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Originally published online as doi:10.1189/jlb.0703351 on October 13, 2003

Published online before print October 13, 2003
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(Journal of Leukocyte Biology. 2004;75:76-86.)
© 2004 by Society for Leukocyte Biology

Adoptive transfer of ex vivo immune-programmed NKT lymphocytes alleviates immune-mediated colitis

Oren Shibolet*,1, Yossef Kalish*,1, Athalia Klein*, Ruslana Alper*, Lydia Zolotarov*, Barbara Thalenfeld{dagger}, Dean Engelhardt{dagger}, Elazar Rabbani{dagger} and Yaron Ilan*,2

* Liver Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and
{dagger} ENZO Biochem, New York, New York

2Correspondence: Liver Unit, Department of Medicine, Hadassah University Hospital, P.O. Box 12000, Jerusalem, Israel IL-91120. E-mail: ilan{at}hadassah.org.il

T lymphocyte-expressing natural killer (NK) cell markers (NKT cells) play a role in immune regulation. Our aim was to evaluate the in vivo effect of adoptive transfer of immune-programmed NKT cells. Colitis was induced in C57/B6 mice by 2,4,6-trinitrobenzenesulfonic acid. NKT, CD4, CD8 lymphocytes, and dendritic cells (DC) were prepared from spleens of naive mice, animals with colitis, and animals with colitis that were orally tolerized. Subsets of splenocytes, NKT, CD4, and CD8 and NKT+CD4, NKT+CD8, and NKT+DC lymphocytes were prepared. Assessment of the T helper cell type 1 (Th1)/Th2 cytokine secretion paradigm in vitro was performed before and following exposure to the antigen. Adoptive transfer of ex vivo immune-programmed lymphocytes from each group was performed into recipient mice, followed by colitis induction. Ex vivo exposure of NKT cells harvested from mice with colitis-to-colitis proteins [colitis-extracted proteins (CEP)] led to a Th2 cytokine shift. The interleukin (IL)-4/interferon-{gamma} (IFN-{gamma}) ratio increased for NKT harvested from colitis-harboring mice following exposure to CEP. Adoptive transfer of NKT lymphocytes harvested from colitis-harboring mice, which were ex vivo-educated, significantly alleviated experimental colitis in vivo. Intrahepatic NKT lymphocytes increased significantly in mice transplanted with NKT lymphocytes harvested from colitis-harboring donor mice, which were ex vivo-exposed to CEP, similar to mice transplanted with NKT lymphocytes harvested from tolerized donors. Exposure of NKT cells to the disease-target antigen induced a significant increase in the IL-4/IFN-{gamma} cytokine ratio. Adoptive transfer of a relatively small number of immune-programmed NKT cells induced a systemic Th1 to Th2-immune shift and alleviated immune-mediated colitis.

Key Words: NK1.1 T cells • oral tolerance • experimental colitis




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