Interleukin-12 inhibits murine graft-versus-host disease.
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.
Sykes
M
M
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
Szot
G L
GL
Nguyen
P L
PL
Pearson
D A
DA
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006183:H-2 Antigens / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000627:therapeutic use* / Q000633:toxicity; D007376:Interleukin-2 / Q000633:toxicity; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D006183:H-2 Antigens; D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma