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Interleukin-12 Inhibits Graft-Versus-Host Disease Through an
Fas-Mediated Mechanism Associated With Alterations in Donor T-Cell
Activation and Expansion
Bimalangshu R. Dey,
Yong-Guang Yang,
Gregory L. Szot,
Denise A. Pearson, and
Megan Sykes
From the Bone Marrow Transplantation Section, Transplantation Biology
Research Center, Surgical Service, Massachusetts General
Hospital/Harvard Medical School, Boston, MA.
We have recently made the paradoxical observation that a single
injection of recombinant murine interleukin-12 (IL-12) on the day of
bone marrow transplantation (BMT) inhibits graft-versus-host disease
(GVHD) in lethally irradiated mice receiving fully major histocompatability complex (MHC)-mismatched bone marrow
and spleen cells. We have now examined the mechanism of this effect of
IL-12 on acute GVHD. By day 4 post-BMT, IL-12-treated mice showed
marked reductions in splenic donor CD4+ and
CD8+ T cells compared with GVHD controls. Expression of
the early activation markers IL-2R alpha chain (CD25) and CD69 on
splenic donor CD4+ cells was considerably higher at early
time points (36 and 72 hours post-BMT) in IL-12-treated mice compared
with GVHD controls. However, the later, GVHD-associated increase in
CD25 and very late antigen-4 (VLA-4) expression on donor T cells was
greatly depressed in IL-12-protected mice compared with GVHD controls. The marked GVHD-associated expansion of host-reactive T helper cells by
day 4 was also completely inhibited in the IL-12-treated group.
Expression of Fas was increased on donor CD4 cells of IL-12-treated mice compared with those of controls on days 3 through 7 post-BMT. Furthermore, the ability of IL-12 to protect against GVHD was at least
partially dependent on the ability of donor cells to express functional
Fas molecules. We conclude that IL-12 treatment at the time of BMT
markedly perturbs the activation of alloreactive donor
CD4+ T cells that play a critical role in the
pathogenesis of acute GVHD. We hypothesize that these perturbations
culminate in Fas-dependent apoptosis of donor T cells, thus impeding
their expansion and their GVHD-promoting activity.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3315-3322
© 1998 by The American Society of Hematology.
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