Oral therapy with human interferon alpha in calves experimentally injected with infectious bovine rhinotracheitis virus.

Fifty-six calves, seronegative for infectious bovine rhinotracheitis (IBR) virus, were randomly divided into 7 equal groups (n = 8) and given 0.0, 0.05, 0.50, or 5.00 international units (IU) of natural or recombinant human interferon alpha per kg body weight (nHuIFN-alpha or rHuIFN-alpha, respectively) orally once daily for 4 consecutive days, starting 2 days before intranasal inoculation with virulent IBR virus. Calves given 0.05 IU nHuIFN-alpha/kg bwt had significantly greater weight gain at days 15 (P < 0.10) and 25 (P < 0.05) than the placebo-treated (0.0 IU) control group. The treatment groups given 0.05 and 0.5 IU nHuIFN-alpha/kg bwt nHuIFN-alpha had fewer days with temperature > 40 degrees C (P < 0.05 and P = 0.10, respectively), and lower mean rectal temperatures on days 8 and 11 (0.05 IU/kg bwt; P < 0.10) or on day 11 (0.5 IU/kg bwt; P < 0.10). None of the calves given 0.05 IU nHuIFN-alpha/kg bwt required antibiotic therapy. Calves given 0.50 IU/kg bwt of nHuIFN-alpha, or 0.05 IU/kg bwt of rHuIFN-alpha had fewer (P < 0.05) total days of antibiotic therapy compared to controls. These data indicate that low dose oral IFN-alpha treatment significantly reduced the clinical effects of IBR virus infection in feedlot cattle in an interferon dose-dependent fashion.

Activity of polymorphonuclear (PMN) leukocytes during bovine herpes virus-1 induced respiratory disease: effect of recombinant bovine interferon alpha I1.

Following infection of cattle with bovine herpes virus-1 there is a state of generalized immunosuppression involving various leukocytes including polymorphonuclear (PMN) leukocytes. Since the PMN is considered to be pivotal in recovery from secondary bacterial infections during bovine respiratory disease, investigations were initiated to determine PMN activity in this disease and whether interferon could modulate PMN activity. In this study, the in vivo administration of recombinant interferon alpha-I1 was shown to increase PMN functions as measured by migration/chemotaxis and generation of reactive oxygen species. This augmented activity of PMN appeared to correlate with the reduction of overall clinical disease, that is, number of sick days, lung lesions and weight loss. In the study administration of interferon by the intranasal or intramuscular route were as effective in stimulating PMN function. Based on these studies it was concluded that the reason for improved performance of calves treated with interferon would be due to its immunomodulatory effects on leukocytes. Although interferon did not alter the initial suppression of PMN functions, these functions returned to normal and exceeded normal activities by 7-9 days post-infection, the time when maximal bacterial activity normally is present.

Use of recombinant bovine alpha 1 interferon in reducing respiratory disease induced by bovine herpesvirus type 1.

Intranasal or intramuscular treatment of calves with recombinant bovine alpha 1 interferon before challenge with bovine herpesvirus type 1 and Pasteurella haemolytica reduced clinical signs, number of sick days, lung lesions, and weight loss. The effective dose was determined to be relatively broad within the range of 1 to 50 mg per animal. No adverse effects were observed even at high doses of interferon (50 mg per animal). Administration before virus infection was more effective than administration at the same time as virus infection. Although interferon administration had dramatic effects on the survival of animals, it did not have much effect on virus secretion in the upper respiratory tract. Therefore, the mechanism by which interferon reduces the susceptibility of animals to viral-bacterial synergy was postulated to be via its immunomodulatory effects.

Effect of bovine alpha 1 interferon on bovine herpesvirus type 1-induced respiratory disease.

Treatment of calves with bovine recombinant alpha 1 interferon prior to challenge with bovine herpesvirus type 1 increased the animals' ability to withstand a subsequent Pasteurella haemolytica challenge. The reduction in viral-bacterial synergy observed following interferon treatment did not appear to be due to a direct effect of the interferon on virus replication in the upper respiratory tract. Thus, even though interferon-treated animals shed slightly less virus from their nasal passages than did untreated animals, this reduction was not statistically significant. Furthermore, there was no difference in the level of intranasal interferon secreted by control or interferon-treated animals. These results suggest that interferon treatment does not affect the production of endogenous interferon. In contrast, a significant difference was observed between the number of days that control animals were sick, the levels of serum fibrinogen and the functional activity of polymorphonuclear neutrophilic granulocytes obtained from infected calves. These results suggest that bovine recombinant alpha 1 interferon may have a greater immunomodulatory effect than a direct antiviral effect in this model. This is further supported by the observation that bovine herpesvirus type 1 is relatively resistant to the direct antiviral effect of bovine recombinant alpha 1 interferon in vitro.

In vitro and systemic effects of recombinant bovine interferons on natural cell-mediated cytotoxicity in healthy and bovine herpesvirus-1-infected cattle.

There is now evidence to suggest that the beneficial effect of treatment of calves with recombinant bovine interferons (IFNs) on the outcome of an infection with bovine herpes-virus-1 (BHV-1) may in part be due to effects other than its direct antiviral activity. This evidence prompted us to study the effect of IFNs on natural cell-mediated cytotoxicity (NC) as a possible mechanism in curtailing clinical disease. In vitro treatment of blood leukocytes not only augmented cytotoxicity to NC-susceptible target cells, but also to cell types usually resistant to killing. In vivo treatment of healthy cattle with IFN-gamma caused a transient rise in NC activity, which was both dose and route dependent. Treatment of calves with IFN-alpha 1 or IFN-gamma prior to BHV-1 infection prevented or diminished the suppression of NC activity usually seen following virus infection. The effect could neither be correlated with serum IFN titers nor with conventional hematologic parameters. A possible mechanism for the IFN effect involving the ontogeny of bovine NC-effector cells and the biological consequences for the local antiviral defense in the lung are discussed.

Evaluation of inactivated infectious bovine rhinotracheitis vaccines.

Sixty-five calves of approximately three months of age and of mixed sex were vaccinated twice at four week intervals with either attenuated or inactivated infectious bovine rhinotracheitis vaccines. Following initial vaccination there was no demonstrable serum infectious bovine rhinotracheitis titer in any of the calves receiving the inactivated vaccine with 20.7% of the calves receiving the attenuated vaccines having demonstrable titers. Following a second administration of vaccine at eight weeks post-initial vaccination 63.9% of the calves receiving the inactivated vaccine had no demonstrable titer with 72.4% of the calves receiving the attenuated vaccine exhibiting a blood titer of four or greater.