Cyclosporine-induced immune suppression alters establishment of HTLV-1 infection in a rabbit model

Abstract

IntroductionHuman T lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL)/lymphoma and is strongly associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of other immune-mediated disorders. 1-3 Despite a strong immune response against HTLV-1, the virus typically is maintained as a persistent infection throughout the lifetime of infected subjects. Critical immunologic parameters, including efficient cytotoxic T-cell responses against HTLV-1-expressing cells, determine viral loads throughout the course of infection and are linked to disease outcomes. 4,5 There have been several reports focused on the effect of immune suppression on pathogenesis of HTLV-1 disease. 6-9 HTLV-1-infected patients who are concurrently treated with immunosuppressive drugs, typically for organ or bone marrow transplantation procedures, often exhibit an accelerated or altered course for the development of HTLV-1-associated diseases. [10][11][12][13] These patients typically receive drugs such as cyclosporine A (CsA) and tacrolimus (FK-506) to prevent organ graft rejection. There are limited reports of the effects of immune suppression on early HTLV-1 infection because of the lack of clinical materials and inability to simulate the initial exposure of HTLV-1 infection on humans.We have used the rabbit model of HTLV-1 infection, in part, because of the ease and consistency of transmission of the viral infection in this species. Rabbits have been used to confirm routes of transmission for the virus infection, monitor sequential immune responses against HTLV-1 infection, test vaccine approaches, and determine virus-host relationships during the course of infection. [14][15][16][17][18] Our current study reported in this work tested the effects of immune suppression on the early spread of HTLV-1 infection in an established rabbit model. New Zealand white rabbits were divided into groups and treated with 10 mg/kg CsA, 20 mg/kg CsA, or saline vehicle control before infection by intravenous inoculation of HTLV-1-infected rabbit cells. Another group of rabbits was treated with 20 mg/kg CsA 1 week after HTLV-1 infection. Plasma CsA concentrations were monitored to ensure that therapeutic concentrations of the drug were obtained during treatment periods. Immune suppression was monitored in the rabbits by measuring lymphocyte proliferation to a recall antigen and mitogen stimulation, as well as flow cytometry and hematologic analysis. HTLV-1 viral expression in rabbits was monitored by testing ex vivo lymphocyte HTLV-1 p19 production, serologic parameters, and proviral loads from peripheral blood lymphocyte cultures. CsA treatment before HTLV-1 infection enhanced early viral expression compared with untreated HTLV-1-infected rabbits, and did alter long-term viral expression parameters. However, CsA treatment 1 week after infection diminished HTLV-1 expression throughout the 10-week study course. Our data indicate that immunologic control during early virus exposure determine...

Viral Expression Directs the Fate of B Cells in Bovine Leukemia Virus-Infected Sheep

“…Our working hypothesis is that the accelerated disappearance of B cells from infected sheep is due to the host immune surveillance. To address this question, infected sheep were treated with daily intravenous injections (at 5 mg/kg body weight/day for 3 weeks) of cyclosporine, an immunosuppressive drug preventing dephosphorlyation of NF-AT by binding to cyclophilin (11). Consistently, cyclosporine abrogated the differences between CFSE and PKH26 kinetics in B cells from 3 infected animals ( Fig.…”

A New Model of Drug-Disease Interaction in Rabbits

“…Cyclosporine, in the present study, acted both as a probe drug [29] for monitoring inhibition of CYP450 and as immunosuppressant to avoid the risk of infection clearance from blood [30].…”

“…Immune suppression, resulting from cyclosporine administration, was monitored by measuring lymphocyte proliferation [30]. WBCs and lymphocytic counts were recorded at baseline, and at day 5 prior to induction of infection [30].…”

“…WBCs and lymphocytic counts were recorded at baseline, and at day 5 prior to induction of infection [30]. Total and differential WBCs were counted using Automated Hematology Analyzer (Sysmex ® xp, Sysmex Corporation, Japan).…”

“…CyA may require 7 days &/or higher blood levels (100-400 ng/mL) to alter lymphocytic count as described elsewhere [30].…”