Blood. 1995 Sep 15;86(6):2429-38.
Interleukin-12 inhibits murine graft-versus-host disease.
Sykes M1, Szot GL, Nguyen PL, Pearson DA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
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.
Bone Marrow Transplantation/adverse effects
Drug Synergism
Graft vs Host Disease/prevention & control*
H-2 Antigens/immunology
Interferon-gamma/blood
Interleukin-12/toxicity
Interleukin-2/toxicity
Mice, Inbred A
Radiation Chimera
T-Lymphocyte Subsets/drug effects*
T-Lymphocyte Subsets/immunology
T-Lymphocytes, Cytotoxic/drug effects
T-Lymphocytes, Cytotoxic/immunology
Th1 Cells/drug effects
Th1 Cells/immunology
R01AI31158/AI/NIAID NIH HHS/United States
R01CA9225/CA/NCI NIH HHS/United States
Mouse Genome Informatics (MGI)