Interleukin-12 Inhibits Murine Graft-Versus-Host Disease

• Published in: Blood 1995-09, Vol.86 (6), p.2429-2438
• Main Authors: Sykes, Megan, Szot, Gregory L., Nguyen, Phuong L., Pearson, Denise A.
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone Marrow Transplantation - adverse effects; Bone marrow, stem cells transplantation. Graft versus host reaction; Drug Synergism; Female; Graft vs Host Disease - prevention & control; H-2 Antigens - immunology; Interferon-gamma - blood; Interleukin-12 - therapeutic use; Interleukin-12 - toxicity; Interleukin-2 - toxicity; Medical sciences; Mice; Mice, Inbred A; Mice, Inbred C57BL; Radiation Chimera; Specific Pathogen-Free Organisms; 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; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V86.6.2429.bloodjournal8662429

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-γ (IFN-γ) levels as compared with those for GVHD controls at early time points, when IFN-γ was produced predominantly by host-type natural killer cells, but led to almost complete inhibition of the later GVHD-associated increase in serum IFN-γ levels, when IFN-γ 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.