Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice

Y Yu, D Wang, C Liu, K Kaosaard… - Blood, The Journal …, 2011 - ashpublications.org
Y Yu, D Wang, C Liu, K Kaosaard, K Semple, C Anasetti, XZ Yu
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic
malignancies through T cell–mediated GVL effects. However, HCT benefits are frequently
offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can
differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer
into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17
differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption …
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic malignancies through T cell–mediated GVL effects. However, HCT benefits are frequently offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17 differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption of T-bet and RORγt have defective differentiation toward Th1 and Th17 and skewed differentiation toward Th2 and regulatory phenotypes, and caused ameliorated GVHD in a major MHC-mismatched model of HCT. GVL effects mediated by granzyme-positive CD8 T cells were largely preserved despite T-bet and RORγt deficiency. These data indicate that GVHD can be prevented by targeting Th1 and Th17 transcription factors without offsetting GVL activity.
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