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... A) Togaviruses -Sindbis [48], Semliki forest [64], and yellow fever [65] viruses. B) Picornaviruses -Encephalomyocarditis virus [83]. ...
... Treatment of mouse thymocytes or of mouse L1210 tumor in culture with interferon results in increased expression of H-2D and H-2K histocompatibility antigens on the cell surface [147,149,150,237]. This increased expression of cell surface antigen does not appear to be dependent on the position of the cells in the cell cycle [48]. In vivo treatment of mice with large doses of partially purified interferon also results in an increase in histocompatibility antigen expression [148]. ...
Interferon, a product of mammalian tissues, was originally described as an antiviral agent over twenty years ago. Only in the past few years has evidence started to accumulate that interferon actually played a role in vivo in natural virus infections.Initially, evidence was accumulated showing that interferon could inhibit the replication of many viruses in vitro. The interferon, through induction of a second antiviral protein, could inhibit in vitro viral transcription or translation. Later, indirect evidence for an effect of interferon on in vivo viral infections was obtained by showing that (a) a temporal relationship existed between the appearance of interferon in viral infections and the progress of the infection and (b) treatment of virally infected animals with exogenous interferon or interferon inducer often resulted in less severe infections.The most recent and direct evidence for a role for interferon in natural viral infections involves the use of an anti-interferon globulin. In several cases, injection of the anti-interferon globulin into animals infected with a wide variety of viruses resulted in a severely altered course of infection. These studies suggest that interferon is directly involved in the progress of viral infections. The involvement of the interferon in the viral infections could be a direct effect of the interferon on viral replication, or an interaction of the interferon with other host defenses, such as the immune system.
mammalian interferons;japanese workers;rabbit skin;antiviral substances;elutions
Es wurde der Ablauf des pathogenetischen Geschehens bei erwachsenen Mäusen nach der intraperitonealen Verabreichung des hochgradig an diese Tierart adaptierten Maul- und Klauenseuchevirus des Stammes «Ken 11/1960/C1», Typ SAT 2, untersucht.
Das Virus hatte hauptsächlich während der «mo»-Passagen (in erwachsenen Mäusen) eine ausgeprägte myotrope Information erfahren, die bevorzugt auf die Muskulatur der Hinterextremitäten der erwachsenen Mäuse ausgerichtet war. Das Virus vermehrte sich primär in der Muskulatur des rechten, injizierten Hinterschenkels. Sodann kam es zur Virämie und in deren Verlauf zur Vermehrung in den anderen der Adaptionsrichtung des modifizierten Virus entsprechenden Zellsystemen, hauptsächlich im linken Hinterschenkel, der als On der sekundären Virusvermehrung angesehen werden kann.
Klinische Verlaufsform und pathologisch-anatomisches Bild entsprachen in jedem Falle dem Ablauf des Infektionsgeschehens.
Im Gegensatz zu der modifikationsbedingten Qualität scheint die Quantität des verabreichten Virus für die klinische Reaktion und die Höhe der Virustiter in der Muskulatur beider Hinterschenkel der erwachsenen Mäuse nur von untergeordneter Bedeutung zu sein. Bis zu einer unteren Grenzdosis von etwa 2,2 log ID50/0,1 ml waren keine signifikanten Unterschiede hierin festzustellen. Diese Grenzdosis kann in gewisser Hinsicht als Kriterium für den Modifizierungsgrad eines in Dauerpassagen attenuierten Maul- und Klauenseuchevirus angesehen werden, vorausgesetzt, sie hat ihren Wert während der letzten Dauerpassagen annähernd beibehalten oder verringert.
Das modifizierte Virus wurde in Rinderversuchen auf seine Eignung als Lebendimpfstoff geprüft. Es wurden drei Vaccinen mit unterschiedlicher Rohvirusgrundlage hergestellt. Diese erwiesen sich alle als völlig unschädlich in weitestem Sinne für hochempfängliche Rinder. Eine Übertragung des Impfvirus mit alien ihren möglichen Folgen vom Impfling auf unbehandelte Kontaktrinder wurde nicht beobachtet.
Bei den Immunitätsprufungen zeichneten sich die Vaccinen Nr. 1 und Nr. 3 durch gute Wirksamkeit aus. Sämtliche damit geimpften Rinder waren praktisch vollimmun gegenüber einer Infektion mit dem homologen Rindervirus durch schwer erkrankte Kontakttiere. Dagegen war die immunisierende Wirksamkeit der Vaccine Nr. 2 schlecht. Von den vaccinierten Rindern war nur eines als immun zu bewerten, die restlichen Tiere hatten alle typische generalisierte Maul- und Klauenseuche-Veränderungen.
Die Befunde der Immunitätsprufungen stehen mit den Ergebnissen der Neutralisationsteste in guter Übereinstimmung. Bei Berücksichtigung der vorliegenden Versuchsbedingungen können Rinder mit einem Neutralisations-Index von 1,5 und darüber als vollimmun und solche mit einem niedrigeren Index als teil- oder nichtimmun angesehen werden.
Die eventuell möglichen Gründe für die unterschiedliche Wirksamkeit der drei Lebendvirus-Impfstoffe werden diskutiert.
Studies on a foot-and-mouth disease virus strain of type SAT 2 modified by continued passage in mice of increasing age
A foot-and-mouth disease virus of type SAT 2 isolated in Kenya in 1960 and modified by 150 passages in mice of increasing age was further studied. In adult mice, injection of the virus into the right thigh muscle produces local primary virus multiplication, followed by viraemia and secondary virus multiplication in the heart and skeletal muscles. The effects comprise swelling of the thigh muscle, lameness, dyspnoea, cyanosis (circulatory damage) and death up to the 72nd hour after injection.
The modified virus was injected intramuscularly (5.0 ml.) as a live vaccine into Zebu-cross (“grade”) cattle when it proved non-pathogenic and was not transmitted further by contact. In immunity tests by contact with sick cattle infected with the homologous virus, a vaccine made from heart and skeletal muscle of unweaned mice proved very effective (6 out of 6 test animals were fully immune); a vaccine from the muscle of the right (infected) thigh (site of primary virus multiplication) was effective (3 out of 4 animals fully immune, 1 partially); and a vaccine prepared from the left thigh muscle (site of secondary virus multiplication) was unsatisfactory (only 1 of the 4 animals became immune). Serum neutralisation tests gave similar results. In all fully immune animals the neutralisation index (log) was greater than 1.5. The reasons for the varying effectiveness of the different vaccines are discussed.
Essais au moyen d'une souche de virus aphteux de type „SAT 2” modifiée par passages continus sur souris d'âges allant en augmentant
Une souche de virus du type SAT 2 isolée en 1960 au Kenia a été examinée, après avoir été modifiée par 150 passages sur souris d'âges toujours plus avancés. Ce virus provoquait, après avoir été injecté dans la musculature de la cuisse droite de souris adultes, une multiplication locale primaire de virus, puis une virémie et une multiplication secondaire du virus dans la musculature cardiaque et du corps. Ce faisant on observait: une enflure des muscles de la cuisse, de la claudication, de la dyspnoe, de la cyanose (troubles circulatoires) et la mort survenant 72 heures après l'infection.
Le virus modifié, injecté par voie intramusculaire (5,0 ml), au titre de vaccin vivant, à des boeufs (croisements de zébus «grade cattle») s'avérait nonpathogène et n'etait pas non plus transmis par contacts. Lors des contrôles d'immunité par contacts avec des boeufs malades qui avaient été infectés au moyen de virus bovin homologue, un vaccin préparé au moyen de muscle cardiaque et du corps de jeunes souriceaux était trouvé d'un bon effet (6 animaux sur 6 testés étant entièrement immuns) tandis qu'un vaccin fait de musculature de la cuisse droite (infectée) (lieu de la première multiplication du virus) était efficace (3 animaux sur 4 étant entièrement immuns et un partiellement) et un vaccin fait de la musculature de la cuisse gauche (lieu de la multiplication secondaire du virus) était trouvé mauvais (un animal seulement sur quattre étant immun). Les résultats de la neutralisation sérique corroboraient ces faits. Chez tous les animaux complètement immunisés, l'index de neutralisation (log) était supérieur à 1,5. Les raisons entrant en ligne de compte pour expliquer les différences d'efficacité des vaccins sont discutées.
Ensayos con una cepa de virus aftoso del tipo „SAT 2” modificado por pases continuados en ratones de edades crecientes
Se estudió una cepa de virus del tipo SAT 2, aislada en 1960 en Kenia, que se había modificado por 150 pases a través de ratones en edades crecientes. Tras inoculación en la musculatura del muslo derecho, este virus ocasionaba allí en ratones adultos una multiplicación primaria local del virus, luego una viremia y multiplicación secundaria del virus en la musculatura del corazón y del esqueleto. Durante este proceso se observó: tumefacción de la musculatura del muslo, cojera, disnea, cianosis (alteraciones circulatorias) y muerte hasta la hora 72 tras la infección.
El virus modoficado, inoculado por vía intramuscular (5,0 ml) como vacuna viva en vacas (“grado bovino” del cruce con cebú), resultó innocuo (no patógeno) y tampoco se transmitía por contacto. En el control de la inmunidad mediante contacto con bóvidos enfermos, infectados con virus bovino homólogo, una vacuna preparada a partir de corazón y musculatura esquelética de ratones lactantes se manifestó como muy activa (6 de 6 animales examinados con inmunidad total), una vacuna de musculatura del muslo (infectado) derecho (lugar de la multiplicación virósica primaria) como activa (3 de 4 animales de control con inmunidad completa, 1 con inmunidad parcial) y una vacuna de musculatura del muslo izquierdo (lugar de la multiplicación secundaria del virus) como mala (solo 1 animal inmune de 4 manipulados). En concordancia con esto se hallaban los resultados de la seroneutralización. En todos los animales con inmunidad total, el índice (log.) de neutralización era superior a 1,5. Se discuten las causas posibles de las diferencias habidas en la actividad de estas vacunas.
The evidence relating the interferon system to the infectious process has been examined. The available evidence supports the view that the interferon system is an important component of the body's nonimmune defenses, which are probably the major causes of recovery from already established virus infections of body tissues. The interferon system can also serve to limit virus spread through the bloodstream. Factors which may influence the interferon system and thereby influence virus infection have been considered. Finally, evidence is presented which indicates that the interferon system is one of the determinants of virulence of certain viruses and is one of the determinants of some persistent virus infections.
Antiviral interferon activity in any one species can be exhibited by a variety of substances that differ in their physical and chemical properties, but the nature of these differences is not understood. Conditions that can lead to the formation of diverse types of interferons have been outlined. Reasons have been adduced why, for certain purposes, purification of interferons is desirable or even necessary, and examples have been presented to show how and to what extent this has been achieved. In spite of some very high purification factors, not a single interferon has been obtained as a pure substance. Therefore, all available knowledge of physical and chemical properties has been obtained by indirect means.
Interferon has been known for a long time but until recently, it was defined simply as a complex of proteins with antiviral activity that occurs when cultured cells are infected by virus. Significant progress has been made in the study of interferons. This article presents the properties of interferon and its mechanism of action, and the use of animal model systems to study interferon.
Since 1959, The Wellcome Foundation Ltd. has been involved in research to develop interferon for practical use. A brief historical perspective is presented on the development and production of interferon alfa-n1.
Repeated intraperitoneal doses of preformed interferon and a single intraperitoneal injection of polyacrylic acid were shown to protect newborn mice from lethal infection with vesicular stomatitis virus. Both survival time and number of surviving mice were considerably increased by the injections. The antiviral activity of interferon and polyacrylic acid was inversely proportional to the dose of challenge virus. Nearly 100% of the mice treated with interferon survived a nearly 100% lethal infection (16 LD50).Polyacrylic acid diminished the mortality rate by 50 %. It is concluded that polyacrylic acid induces good host resistance to viruses and may be suitable in the prophylaxis of virus infections in vivo.
Inoculation of the chorioallantoic membrane (CAM) of fertile chicken eggs with Coxsackie virus 24 hours prior to inoculation with Rous sarcoma virus resulted in about a fourfold decrease of the number of pocks formed by Rous sarcoma virus. The size and number of occasionally occurring gross tumors were also considerably reduced. On the other hand, the decrease of the number of pocks caused by ultraviolet-irradiated Coxsackie virus was negligible. However, the size and number of gross tumors were reduced to the same degree as by active Coxsackie virus. Ultraviolet-irradiated influenza virus caused about a tenfold, and interferon about a fivefold, decrease of the number of pocks formed by Rous sarcoma virus and also a considerable reduction of size and number of gross tumors.In control experiments with Semliki Forest virus as the challenge virus in plaque assays, interference was obtained with active Coxsackie virus, ultraviolet-irradiated influenza virus, and interferon.Coxsackie virus did not in any of the systems used produce measurable amounts of interferon or interferon-like substances and the mechanism of the interference between Coxsackie virus and Rous sarcoma virus remains open. In the case of influenza virus the interference phenomenon described is apparently due to production of interferon on the CAM.
During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released. This factor, recognized by its ability to induce interference in fresh pieces of chorio-allantoic membrane, was called interferon. Following a lag phase interferon was first detected in the membranes after 3 h incubation and thereafter it was released into the surrounding fluid.
The mechanism of action of interferon has been investigated in two different cell systems, with concordant results. Interferon is able to suppress the one-cycle synthesis of poliovirus in embryonated eggs inoculated with infectious polio ribonucleic acid (RNA). This observation represents the basis of a sensitive method for quantitative bioassay of interferon activity. Interferon-treated chick embryo cells infected with Western equine encephalitis (WEE) virus do not yield detectable infectious viral RNA, as shown by extraction with cold phenol. It appears that interferon action occurs within the cell, after penetration of virus and before formation of mature virus particles. A close relationship with viral RNA metabolism is suggested.
Chick embryo interferon was purified from allantoic fluid of embryonated eggs infected with influenza A virus. Purification consisted essentially of acid precipitation to remove virus and extraneous protein, concentration and purification by precipitation with Zn++, column chromatography on CM-cellulose, and zone ionophoresis on pevikon. The interferon was purified 4500 times with respect to initial protein and one unit of interferon activity was 0.0042 μg protein in the chick embryo cell-EEE virus assay system used. Interferon was found to be a slightly basic protein of low molecular weight and free of nucleic acid as well as constituents giving absorption in the visible spectrum. A trace amount of carbohydrate was found. Detailed findings in the analyses are presented. The striking difference in properties of interferon from those described heretofore by other workers appears to lie in previous failure of purification. Both crude and purified chick interferon were active in suppressing Rous sarcoma development and NDV virus infection in susceptible chicks but were without therapeutic effect.
Leeuwenhoek ned. Tijdschr. 27, 261
- P Denys
- Jr
- A Prinzie
- De Somer
- P De
- P Somer
- A Prinzie
- P Denys
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- E Schonne
Denys, P., Jr., Prinzie, A., De Somer, P. (1961) Leeuwenhoek ned. Tijdschr. 27, 261. De Somer, P., Prinzie, A., Denys, P., Jr., Schonne, E. (1962) Virology, 16,63. Hitchcock, B. A., Isaacs, A. (1960) Brit. med. J. ii, 1268.
Recent Advances in Cardiology
- Prof Rab And Others Brigden
- W
- G London Forbes
- A Usher
- W T Longcope
- D C Frieman
- F J Talbot
- S Katz
- M J E Mathews
- De Somer
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