IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host-disease

J. Szebeni, M. G. Wang, D. A. Pearson, G. L. Szot, M. Sykes

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Abstract

We have recently demonstrated that a short course of high-dose IL-2 administered 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 their graft-vs.- leukemia effects. Since CD4+ T-lymphocytes produce a variety of cytokines, some of which have recently been implicated in the pathogenesis of GVHD, we have studied the possible effect of IL-2 administration on serum levels of various cytokines. Acute GVHD was induced in lethally irradiated B10 mice by bone marrow transplantation (BMT) 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 inocula with or without a protective course of IL-2 treatment. A marked increase in serum IFN-γ levels was noted on days 3 through 5 post- BMT in GVHD mice compared with syngeneic BMT control recipients. This GVHD- induced rise in serum IFN-γ was markedly inhibited in IL-2-protected mice. Murine IL-2 levels were only slightly increased in sera of GVHD mice, and were not influenced by treatment with human recombinant IL-2. Serum levels of the monokines TNF-α and IL-1α showed variable early elevations in GVHD mice with or without IL-2 treatment, and were not different from levels observed in syngeneic controls. Serum levels of IFN-γ, IL-1α, and TNF-α all declined markedly by day 7 to 8 post-BMT, when GVHD mortality begins. Administration of neutralizing anti-IFN-γ mAb did not attenuate and tended to accelerate GVHD mortality, and administration of exogenous IFN-γ did not overcome the protective effect of IL-2 against GVHD. Together, our 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 specifically inhibits the GVHD-associated production of IFN-γ, but this inhibition in itself does not explain and may even mitigate the protective effect of IL-2 against early GVHD mortality. However, the demonstration that IL-2 markedly inhibits the production of a GVHD-associated cytokine raises the possibility that alterations in the production of as yet undefined cytokines may be responsible for IL-2-induced GVHD protection.

Original languageEnglish
Pages (from-to)1385-1393
Number of pages9
JournalTransplantation
Volume58
Issue number12
Publication statusPublished - Dec 1 1994

ASJC Scopus subject areas

  • Transplantation

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    Szebeni, J., Wang, M. G., Pearson, D. A., Szot, G. L., & Sykes, M. (1994). IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host-disease. Transplantation, 58(12), 1385-1393.