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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1513.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 2024-2032
TRANSPLANTATION
Total lymphoid irradiation nonmyeloablative preconditioning
enriches for IL-4-producing CD4+-TNK cells and skews
differentiation of immunocompetent donor CD4+
cells
Shawn M. Rigby,
Todd Rouse, and
Elizabeth H. Field
From the Department of Internal Medicine, University of
Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City; and
the Department of Veterans Affairs Medical Center, Iowa City, IA.
Preconditioning with the nonmyeloablative regimen total lymphoid
irradiation (TLI) before hematopoietic cell transplantation facilitates
the establishment of mixed chimerism and protects against
graft-versus-host disease. We reported that the development of mixed
chimerism requires interleukin (IL)-4 and is associated with increased
host anti-donor TH2 cells, but the effect of TLI on the
differentiation of immunocompetent donor cells has not been
investigated. To examine the extent to which TLI preconditioning influences donor T cells, we measured responses of transgenic CD4+ cells specific for ovalbumin peptide (OVA-Tg)
following in vivo and in vitro antigen stimulation in a
TLI-preconditioned environment. OVA-Tg cells that were adoptively
transferred into TLI-preconditioned mice that express cross-reactive
antigens produced more IL-4 and less interferon- and IL-2 than
controls when stimulated with OVA peptide one week later. OVA-Tg primed
in vitro with spleen from TLI-preconditioned mice generated more
TH2 and fewer TH1 cells when stimulated in
recall enzyme-linked immunosorbent spot (ELISPOT) assays with OVA
peptide. Naive OVA-Tg up-regulated CD69 and CD25 normally following
stimulation with OVA peptide in the presence of spleen from
TLI-preconditioned mice, but proliferated less and secreted less IL-2
than controls. Surprisingly, naive OVA-Tg secreted IL-4 in primary
cultures that were stimulated with OVA peptide in the presence of
spleen from TLI-preconditioned mice. This response depends on
CD4+ cells from TLI-spleen, which constitutively produce
IL-4 and are composed primarily of CD4+-natural killer T
(TNK) cells. Thus, TLI preconditioning enriches for IL-4-secreting and
TNK-like CD4+ cells that may function in the protection
from graft-versus-host disease by redirecting the differentiation of
immunocompetent donor CD4+ cells toward TH2 and
away from pathogenic TH1 cells.
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