       Document 0407
 DOCN  M9620407
 TI    The role of CD8+ T lymphocytes in coxsackievirus B3-induced myocarditis.
 DT    9602
 AU    Henke A; Huber S; Stelzner A; Whitton JL; Department of
       Neuropharmacology, Scripps Research Institute, La; Jolla, California
       92037, USA.
 SO    J Virol. 1995 Nov;69(11):6720-8. Unique Identifier : AIDSLINE
       MED/96013765
 AB    Coxsackievirus infections have previously been shown to cause acute or
       chronic myocarditis in humans, and several mouse models have been
       established to study the pathology of this disease. Myocardial injury
       may result from direct viral effects and/or may be immune mediated. To
       determine the relative roles of these processes in pathogenesis, we have
       compared coxsackievirus B3 (CVB3) infections of normal and
       immuno-compromised transgenic knockout (ko) mice. CVB3 was able to
       infect all strains used (C57BL/6, CD4ko, and beta-microglobulin ko [beta
       2Mko]), and following intraperitoneal injection, two disease processes
       could be distinguished. First, the virus caused early (3 to 7 days
       postinfection) death in a viral dose-dependent manner. Immunocompetent
       C57BL/6 mice were highly susceptible (50% lethal dose = 70 PFU), while
       immunodeficient transgenic ko mice were less susceptible, showing 10-
       and 180-fold increases in the 50% lethal dose (for CD4ko and beta 2Mko
       mice, respectively). Second, a histologic examination of surviving CD4ko
       mice at 7 days postinfection revealed severe myocarditis; the
       inflammatory infiltrate comprised 40 to 50% macrophages, 30 to 40% NK
       cells, and 10 to 20% CD8+ T lymphocytes. The infiltration resolved over
       the following 2 to 3 weeks, with resultant myocardial fibrosis. In vivo
       depletion of CD8+ T lymphocytes from these CD4ko mice led to a marked
       reduction in myocarditis and an increase in myocardial virus titers.
       beta 2Mko mice, which lack antiviral CD8+ T cells, are much less
       susceptible to early death and to the development of myocarditis. We
       conclude that our data support a strong immunopathologic component in
       CVB3-induced disease and implicate both CD4+ and CD8+ T cells. Compared
       with immunocompetent animals, (i) mice lacking CD4+ T cells (CD4ko) were
       more resistant to virus challenge, and (ii) mice lacking CD8+ T cells
       (beta 2Mko and in vivo-depleted CD4ko) showed enhanced survival and a
       reduced incidence of the later myocarditis. Nevertheless, the picture is
       complex, since (iii) removal of the CD4+ component, while protecting
       against early death, greatly magnified the severity of myocarditis, and
       (iv) removal of the CD8+ cells from CD4ko mice, although protecting
       against early death and later myocarditis, led to markedly increased
       virus titers in the heart. These data underscore the complex balance
       between the costs and benefits of effective antiviral immune responses.
 DE    Animal  Antibodies, Viral/BIOSYNTHESIS/BLOOD  Apoptosis  Comparative
       Study  Coxsackievirus Infections/*IMMUNOLOGY/PATHOLOGY
       *Coxsackieviruses B  CD8-Positive T-Lymphocytes/*IMMUNOLOGY
       Heart/VIROLOGY  Immunohistochemistry  Lymphocyte Depletion  Male  Mice
       Mice, Inbred C57BL  Mice, Knockout  Mice, Transgenic
       Myocarditis/*IMMUNOLOGY/PATHOLOGY/*VIROLOGY  Myocardium/PATHOLOGY
       Species Specificity  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       P.H.S.  Time Factors  Tumor Necrosis Factor/ANALYSIS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

