inflammation resulting from conditioning-associated damage and show that T cell parameters during this window can serve as prognostic biomarkers for risk of later GVHD development.
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