ABSTRACT
SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
Subject(s)
Antineoplastic Agents/pharmacology , Hematopoiesis/physiology , Hematopoietic Stem Cells/drug effects , Idarubicin/toxicity , Piperazines/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Benzamides , Body Weight/drug effects , Bone Marrow/drug effects , Bone Marrow/pathology , Drug Administration Schedule , Female , Hematopoiesis/drug effects , Hematopoietic Stem Cells/cytology , Idarubicin/administration & dosage , Imatinib Mesylate , Mice , Mice, Nude , Piperazines/administration & dosage , Piperazines/toxicity , Pyrimidines/administration & dosage , Pyrimidines/toxicity , Spleen/drug effects , Spleen/pathology , Weight LossABSTRACT
IL-15 is a T cell growth factor that shares many functional similarities with IL-2 and has recently been shown to be present in tissue and organ allografts, leading to speculation that IL-15 may contribute to graft rejection. Here, we report on the in vivo use of an IL-15 antagonist, a soluble fragment of the murine IL-15R alpha-chain, to investigate the contribution of IL-15 to the rejection of fully vascularized cardiac allografts in a mouse experimental model. Administration of soluble fragment of the murine IL-15R alpha-chain (sIL-15Ralpha) to CBA/Ca (H-2k) recipients for 10 days completely prevented rejection of minor histocompatibility complex-mismatched B10.BR (H-2k) heart grafts (median survival time (MST) of >100 days vs MST of 10 days for control recipients) and led to a state of donor-specific immunologic tolerance. Treatment of CBA/Ca recipients with sIL-15Ralpha alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2d) heart grafts. However, administration of sIL-15Ralpha together with a single dose of a nondepleting anti-CD4 mAb (YTS 177.9) delayed mononuclear cell infiltration of the grafts and markedly prolonged graft survival (MST of 60 days vs MST of 20 days for treatment with anti-CD4 alone). Prolonged graft survival was accompanied in vitro by reduced proliferation and IFN-gamma production by spleen cells, whereas CTL and alloantibody levels were similar to those in animals given anti-CD4 mAb alone. These findings demonstrate that IL-15 plays an important role in the rejection of a vascularized organ allograft and that antagonists to IL-15 may be of therapeutic value in preventing allograft rejection.
Subject(s)
Graft Enhancement, Immunologic , Graft Survival/immunology , Heart Transplantation/immunology , Interleukin-15/antagonists & inhibitors , Receptors, Interleukin-2/administration & dosage , Receptors, Interleukin-2/physiology , Animals , Cytokines/biosynthesis , Cytotoxicity, Immunologic , Graft Enhancement, Immunologic/methods , Heart Transplantation/pathology , Injections, Intraperitoneal , Interleukin-15/metabolism , Isoantibodies/biosynthesis , Isoantibodies/blood , Lymphocyte Activation , Male , Mice , Mice, Inbred AKR , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred CBA , Receptors, Interleukin-15 , Solubility , T-Lymphocytes, Cytotoxic/immunology , Transplantation, HomologousABSTRACT
IL-15 has recently been detected in the synovium of patients with rheumatoid arthritis. IL-15-activated T cells induce significant TNF-alpha synthesis by macrophages via a cell contact-dependent mechanism, suggesting a key regulatory role for IL-15. Here, we report that the administration of a soluble fragment of IL-15Ralpha into DBA/1 mice, profoundly suppressed the development of collagen-induced arthritis. This was accompanied in vitro by marked reductions in Ag-specific proliferation and IFN-gamma synthesis by spleen cells from treated mice compared with control mice and in vivo by a significant reduction in serum anti-collagen Ab levels. These data directly demonstrate a pivotal role for IL-15 in the development of inflammatory arthritis and also suggest that antagonists to IL-15 may have therapeutic potential in rheumatic diseases.
