Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor.
Human T lymphotropic virus type I (HTLV-I) is the causative agent of an inflammatory neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). An ongoing lymphocyte activation exists in patients with HAM/TSP, which was demonstrated by the spontaneous proliferation of their PBMC ex vivo. It was shown that spontaneous proliferation present in HAM/TSP is due, in part, to an IL-2/IL-2R autocrine loop. However, addition of Abs against IL-2 or IL-2R alpha only partially inhibited the spontaneous proliferation. Since IL-15 is a cytokine with similar functional characteristics to those of IL-2, we reasoned that IL-15 might be an additional growth factor that contributes to the spontaneous proliferation observed in HAM/TSP. In this study, we demonstrated that IL-15 mRNA expression was elevated in PBMC obtained from HAM/TSP patients when compared with those of the normal donors. Furthermore, we showed that the addition of blocking Abs against IL-15 or its receptor inhibited the spontaneous proliferation of HAM/TSP PBMC. Addition of Abs directed toward both IL-15 and IL-2, or their receptors, inhibited the proliferation almost completely. These data suggest the existence of two autocrine loops involving IL-15/IL-15R and IL-2/IL-2R, both contributing to the spontaneous proliferation of HAM/TSP PBMC.
Azimi
N
N
Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA. nazli@helix.nih.gov
Jacobson
S
S
Leist
T
T
Waldmann
T A
TA
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016356:Gene Products, tax / Q000096:biosynthesis / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D015493:Paraparesis, Tropical Spastic / Q000209:etiology / Q000276:immunology* / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000911:Antibodies, Monoclonal; D016356:Gene Products, tax; C508024:IL15RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2