Pathogenesis of HTLV-I-associated inflammation: Exploration through therapeutic intervention

Lead Research Organisation: Imperial College London
Department Name: Unlisted

Abstract

HAM/TSP is a chronic disease of the spinal cord, caused by a virus called HTLV-I. Worldwide approximately 20 million persons are infected, many in member states of the Commonwealth. Infection with HTLV-I is lifelong, and about 3% will develop this chronic debilitating disease, of which half will become wheelchair dependent. We, and others, have shown a strong and persistent immune response to HTLV-I in carriers and patients with HAM/TSP, but this fails to clear the virus. However, carriers with a low burden of virus in the blood have a low risk of developing disease. The immune response in these carriers seems better able to kill infected cells. A less efficient response is associated with a higher viral burden that drives the immune response with a resultant release of chemicals by the immune cells that inadvertently cause harm, most especially to cells in the spinal cord. Our understanding of HAM/TSP suggests that targeting the immune response should improve the health of our patients especially if the disease is diagnosed early. To identify the best type of treatment we are planning three studies of drugs that target the immune response in different ways. Each has been used in other inflammatory conditions but never before studied in HAM/TSP. We aim to study the extent and duration of the clinical response and to associatedthis with the different effects that the therapies have on the immune response and on the number of HTLV-I infected cells in the blood. This in turn will improve our knowledge and understanding of the disease and should lead to better therapy. Our results will be shared with our patients through a newsletter and made available on the clinic website.

Technical Summary

Human T-Lymphotropic Virus Type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)is a chronic, disabling, frequently painful condition for which no effective treatment has been found. As well as hosting HTLV-I infection, T-lymphocytes are implicated in the pathogenesis of HAM, having been demonstrated in circulating blood, cerebrospinal fluid and the spinal cord of patients, with the secretion of neurotoxic cytokines damaging by-stander cells the favoured hypothesis. Previous studies have investigated, amongst others, corticosteroids, vitamin C, interferons, heparin and nucleoside analogues without clear demonstration of more than transient improvement.
Successful therapy or prevention of HAM/TSP might be achieved by:
? Inhibiting T-cell activation (i.e. suppressing HTLV-I transcription, reducing HTLV-I replication and suppressing T-cell responsiveness to antigen)
? Targeting key mediators of HTLV-I-associated inflammation (i.e. inhibiting neurotoxic cytokines)
? Reducing the number of T-cells (i.e. depleting the substrate for infection as well as depleting the cells implicated in HTLV-I-associated inflammation)
We therefore propose to investigate three novel therapies for HAM.
First, ciclosporin A, to down regulate the immune response to HTLV-I both centrally and peripherally. Second, an anti-tumour necrosis factor antibody (Infliximab) to target a key neurotoxic cytokine. Third, the use of a humanised anti-CD52 monoclonal antibody (Campath-1H) to deplete T-lymphocytes and thereby reduce both the viral burden and the inflammatory response.
We will use these clinical studies to dissect the pathogenesis of HAM in vivo.
Each therapy will be administered in an open-label study of 6 - 10 patients for 12 months with a further 6 months follow-up. The outcome measures will be clinical, virological and immunological. Thus in addition to routine safety biochemisty and haematology, we will measure disability and markers of inflammation. We will explore viral burden, by quantify HTLV-I load in peripheral blood and CSF lymphocytes using real-time PCR, viral activity, by detection of HTLV Tax expression ex vivo, and viral replication, by detection of HTLV 2 LTR DNA circles in peripheral blood lymphocytes. We will access the effect of therapy on the cellular immune response using a lytic efficiency assay to determine HTLV-I specific cytotoxic T-lymphocyte function and ELISAs and ELIspots to quantify the cytokine response.
Results will be presented at international and national conferences and published in peer-reviewed journals. The results will be presented in suitable terminology for patients with HAM/TSP through a clinic website. We anticipate that the results will inform the design of a multicentre, randomised controlled trial of therapy for HAM/TSP.

Publications

10 25 50
 
Description Protocol: HAM therapy with ciclosporin
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Title Biological samples 
Description Blood and CSF samples have been collected and stored for further research from patients with early or progressing HTLV-1-associated myelopathy before, during and after treatment with ciclosporin or infliximab 
Type Of Material Biological samples 
Provided To Others? No  
Impact Demonstration of greater reduction in HTLV-1 viral load in CSF than in blood during treatment with Ciclosporin and association with clinical improvement 
 
Title HTLV ELIspots - Interferon gamma, IL-2 
Description We have developed HTLV-1 Tax and HTLV-1 HBZ ELIspots to detect the frequency of IL-2 secreting and IFNg secreting CD4 positive and CD8 positive lymphocytes 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact We have demonstrated that HBZ is expressed in vivo and shown the importance of a cellular response to HBZ in controlling HTLV viral load. (Manuscript 1 published in JID, manuscript 2 in preparation) 
 
Title Treatment of HTLV-1 associated myelopathy 
Description Proof of concept study of ciclosporin for the treatment of HTLV-1 associated myelopathy. Study completed in 2009. First evidence of efficacy in this rare disease. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Closed
Clinical Trial? Yes
Impact Demonstration of selective effect on CSF HTLV viral load 
URL https://clinicaltrials.gov/show/NCT00773292
 
Description HTLV Patient Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Presentation of research to our National Patient Forum. Included a presentation by a study participant

Increased interest by patients in proposed future studies
Year(s) Of Engagement Activity 2009