chiniofon and Myocarditis

The effects of the anti picornaviral drug WIN 54954 (5-(5-(2.6-dichloro-4-(4.5-dihydro-2-oxazolyl)phenoxy)pentyl)-3-me thyl- isoxazole) and the immune modulator LS 2616 (Quinoline-3-carboxamide) on plasma cachectin/TNFa and g-interferon (IFN-g) responses were investigated during the clinical course of a myocarditic coxsackievirus B3 (CB3) infection in the mouse. Virus as well as inflammatory and necrotic lesions were found in the hearts on days 4 and 7 post inoculation (p.i.), respectively. This was demonstrated using in situ virus RNA hybridization and immune histological techniques with monoclonal antibodies against lymphocyte subsets. The CB3 infection increased TNFa levels during the first three days of disease. This response was suppressed by WIN 54954 and LS 2616. IFN-g was decreased in infected mice in the late phase of the disease (day 11). Therapy, however, was protective, and WIN 54954 even tended to increase the IFN-g response at day 5, corresponding to the time when viremia peaks. These results indicate that cytokines may serve as prognostic markers in the therapy of infectious diseases and also that WIN 54954 and LS 2616 are both possible candidates for treatment of coxsackievirus infections in man. It is suggested that a combined antiviral and immune stimulatory treatment could be of future value.

Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Coxsackievirus Infections; Enterovirus B, Human; Female; Hydroxyquinolines; Interferon-gamma; Isoxazoles; Mice; Mice, Inbred BALB C; Myocarditis; Tumor Necrosis Factor-alpha

Quinoline-3-carboxamide (LS 2616) is a broadly acting immunostimulator with anti-inflammatory effects in Coxsackie virus B3-induced myocarditis in female BALB/c mice. This infection caused extensive inflammatory and necrotic lesions in the myocardium 7 days after inoculation (6.8% of tissue section area). The damaged area was reduced (to 3.7% (p less than 0.05] and the lethality decreased when LS 2616 was administered over 14 days, starting 7 days before the inoculation. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was elucidated by a newly developed immune histochemical staining technique. LS 2616 increased the number of class II-expressing cells 3-fold (p less than 0.01) and the CTL, Ts:Th cell ratio by 55% (p less than 0.05), whereas Lyt-1+ and TIB+ cells were unaffected. After 7 days of LS 2616 treatment, spleen lymphocyte activity tended to increase (T cells by 21% (NS) and B cells by 60% (p less than 0.05), respectively). The activity of NK cells increased by 51% (p less than 0.01). LS 2616 may thus have potential in therapy of human inflammatory disorders, such as myocarditis.

Topics: Adjuvants, Immunologic; Animals; Coxsackievirus Infections; Enterovirus B, Human; Female; Hydroxyquinolines; Lymphocytes; Mice; Mice, Inbred BALB C; Myocarditis; Premedication; Spleen; Thymus Gland

We have studied the effects of immunotherapy in coxsackievirus B3-induced myocarditis in male BALB/c mice. A single i.p. injection of the synthetic interferon inducer poly I:C conferred an almost total protection from lethality when administered at 0 h or 24 h after infection. Poly I:C treatment at 48 h after infection, as well as daily i.p. injections of the quinoline-3-carboxamide LS 2616, a new stimulator of NK-cell activity, gave no protection from lethality. The inflammatory lesions and necrosis in the ventricular myocardium 7 days after virus inoculation (3.1% of section area) were reduced in the poly I:C (24 h) treated group (1.0% of tissue section area). A less pronounced reduction was seen in the LS 2616 and poly I:C (48 h) treated groups (1.7 and 1.9% of tissue section area, respectively). The response patterns of the studied lymphocyte subpopulations were different with these two compounds, TIB+ (pre-B)-cells increased with poly I:C treatment (49%), but decreased with the LS 2616 treatment (65%). The Lyt 1+ (pan T)-cells responded similarly. Poly I:C (24 h) and LS 2616 treatment tended to increase the number of class II expressing cells (1.9- and 2.9-fold, respectively). The titer of neutralizing antibodies to coxsackievirus B3 was significantly increased in the LS 2616 treated group (1:80) but not significantly so in the poly I:C treated groups (1:40) as compared to the infected and non-infected control groups (1:20 and less than 1:5, respectively).

Topics: Adjuvants, Immunologic; Animals; Antibodies; Coxsackievirus Infections; Enterovirus B, Human; Hydroxyquinolines; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Myocarditis; Poly I-C