IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host-disease.
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-gamma 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-gamma 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-alpha and IL-1 alpha 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-gamma, IL-1 alpha, and TNF-alpha all declined markedly by day 7 to 8 post-BMT, when GVHD mortality begins. Administration of neutralizing anti-IFN-gamma mAb did not attenuate and tended to accelerate GVHD mortality, and administration of exogenous IFN-gamma 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-gamma, 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.
Szebeni
J
J
Transplantation Biology Research Center, Massachusetts General Hospital, Boston 02129.
Wang
M G
MG
Pearson
D A
DA
Szot
G L
GL
Sykes
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood* / Q000276:immunology / Q000401:mortality; D007371:Interferon-gamma / Q000097:blood* / Q000276:immunology / Q000494:pharmacology; D007375:Interleukin-1 / Q000097:blood; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma