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Interleukin-12 inhibits murine graft-versus-host disease
M Sykes, GL Szot, PL Nguyen and DA Pearson
Department of Pathology, Massachusetts General Hospital, Harvard Medical
School, Boston 02129, USA.
Interleukin-12 (IL-12) is a potent immunostimulatory cytokine and an
inducer of type-1 T-helper cell activity and of cytotoxic T lymphocyte and
natural killer cell function. We report here the paradoxical observation
that a single injection of 4,900 IU of recombinant murine IL-12 inhibits
acute graft-versus-host disease (GVHD) in a fully major histocompatibility
complex (MHC) plus multiple minor antigen-mismatched bone marrow
transplantation (BMT) model (A/J-->B10). The protective effect was
enhanced by administration of T-cell-depleted host-type BM cells, and
complete donor-type lymphohematopoietic reconstitution was observed in most
animals. Treatment with a protective course of IL-12 led to increased serum
interferon-gamma (IFN-gamma) levels as compared with those for GVHD
controls at early time points, when IFN-gamma was produced predominantly by
host-type natural killer cells, but led to almost complete inhibition of
the later GVHD-associated increase in serum IFN-gamma levels, when
IFN-gamma is produced predominantly by CD4+ T cells. Furthermore, IL-12
treatment was associated with marked alterations in the kinetics of donor
T-cell expansion. Reductions in donor CD4+ and CD8+ T cells were observed
in the spleen on day 4 post- BMT, but a marked increase in donor CD8+ cells
was observed on day 7. Unlike broadly immunosuppressive methods for
inhibiting GVHD, which are associated with loss of antileukemic effects,
IL-12 has the potential to mediate antileukemic effects of its own;
therefore, the GVHD- inhibitory effects of IL-12 described here suggest a
potential application for this cytokine in clinical BMT.
Volume 86,
Issue 6,
pp. 2429-2438,
09/15/1995
Copyright © 1995 by The American Society of Hematology
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