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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3367-3375
IMMUNOBIOLOGY
Selective T-cell subset ablation demonstrates a
role for T1 and T2 cells in ongoing acute
graft-versus-host disease: a model system for the reversal of
disease
Jinli Liu,
Britt E. Anderson,
Marie E. Robert,
Jennifer M. McNiff,
Stephen G. Emerson,
Warren D. Shlomchik, and
Mark J. Shlomchik
From the Departments of Laboratory Medicine, Pathology,
and Dermatology and the Section of Immunobiology, Yale University
School of Medicine, New Haven, CT; and the Department of Medicine,
Section of Hematology and Oncology, University of Pennsylvania School
of Medicine, Philadelphia, PA.
Graft-versus-host disease (GVHD) is a major cause of morbidity and
mortality of allogeneic stem cell transplantation. Strategies to
control GVHD while maintaining graft versus leukemia (GVL) include
herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In
this regard, whether cytokine polarization occurs and to what degrees
various subsets of cytokine-producing T cells mediate GVHD or GVL has
been an active area of research using cytokine or cytokine antibody
infusion or genetically deficient mice. This study takes a different
approach that allows simultaneous investigation into both the
mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide
gene-based T-cell deletion. A source of donor T cells, splenocytes from
mice transgenic for HSV-tk controlled by elements of either the
interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk,
respectively) was used, thus allowing investigation into the roles of
T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather
than prevention of GVHD, GCV was started at peak disease. Remarkably,
treatment at this late time point rescued mice from the clinical
effects of GVHD caused by T cells expressing either transgene. Thus,
both T1 and T2 cells play an important role in clinical GVHD in a minor
histocompatibility antigen-mismatched setting. In addition,
because clinical disease was reversible even at its maximum, these
observations provide controlled evidence that this strategy of
treating ongoing GVHD could be effective clinically.
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