tacrolimus and HTLV-I-Infections

Infection by the human T-cell lymphotropic virus type I (HTLV-I) causes T-cell activation by at least two separate mechanisms. One mechanism involves activation of the T cells harboring the virus and is exemplified by in vivo infected nonimmortalized T-cell clones that display a prolonged state of activation. This HTLV-I-induced T-cell activation is inhibited by rapamycin, a drug that inhibits p70 S6-kinase and blocks cell cycle in G1, but is not inhibited by FK506 or cyclosporin A, both of which inhibit interleukin-2 (IL-2) production. The phenotype of this pathway is consistent with an hyperactive IL-2R pathway or CD28 pathway, indicating that HTLV-I may contribute a costimulatory signal to the infected T cell. As a separate mechanism, HTLV-I-infected T cells can induce activation of uninfected T cells via T-T-cell interaction mediated by the LFA-3-CD2 pathway. This may induce IL-2 production from the uninfected T cells, leading to a more generalized activation of the immune system that potentially could provide a basis for some of the diseases associated with HTLV-I. Moreover, this THTLV-I-T-cell interaction could explain the spontaneous proliferation observed in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Topics: CD2 Antigens; CD28 Antigens; Cyclosporine; Cytokines; G1 Phase; Gene Products, tax; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Polyenes; S Phase; Sirolimus; T-Lymphocytes; Tacrolimus

A 56-year-old HTLV-I-positive woman, initially diagnosed as having Sjögren's syndrome, presented with muscle weakness, myalgia, face erythema and leg edema. Based on the presence of various autoantibodies, the diagnosis of overlap syndrome (dermatomyositis/Sjögren's syndrome) was made. Treatment with high-dose corticosteroid plus cyclosporine improved her symptoms. However, three months after the start of these treatments, exacerbation of myositis occurred. A muscle biopsy revealed prominent perivascular accumulation of mononuclear cells with perifascicular atrophy, which were consistent with dermatomyositis. Tacrolimus, which was substituted for cyclosporine led to marked improvement of the myositis symptoms.

Topics: Dermatomyositis; Female; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Middle Aged; Sjogren's Syndrome; Tacrolimus; Treatment Outcome

Mononuclear cells from subjects infected with human T lymphotrophic virus type I (HTLV-I) display a unique ability to proliferate in vitro in the absence of mitogens or exogenous growth factors. Subjects who have developed an HTLV-I-associated myelopathy (HAM) show an even higher degree of spontaneous proliferation concomitant with transcription of the HTLV-I provirus. The mechanism underlying HTLV-I-induced T cell activation was investigated by characterizing a series of HTLV-I-infected T cell clones generated from the blood of subjects with HAM. Approximately 15% of the T cell clones generated were HTLV-I infected as determined by polymerase chain reaction and Southern blotting. Infected T cell clones displayed altered growth kinetics as they continued to incorporate tritiated thymidine 7 to 14 days after stimulation, a time when noninfected T cell clones had returned to a resting state. This was not due to transformation as all the T cell clones required periodic restimulation with mitogens and feeder cells for continued growth. Although HTLV-I-infected T cell clones showed increased expression of the IL-2 receptor p55 chain, the spontaneous clonal proliferation was not inhibited by anti-IL-2 receptor mAb. Moreover, the spontaneous clonal proliferation was insensitive to cyclosporin A and FK 506 while being highly sensitive to rapamycin, which is known to inhibit IL-2-mediated signaling. Together these results demonstrate that IL-2 is not required for the HTLV-I-induced spontaneous clonal proliferation and further suggest that HTLV-I may induce signaling pathways replacing an IL-2 receptor signal proximal to the site of action of rapamycin.

Topics: Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Base Sequence; CD3 Complex; Clone Cells; Cyclosporine; HTLV-I Infections; Humans; Interleukin-2; Lymphocyte Activation; Molecular Sequence Data; Polyenes; Receptors, Antigen, T-Cell; Receptors, Interleukin-2; RNA, Messenger; Sirolimus; T-Lymphocytes; Tacrolimus