The human T lymphotropic virus type I (HTLV-I) is associated with a chronic progressive myelopathy known as HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic progressive form of multiple sclerosis (MS). Other viruses such as human herpes virus type 6 (HHV-6) and a recently described human endogenous retrovirus have also been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aid in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology. Areas of research addressing these neurovirological and neuroimmunological issues include: 1) The host immune response to viruses from patients with HAM/TSP and MS and role that cytokines and chemokines may play in these disorders; 2) The immunohistochemical detection of viruses in the central nervous system and lymphoid organs of affected patients ; 3) The characterization and manipulation of transgenic mice which express the HTLV-I tax gene under the control of an astrocyte specific promoter, as a model for HAM/TSP; 4) Immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are; 1) High frequencies of CD8+ HTLV-I tax specific T cells in PBL of HAM/TSP could be detected ex vivo by use of novel HTLV-I tax peptide loaded HLA A2/immunoglobulin chimeras. A selective enrichment of these cells were demonstrated in lymphocytes present in cerebrospinal fluid; 2) Correlations with HTLV-I proviral load are being assessed using quantitative PCR Taqman technology; 3)High frequencies of CD8+ T cells producing TNF-a and IFN-g were detected in PBL of HAM/TSP patients by intracellular cytokine techniques. These cells could not be detected in PBL of HTLV-I infected asymptomatic carriers; 4) Identification of altered peptide ligands which have been shown to specifically interfere with antigen-specific CTL clones and bulk HTLV-I specific PBL populations. The ability to specifically interfere with potentially pathogenic T cell populations may have clinical applications as a therapeutic in HAM/TSP; 5) Screening of combinatorial peptide libraries for potential molecular mimics of HTLV-I tax have begun; 6) The lymphokine, IL-15, has been shown to be expressed in PBL of HAM/TSP patients and upregulated by the HTLV-I tax gene. The role of this lymphokine on CD8+ T cells is also being explored; 7) The HTLV-I tax/GFAP transgenic mouse appeared more resistant to experimental allergic encephalomyelitis than control mice suggesting that HTLV-I tax may upregulate factors that protect mice; 8) HHV-6 DNA sequences continue to be demonstrated in the serum as well as urine, saliva and PBL of MS patients and correlations with MS clinical activity have been demonstrated; 9) Lymphoproliferative assays have demonstrated an increased proliferative response in MS PBL compared to normal controls to lysates from HHV6 strain A infected T cell lines; 10) A clinical trial of recombinant interferon b1a has begun for the treatment of HAM/TSP. Collectively, these results continue to define the role of human viruses that are associated with chronic progressive neurologic disease. - Multiple Sclerosis, HTLV-I, HAM/TSP, Pathogenesis, Immunology, Transgenic mice - Human Subjects
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