J. Szebeni et al., IL-2 INHIBITS EARLY INCREASES IN SERUM GAMMA-INTERFERON LEVELS ASSOCIATED WITH GRAFT-VERSUS-HOST DISEASE, Transplantation, 58(12), 1994, pp. 1385-1393
We have recently demonstrated that a short course of high-dose IL-2 ad
ministered to lethally irradiated mice leads to marked protection from
early and late GVHD mortality, especially when T cell-depleted (TCD)
host-type bone marrow cells (BMC) are also administered. IL-2 inhibits
the GVHD-inducing activity of donor CD4(+) cells without inhibiting t
heir graft-vs.-leukemia effects. Since CD4(+) T-lymphocytes produce a
variety of cytokines, some of which have recently been implicated in t
he pathogenesis of GVHD, we have studied the possible effect of IL-2 a
dministration on serum levels of various cytokines. Acute GVHD was ind
uced in lethally irradiated B10 mice by bone marrow transplantation (B
MT) with MHC-mismatched allogeneic (A/J) BMC and splenocytes. TCD B10
(host-type) BMC were coadministered to maximize the protective effect
of IL-2. Serum cytokine levels were compared in recipients of these in
ocula with or without a protective course of IL-2 treatment. A marked
increase in serum IFN-gamma levels was noted on days 3 through 5 post-
BMT in GVHD mice compared with syngeneic EMT control recipients. This
GVHD-induced rise in serum IFN-gamma was markedly inhibited in IL-2-pr
otected mice. Murine IL-2 levels were only slightly increased in sera
of GVHD mice, and were not influenced by treatment with human recombin
ant IL-2. Serum levels of the monokines TNF-alpha and IL-1 alpha showe
d variable early elevations in GVHD mice with or without IL-2 treatmen
t, and were not different from levels observed in syngeneic controls.
Serum levels of IFN-gamma, IL-1 alpha, and TNF-alpha all declined mark
edly by day 7 to 8 post-BMT, when GVHD mortality begins. Administratio
n of neutralizing anti-IFN-gamma mAb did not attenuate and tended to a
ccelerate GVHD mortality, and administration of exogenous IFN-gamma di
d not overcome the protective effect of IL-2 against GVHD. Together, o
ur results indicate that GVHD is associated with high serum levels of
several proinflammatory cytokines in the first week post-BMT, but that
these levels decline by the time when GVHD mortality begins. IL-2 spe
cifically inhibits the GVHD-associated production of IFN-gamma, but th
is inhibition in itself does not explain and may even mitigate the pro
tective effect of IL-2 against early GVHD mortality. However, the demo
nstration that IL-2 markedly inhibits the production of a GVHD-associa
ted cytokine raises the possibility that alterations in the production
of as yet undefined cytokines may be responsible for IL-2-induced GVH
D protection.