key: cord-0008960-54lhjvt8 authors: Straub, Otto Christian title: Studies on the suitability of alpha-hybrid interferon application in cattle date: 2001-06-07 journal: Comp Immunol Microbiol Infect Dis DOI: 10.1016/0147-9571(95)00013-x sha: c685660b3dc77ec18ad80a471390122cea858dd4 doc_id: 8960 cord_uid: 54lhjvt8 Twelve cattle with body wts ranging from 100 to 250 kg were treated using various doses and routes for four days with an E. coli derived alpha-hybrid interferon. The lowest parenteral doses (10(4) units per kg body wt) and the orally administered interferon did not lead to any disturbances, whereas the higher dosages led to marked changes in body temperature, pulse and respiration rates. Animals with the highest dose (10(8) units per kg body wt) became extremely distressed. The blood picture showed distinct changes, with very low leukocyte counts during treatment, which took weeks to recover. It is suggested that the dosages that did not lead to clinical symptoms are best suited for prophylactic or therapeutic purposes. After detection and first application of interferon (IFN) an IFN-rush started. IFN was almost considered as a panacea. Viral agents were the initiators that stimulated the various cells to produce IFN. In cattle the virus inducing the highest titers in mucous membranes of the respiratory and genital tracts was BHVI [1] , and a highly passaged avirulent strain of BHV1 [2] was for many years successfully used as a paramunity inducer to minimize the effects of crowding disease and treating bovine vaginitis [3] . These findings were later confirmed and it was shown that a ts-mutant of BHV1 also induces IFN production [4] . Differences in IFN induction in the respiratory tract of calves by three different parainfluenza-3-vaccines were described later [5] . IFN activity in the intestinal tract induced by rotavirus was also demonstrated 240 Otto Christian Straub [6] . Subsequently various synthetic, cell culture or bacteria derived alpha-IFNs were developed and first tested in ritro [7 11 ] with positive results. However, when the IFNs were tested in t, ivo different results were reported. A distinct protective effect was not achieved with transmissible gastroenteritis virus in newborn pigs [10] and also not with paranfluenza-3-virus in cattle [12] . Positive results were obtained in treating cattle prophylactically against BHVI [13] , bovine virus diarrhoea virus disease [14] and vaccinia virus infection [15] and for therapeutic reasons in rota and corona virus infections [16] . An effect on the course of a foot-and-mouth disease virus infection was also described [2] . The object of this study was to examine the effects of different doses and modes of administration of an E. coli derived alpha-hybrid IFN which had been tested previously in tissue cultures and orally in calves suffering from digestive tract disorders [16] . The alpha-hybrid-IFN (ahIFN) was an E. coli derived purified, antibody free, slightly modified lymphoblastoid interferon with a specific activity of 3 x 108 units per ml, developed and provided by Hoechst AG, Frankfurt. Twelve cattle with body weights ranging from 100 to 250 kg were parenterally or orally treated with various doses of ahlFN as summarized in Table 1 . The white blood cell picture of all animals was determined before administration of ahIFN, together with body temperature, pulse and respiration rates. They were repeated immediately after the administrations and at hourly intervals, in general until 9 h later. The white blood cell count was also determined at intervals indicated in Tables 2 and 3 . After the intravenous administration there was no increase in animals with the low dose (Nos. 401 and 402, Table 1 ), but the higher doses produced a distinct elevation, with the maximum being reached between the 3rd and 6th hour (40.8'C). Following consecutive treatments, the increases were less marked. Only one animal (No. 435, Table 1 ) reached 40.8C during the 5th hour. No difference was observed between i.v., i.m. and s.c. administrations. Orally administered ahIFN did not produce any changes. A marked rise was only observed in those animals which received the highest dose (Nos. 435 and 436, Table 1 ) coinciding with the rise in temperature. The same response occurred on the following days with no reaction in the animals treated orally. Only the lowest dose and the orally treated animals failed to exhibit a distinct rise, but all the others reacted with a marked increase. Animal No. 427 started, for example, with a rate of 32/min and reached 106 after 2 h and No. 436 started with a rate of 30/min which Alpha-hybrid interferon Tables 2 and 3 . These were observed in the 2 animals (Nos. 435 and 436, Table 1 ), which received the highest dose. In summary, No. 435, increased serious nasal discharge 3 h after the first injection, still present on day 2, but with laboured breathing and anorexia 2 h later. Increased salivation 1 h after the third treatment. Animal No. 436, trembling and cough 403 5400 4300 3900 4700 3800 419 11,800 7800 7600 12,800 7800 427 8100 ll,100 II,100 10,600 10,800 429 5100 6100 5400 1800 7700 430 6100 5400 5500 7500 6300 436 8500 6600 9700 8600 8100 Table 3 . Absolute numbers of neutrophils (N) and lymphocytes (L) before first administration of ahIFN, I day, 1 week, 2 and 4 weeks after the last injection per mm 3 of blood L 403 1350 3888 473 3612 507 3354 1034 3525 874 2698 419 3422 7906 1482 5694 1216 5472 2032 8763 1404 6240 427 1458 6561 5328 5772 5328 5550 5512 5088 4578 6213 429 1275 3774 1098 4941 1890 3510 234 1548 2772 4697 435 1586 4392 756 4644 2035 3465 1950 5100 1827 4284 436 1530 6885 594 5940 2716 6984 2064 6536 1620 6399 after l h and a foamy nasal discharge after 2 h; no other signs were observed after the other injections. The oral administration of 1 2 × 106 or parenteral injection of 104 units ahIFN/kg body wt did not lead to any disturbances. Hofmann et al. [16] used approximately the same dose for the treatment of digestive disorders in calves. It seems most likely therefore that the positive results can be attributed to the treatment, since this could substantiate the efficacy of ahIFN treatment in vitro and in vivo with rota-and coronaviruses. However, higher doses certainly do more harm than good, and not only for short periods of time as judged by the clinical signs, but for long periods of time, as is evident from the changes in the white blood picture. The route of parenteral administration does not seem to be relevant. The same is obviously true for the body weight resp. age. The results are in general agreement with those obtained by Gitlespie and coworkers [17] . It is not unexpected that IFN administration does not influence PI3-virus infections [12] , as PI3-virus induces IFN activity [5] . The same is true for BHVI [1] . Therefore, there is no justification to administer IFN prior to BHV1 exposure [13] . The results are encouraging concerning BVDV infections [14] . If IFN acts as an immunostimulant [13] , it could be used to improve the immune response, especially following the vaccination with inactivated BVDV vaccines. Die lokale lnterferonbildung im Respirations-und Genitaltrakt nach experimenteller |nfektion mit Rhinotracbeitis (IBR)-und Bl~ischenausschlag (IPV)-Virus Lokale Interferonbildung beim Rind nach intranasaler Infektion mit avirulentem IBR/IPV-Virus und deren Wirkung auf eine anschliel3ende Infektion mit Maul-und Klauenseuche-Virus Impiego di un interferonizzante locale (BAYFERON) in bovine con vulvo vaginite Induction of bovine endogenic interferon with thermosensitive mutant and virulent BHV-1. Proliferation of lymphocytes in vitro under the influence of phytohaemagglutinin (PHA) and BHV-1 antigen Comparison of interferon production in cattle after intranasal infection with parainfluenza-3 live vaccine and avirulent IBR/IPV herpesvirus Interferon activity in rotavirus infected newborn calves Susceptibility of bovine rotavirus to interferon Antiviral effects of bovine interferons on bovine respiratory tract viruses In vitro protective effect of bacteria-derived bovine interferon alphat I against selected bovine viruses Effect of recombinant DNA-derived bovine-1 interferon on transmissible gastroenteritis virus infection in swine Effect of recombinant DNA-derived bovine and human interferons on replication of bovine herpesvirus-l, parainfluenza-3, and respiratory syncytial viruses Studies on the effect of recombinant human-I interferon on experimental parainftuenza type 3 virus infections of the respiratory tract of calves Effect of bovine 1 interferon on bovine herpesvirus type 1-induced respiratory disease The prophylactic effects of E. coil-derived bovine interferon alpha~ 1 on bovine virus diarrhoea virus disease in calves after intramuscular administration Protection of cattle from infection with vaccina virus by bovine interferon C Erste Erfahrungen bei der Behandlung yon virusbedingten K~ilberdurchf~illen mit gentechnisch erzeugtem Interferon Levels of interferon in blood serum and toxicity studies of bacteria-derived bovine alpha~ I interferon in dairy calves