Article

THE COURSE OF VIRUS-INDUCED RABBIT PAPILLOMAS AS DETERMINED BY VIRUS, CELLS, AND HOST.

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Abstract

An experimental analysis of the factors responsible for the observed differences in the course of virus-induced papillomas of the rabbit has shown that some are referable to the virus, others to the cells, and yet others to host influences. The interplay of these factors affords enlightening illustration of the nature of the cell-virus relationship in virus-induced tumors. Retrogression of the rabbit papillomas appears to be consequent on a generalized resistance of host origin, elicited by and directed against the proliferating, virus-infected cells.

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... In a third (D. R. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] cancer was first noted on the 141st day, in one of the confluent masses resulting from virus plus MC, although this mass, like its fellow, had seemed previously to differ no whir from the control masses, either in time of formation or in vigor. The malignant growth enlarged swiftly and on the 183rd day the animal succumbed. ...
... The mild virus W. R. 152 was a fortunate choice. Such viruses give rise to growths that are especially liable to disappear, but Kidd has shown that when retrogression takes place confluent masses persist much longer than individual papiUomas of the same inoculation (17); and in this knowledge virus W. R. 152 was brought to bear under such conditions that it gave rise to broad masses of papiUomatous tissue. A large proportion of those serving as controls dwindled eventually, as was to have been expected, but none disappeared during the period of test. ...
... The confluent masses frequently showed less vigor than the controls, some being dry almost to the base, whereas these latter, situated at corresponding places on the other side of the host, were fleshy. When retrogression occurred, a change which regularly implicates in greater or less degree all the growths resulting from the same inoculum on the individual rabbit (17), the papillomas influenced by 9"10 dwindled the more rapidly. This may well have been due to their less dense or imperfect confluence, since individual papillomas vanish first, as already remarked. ...
Article
Areas of rabbit skin previously rendered hyperplastic with turpentine were scarified, inoculated with the Shope papilloma virus, and covered with a dressing that contained 20-methylcholanthrene (MC) or 9:10-dimethyl-1:2-benzanthracene (9:10). The dressing was left on until healing had been well completed, a matter of 5 to 7 days. The papillomas which subsequently arose often appeared later, were fewer, and remained less vigorous than those due to the action of virus alone, but throughout several months they appeared to differ from these in no other ways. Then, more or less abruptly, the large majority became carcinomatous, frequently at several situations, whereas with few exceptions the control growths underwent no such alteration. The cancers were of the sorts ordinarily deriving, by secondary change, from epidermal cells infected with the virus. Collateral data have made plain that the hydrocarbons acted in their carcinogenic capacity to bring on the cancers. Indeed in control tests 9: 10 sometimes conferred latent neoplastic potentialities on uninoculated epidermis exposed to it while healing after scarification, a fact disclosed months later by painting these expanses with chloroform until hyperplasia occurred. Under the promoting influence of this agent papillomas formed which had the distinctive morphology of those induced by the chemical carcinogens. So strong and enduring were the effects of MC and 9:10 as to cause cancers to arise from many virus papillomas which were retrogressing after months of proliferation, that is to say under circumstances ordinarily unfavorable to malignant change. The facts justify the conclusion that the virus and the hydrocarbons acted jointly and in their carcinogenic capacities.
... The simultaneous disappearance of many warts in individual rabbits (Kidd, 1938) is evidence for systemic immunity. After noting the spontaneous regression after 1±2 months of experimentally-induced canine oral papillomas (Fig. 1), M'Fadyean and Hobday (1898) proposed that`the credit claimed for some methods of treatment may be undeserved'. ...
... As discussed above, the inability to enhance wart regression by passive transfer of immune serum in both the dog (Chambers et al., 1960) and rabbit (Kidd, 1938;Evans et al., 1962a) suggested that lesion regression was probably effected by cellular, rather than humoral, immunity. Further evidence for the role of cellular immunity came from the resistance of regressor rabbits to infection by naked DNA, which would be able to bypass the immunity due to neutralising antibodies (Evans and Ito, 1966). ...
Article
Papillomaviruses are species- and tissue-specific double-stranded DNA viruses. These viruses cause epithelial tumours in many animals, including man. Typically, the benign warts undergo spontaneous, immune-mediated regression, most likely effected by T-cells (especially CD4, but also CD8 subsets), whereas humoral immunity can prevent new infections. Some papillomavirus infections fail to regress spontaneously and others progress to malignant epithelial tumours. Additionally, the impact of these lesions is greater in immunosuppressed individuals. Many therapies are ineffective, and there is much interest in the potential for immunological intervention in papillomavirus infections of man and animals. Vaccination can be achieved with 'live' virus, formalin-inactivated virus, synthetic virus-like particles, and DNA vaccination. There has been much recent progress in the development of such vaccines for papillomavirus infections in the rabbit, ox and dog. Success in these animal models suggests that similar approaches may prove useful for prophylactic or therapeutic vaccination against the important human papillomaviruses involved in the development of cutaneous and anogenital warts, laryngeal papillomatosis, and cervical cancer.
... Natural infections in animals have provided very strong evidence for the importance of cell-mediated immunity in both natural infection and following vaccination. The observation that passively transferred serum failed to clear warts in the rabbit ( Evans and Ito, 1966;Kidd, 1938), yet offered protection from canine oral papillomavirus (COPV) challenge in dogs ( Suzich et al., 1995) implied that humoral immunity was not involved in lesion regression suggesting that cell-mediated responses must be crucial; a notion further supported by the observation that, in the rabbit, seroconversion was not required for regression of cotton tail rabbit papillomavirus (CRPV)-induced papillomas (Selvakumar et al., 1995a). Positive skin tests using viral proteins in rabbits with regressing papillomas ( Hopfl et al., 1993), together with in vitro responses of peripheral blood lymphocytes to viral proteins, clearly indicate active cellular immunity to CRPV. ...
Article
Cell-mediated immunity plays a key role in the regression of papillomavirus-induced warts and intra-epithelial lesions but the target antigens that induce this response are not clear. Canine oral papillomavirus (COPV) infection of the oral cavity in dogs is a well-characterized model of mucosal papillomavirus infection that permits analysis of the immune events during the infectious cycle. In this study we show that during the COPV infectious cycle, systemic T cell responses to peptides of several early proteins particularly the E2 protein, as assayed by delayed type hypersensitivity, lymphoproliferation and IFN-gamma ELISPOT, can be detected. The maximal response occurs in a narrow time window that coincides with maximal viral DNA replication and wart regression: thereafter, systemic T cell responses to early proteins decline quite rapidly. Vaccination using particle-mediated immunotherapeutic delivery (PMID) of codon-modified COPV E2 and E1 genes induces strong antigen-specific cell-mediated immune responses in the vaccinated animals. These data show that therapeutic immunization by PMID with codon-modified E2 is completely effective, that to E1 is partially protective, that this correlates with the intensity of antigen-specific cell-mediated immune responses and, further, they emphasize the importance of these responses and the route of immunization in the generation of protective immunity.
... The failure of passively transferred serum to clear warts in the dog (Chambers et al., 1960), and rabbit (Kidd, 1938;Evans et al., 1962), suggested that humoral immunity played no part in lesion regression. Cellular infiltrates have been observed in regressing papillomas of the pig (Parish, 1961), horse (Hamada et al., 1990), deer (Sundberg et al., 1985), sperm whale (Lambertsen et al., 1987), ox (Knowles et al., 1996), and rabbit (Kreider, 1963;Okabayashi et al., 1991Okabayashi et al., , 1993. ...
Article
One hundred years have passed since the first reports of transmissible warts in the dog were noted in this journal by its founder (M'Fadyean and Hobday, 1898; Penberthy, 1898). These early observations by M'Fadyean, Penberthy and Hobday started a line of enquiry leading to the development of efficient vaccines which may play a key role in the control of important animal and human diseases. This brief review outlines the role that studies on canine papillomaviruses have played in recent vaccine developments.
... Studies of the Shope skin papilloma of rabbits suggest that regression is brought about by a host resistance directed toward the papilloma cell rather than toward the virus (11,19). A host resistance directed toward the papilloma cell is suggestive of the immune mechanism which is involved in the rejection of homografts of transplantable tumors and normal tissues. ...
... Cottontail rabbit papillomavirus (CRPV) studies established over 60 y ago that antibodies elicited by the injection of intact virions protect against experimental challenge by the homologous viral type (Shope, 1935). Intact virions displaying immunodominant epitopes were found to be needed to induce protective antibodies (Shope, 1935;Kidd, 1938;Pilacinski et al, 1986;Jin et al, 1990;Ghim et al, 1991). It was demonstrated that the L1 major capsid protein of HPV expressed in eukaryotic cells self-assembles into virus-like particles (VLP), which resemble authentic virions without the viral genome and its transforming genes. ...
Article
The development of potential therapeutic and prophylactic vaccines for human papillomavirus (HPV) infection is a very exciting area of HPV research. There are a number of features of HPV biology that makes the development of a vaccine particularly difficult, although there are several examples of vaccines that have had spectacular success in the prevention of other viral diseases. Our poor understanding of the immune response to HPV infection is the first problem. We do not understand the mechanism by which spontaneous clearing of warts is generated and therefore cannot particularly target this pathway in the development of a vaccine. Furthermore, there is no in vitro culture system nor an animal model for HPV. Another problem is that there is no ready source of live virus that might be exploited for a live attenuated viral vaccine, such as was used with poliovirus. Although most other viruses spend a portion of their life cycle in the systemic circulation where they are vulnerable to neutralizing antibodies, HPV remain exclusively in the epithelium and thus antibodies must transverse the basement membrane and reach the other layers of the skin or mucosa to be effective in preventing infection. Significant progress is being made in the development of potential vaccine candidates despite these and other confounding factors.Keywords: antibodies, virus-like particles
... Tracings were made on cellophane in a few cases while the growths were dwindling, in order to record their exact situations; and after they had vanished tarring was begun anew. Some reappeared, but one cannot be sure that the tarring was responsible since recurrence can take place without it (20). Recently we have found that renewed tarring may call forth tar tumors where they were before, months after seemingly complete disappearance. ...
Article
Tarring the ears of rabbits of one sort with a single kind of tar evoked epidermal tumors of a few sharply defined types, namely ordinary papillomas, carcinoids, carcinomas, and "frill horns." These last, relatively infrequent, are now recognized for the first time. The carcinoids have proved to be the expression of a spurious malignancy of papillomas, resulting from intercurrent influences, and they were wholly dependent upon these for their threatening aspect and behavior. Chief amongst such influences was continued tarring. It had the effect of establishing the papillomas, stimulated their proliferation, complicated their morphology, and rendered some of them disorderly, aggressive, and anaplastic. It brought all of the tissues of the ears into an excitable state, and often this state endured long after the skin had apparently returned to normal. The characters of the papilloma-carcinoids and of the frill horns were so different and distinctive as to imply the action of differing, specific causes. The papillomas were very like those induced with the Shope virus, and hence a point-to-point comparison was made of their manifestations, including the derivation of carcinomas from them. This comparison demonstrated that the unknown cause of the tar papillomas provoked neoplastic phenomena which were identical in all essential respects with those due to the virus. To suppose, for experimental purposes, that the papillomas which tarring elicits are caused by a virus rendered pathogenic by this procedure, is to demand least of the unknown. Yet it does not follow that they must be due to a virus.
Article
The majority of domestic rabbits developed invasive, metastatic, and, ultimately, lethal epidermoid carcinomas. The Shope papilloma has a restricted geographic range, mostly confined to the high plains of the western United States. SPV (Shope papilloma virus) produced papillomas with equal facility on the skins of laboratory-infected jackrabbits, snowshoe hares, domestic rabbits, and cottontails. Papillomas cannot be induced in fetal, neonatal, suckling, or adult rat skin by direct inoculation of SPV suspensions or infectious DNA. Susceptibility to SPV infection is also determined by factors related to cell phenotype. Rabbit epidermal cell transformation by SPV requires interaction with mesenchyme. Vitamin A deficiency or excess can produce striking alterations in the differentiation of epithelia of various types. SPV replication in cottontail papillomas is also modulated by phenotypic factors—namely, epidermal maturation and keratinization. Independent studies have confirmed the presence of arginase in Shope papilloma but have not supported the assertion that the enzyme is encoded by the SPV genome. The Shope papilloma-carcinoma complex is an excellent model of neoplastic progression. Papillomas that become malignant undergo a characteristic series of gross morphological changes.
Article
The interface between the tumor and the host is often the site of leucocytic infiltration. We will examine the idea that the infiltrating leucocytes of human and experimental tumors are components of the host immunological defense against the tumor, and that the presence of the infiltrate is a marker of favorable prognosis. Leucocytes could infiltrate tumors because of an active immune response, either nonspecific or specifically directed to tumor-associated antigens. Leucocyte influx may also occur because of chemotactic factors secreted by the tumor cells. Some tumors release factors which enhance vascular permeability and permit improved access by leucocytes to the tumor focus. The consequences of leucocytic infiltration include tumor cell cytolysis, cytostasis, or stimulation of proliferation. The present state of our knowledge of the interactions between tumor cells and infiltrating leucocytes precludes broad generalization of mechanisms. Further study will probably reveal that the mechanisms are diverse, and that there are some systems in which immune interactions occur at this interface and others in which they do not.
Article
Papillomas induced by the cottontail rabbit papillomavirus (CRPV) progress at a high frequency to carcinomas. In this regard, CRPV and its tumors can serve as an animal model for highly oncogenic human papillomaviruses. We have previously shown that immunization with major structural protein L1 elicits neutralizing antibodies and protects rabbits from papilloma development (Y.-L. Lin, L.A. Borenstein, R. Selvakumar, R. Ahmed, and F.O. Wettstein, Virology 187:612-619, 1992). In this study, we demonstrated that vaccination with the TrpE-L1 fusion protein not only protected rabbits from papilloma development but also prevented latent infection. This was indicated by the failure to amplify CRPV sequences by polymerase chain reaction in biopsies from infection sites of immunized animals. Furthermore, we showed that TrpE-L1 immunization protected rabbits from papilloma formation induced by virus but not from that induced by viral DNA. To explore the possibility of developing vaccines based on L1 subfragments, we mapped the linear L1 epitopes recognized by TrpE-L1-immunized rabbits and by virus-infected rabbits resistant to superinfection. Sera from papilloma-bearing rabbits reacted with one major epitope located at the carboxy-terminal end of L1, between amino acids (aa) 480 and 505. A second epitope, and in some animals a third one, was located in the amino-terminal region, between aa 78 and 101, as well as between aa 37 and 62. Sera from TrpE-L1-immunized animals recognized only one major epitope, located between aa 6 and 37. Immunization of rabbits with L1 subfragment fusion proteins led to seroconversion, but no neutralizing antibodies were produced and the animals were not protected against papilloma formation. The data indicate that a successful papillomavirus vaccine must be based on immunization with full-length native L1 and that further simplification to smaller peptides containing major linear epitopes is not feasible.
Article
Human papillomavirus-like particles (VLPs), self-assembled after high level expression of the papillomavirus L1 virion capsid protein in non-mammalian cells, are attractive candidates for a subunit vaccine to prevent genital HPV infection and the subsequent development of cervical cancer. In animal studies, purified VLPs induce high titers of antibodies against conformational type specific L1 epitopes. These antibodies neutralize homologous virions in in-vitro assays and protect against experimental challenge in several animal models. The encouraging results in animals justify the initiation of human trials of HPV VLP-based vaccines. Factors to be considered when designing these trials are discussed.
Article
Full-text available
We previously reported the partial characterization of two cottontail rabbit papillomavirus (CRPV) subtypes with strikingly divergent E6 and E7 oncoproteins. We report now the complete nucleotide sequences of these subtypes, referred to as CRPVa4 (7,868 nucleotides) and CRPVb (7,867 nucleotides). The CRPVa4 and CRPVb genomes differed at 238 (3%) nucleotide positions, whereas CRPVa4 and the prototype CRPV differed by only 5 nucleotides. The most variable region (7% nucleotide divergence) included the long regulatory region (LRR) and the E6 and E7 genes. A mutation in the stop codon resulted in an 8-amino-acid-longer CRPVb E4 protein, and a nucleotide deletion reduced the coding capacity of the E5 gene from 101 to 25 amino acids. In domestic rabbits homozygous for a specific haplotype of the DRA and DQA genes of the major histocompatibility complex, warts induced by CRPVb DNA or a chimeric genome containing the CRPVb LRR/E6/E7 region showed an early regression, whereas warts induced by CRPVa4 or a chimeric genome containing the CRPVa4 LRR/E6/E7 region persisted and evolved into carcinomas. In contrast, most CRPVa, CRPVb, and chimeric CRPV DNA-induced warts showed no early regression in rabbits homozygous for another DRA-DQA haplotype. Little, if any, viral replication is usually observed in domestic rabbit warts. When warts induced by CRPVa and CRPVb virions and DNA were compared, the number of cells positive for viral DNA or capsid antigens was found to be greater by 1 order of magnitude for specimens induced by CRPVb. Thus, both sequence variation in the LRR/E6/E7 region and the genetic constitution of the host influence the expression of the oncogenic potential of CRPV. Furthermore, intratype variation may overcome to some extent the host restriction of CRPV replication in domestic rabbits.
Article
Six out of eight epidermal papillomas, induced with tar in mice of homogeneous strain, have grown after transfer to the subcutaneous tissue of sucklings and weanlings. Five of them have been thus maintained for nearly or quite a year and a half, and in seven to nine successive groups of mice. The tumor studied longest has been kept going in five parallel lines since its primary implantation. The papillomas have all grown progressively in most instances, and proved fatal. None has altered except through the occurrence of derivative cancers, but these have arisen so often as only to be excluded on transfer by a rigorous selection of grafts. Histologically the papillomas have been of a single, completely unaggressive kind, yet transfer has disclosed great differences in their abilities. The tumors they form are of unique sorts. The cells of some are able-bodied (Type A), capable of spreading along bare connective tissue and keratinizing like normal, reparative epidermis. They line graft pockets, differentiate into the free space these provide, and form cysts densely packed with keratin. The papilloma is thus turned outside in. The cysts become huge as keratin accumulates in them, and eventually they rupture with result either in subcutaneous dissecting cysts or keratinizing surface growths that are often prodigious in size and fantastic in shape, but sometimes are completely like the cutaneous papillomas ordinarily induced by carcinogens, and tend, when small, to regress or come away as these frequently do. One growth of Type A was placed in the peritoneal cavity or in the liver, spleen or lung, and at all these situations it formed introverted cysts resembling the subcutaneous. The cells of other papillomas are more or less crippled (Type C). In extreme instances they are unable to spread laterally, and produce relatively little keratin. They fail to line graft pockets, but their keratin inflames the exposed connective tissue, extravasation ensues, and a continually enlarging, fluid-filled cyst forms, with walls that are bare except where a stalked or cauliflower papilloma exists, projecting inwards. At last the cyst ruptures and a second dissecting cyst forms, also devoid of papilloma tissue; or else the overlying skin undergoes pressure necrosis, the cyst fluid escapes through a rent, and fatal infection ensues. All gradations exist between Type A and Type C. The cancers derivative from both exhibit a marked disability,—though invasive they are almost or quite unable to extend along bare connective tissue. The papillomas that are possessed of this faculty spread beyond them along the cyst wall, and kill the host through their unceasing activity. In collateral work a papilloma was transplanted that was found protruding from the external auditory canal of a mouse which had received an intramuscular injection of methylcholanthrene many months previously. The tumor is now in its 5th generation, after 15 months. The growths it forms are of Type A. All of the papillomas are functioning tumors, with their own cells as the functioning product. Their papilliferous shape, when on the skin, is due solely to inability of their cells to gain space in other ways. Intrinsically they are keratomas. The papillomas do well after transfer to deep situations because the growth of their cells is indirectly promoted, through favoring local conditions. No direct promotion takes place like that when the cells of prostatic and mammary tumors are stimulated to multiply by hormones. Doubtless many agents act in both ways, that is to say by dual promotion.
Article
PAPILLOMAS of rabbit skin induced by the virus of Shope are known to undergo complete regression in some animals and to persist indefinitely in others. Carcinomatous change is seen in a high proportion at 6-18 months 1. The regression process presents two features of broad significance in the field of tumour immunology: (1) It constitutes rejection of an autologous tumour; (2) The rejection mechanism is effective in some animals and inadequate or absent in others.
Article
Areas of rabbit skin previously rendered hyperplastic with turpentine were scarified, inoculated with the Shope papilloma virus, and covered with a dressing that contained 20-methylcholanthrene (MC) or 9:10-dimethyl-1:2-benzanthracene (9:10). The dressing was left on until healing had been well completed, a matter of 5 to 7 days. The papillomas which subsequently arose often appeared later, were fewer, and remained less vigorous than those due to the action of virus alone, but throughout several months they appeared to differ from these in no other ways. Then, more or less abruptly, the large majority became carcinomatous, frequently at several situations, whereas with few exceptions the control growths underwent no such alteration. The cancers were of the sorts ordinarily deriving, by secondary change, from epidermal cells infected with the virus. Collateral data have made plain that the hydrocarbons acted in their carcinogenic capacity to bring on the cancers. Indeed in control tests 9: 10 sometimes conferred latent neoplastic potentialities on uninoculated epidermis exposed to it while healing after scarification, a fact disclosed months later by painting these expanses with chloroform until hyperplasia occurred. Under the promoting influence of this agent papillomas formed which had the distinctive morphology of those induced by the chemical carcinogens. So strong and enduring were the effects of MC and 9:10 as to cause cancers to arise from many virus papillomas which were retrogressing after months of proliferation, that is to say under circumstances ordinarily unfavorable to malignant change. The facts justify the conclusion that the virus and the hydrocarbons acted jointly and in their carcinogenic capacities.
Article
In order to explain satisfactorily the basic features of cancer a theoretical cause of cancer should be endowed with the following fundamental properties: (1) It should exhibit an affinity for cells and induce them to grow while multiplying along with them. (2) It should be specific for cells so that the same lesion is repeated, yet able to change so that many different lesions are produced. (3) It should be able to remain in a latent state in tissues and be conditioned by genetic and surrounding conditions such as those attending old age. (4) It should be capable of existing either in a free or in an occult state. Viruses fulfill all these requirements. Nevertheless the so-called virus or infectious theory of cancer is not at all popular, most workers favoring endogenous theories. Arguments for and against these doctrines are reviewed, especially those centering on comparisons between bacterial virulence and cell malignancy and the nature of the principles changing bacterial types.
Chapter
Weit vor der Zeitrechnung wurde der Begriff Carcinoma von Hippokrates für eine Geschwulstkrankheit des Menschen eingeführt, die nach wie vor den Arzt und die Patienten gleichermaßen beunruhigt. Gestützt auf die Beobachtung erneut auftretender Tumoren im Operationsbereich entfernter Krebsgeschwülste, drängte sich schon früh die Frage nach den Bedingungen und nach der Natur der Faktoren auf, die eine Übertragbarkeit des Krebses möglich machen. Engel-Reimers und Reincke teilten 1870 Befund und Verlauf zweier Fälle von Impfrezidiven in Punktionskanälen bei carcinomatöser Peritonitis mit. E. Hahn (1888) transplantierte bei einer Frau mit einem inoperablen Mamma-Carcinom gesunde Haut und verpflanzte auf die Entnahmestelle die exstirpierte carcinomatöse Haut und mußte nach 6 Wochen feststellen, daß die Geschwulstknötchen in das gesunde Gewebe hineinwucherten. Über zwei ähnliche Versuche eines anonymen Chirurgen berichten Cornil (1891) unter berechtigtem Protest vieler Mitglieder der Akademie der Wissenschaft in Paris.
Article
A considerable variety of tumors, both benign and malignant, result from the localization of the rabbit papilloma virus in skin which has been prepared by repeated tarrings. They appear only in individuals highly susceptible to the action of the virus, and are more likely to be engendered by highly pathogenic inocula. No evidence has been found that differences in the potentialities of the virus entities are responsible for the diversity of the growths. This is referable to changes in the epidermal cells; and much more preliminary tarring is required to produce these changes than suffices to cause localization of the virus out of the blood stream with a resulting papillomatosis of the ordinary sort. The character of the individual anomalous tumors depends in some degree upon the extent of the preparatory changes in the cells, malignant growths being more frequent when the epidermis has been tarred for a relatively long period. All are focal or punctate in origin, and they exhibit their peculiar characters from the first, none being due to secondary alterations in ordinary papillomas. Tarring after the virus has localized in the epidermis does not significantly increase their number. They are the outcome of the state of the cells at the time of virus infection. Tarring exerts important influences in addition to changing the cells in such a way that unusual tumors result from the action of the virus. The procedure is notably effective in determining localization of the virus out of the blood stream; enables it to produce growths when otherwise it would not do so though present in the tarred skin; stimulates the proliferation of the tumors engendered; makes them disorderly and aggressive; and hastens the anaplasia of such of them as are malignant. It has similar effects upon the tar tumors, as will be demonstrated in a subsequent paper.
Article
1. Durch Rntgenbestrahlung der Kaninchenhaut vor der Infektion mit dem Shope-Virus oder whrend der Latenzzeit lt sich die sptere Papillomentwicklung unterbinden (1000–2000 r) oder deutlich hemmen (500–1000 r). Diese primr infektionshemmende Wirkung der Rntgenstrahlen luft parallel mit einer Mitosenhemmung in der Haut; sie ist reversibel und hlt bei 1000 r etwa 3–4 Wochen lang an. Whrend dieser Zeit wird das Shope-Virus in der bestrahlten Haut inaktiviert, vermutlich infolge der durch die Bestrahlung gestrten DNS-Synthese. 2. Im Einklang hiermit bleibt nach einer Infektion auf bestrahlter Haut die Immunisierung aus, whrend normalerweise mit Shope-Virus infizierte Kaninchen gegen eine Zweitinfektion immun sind. 3. Nach dem Abklingen der Hemmwirkung ist in bestrahlter Haut die Empfindlichkeit gegenber dem Shope-Virus erhht. Rntgenbestrahlungen mit Dosen von 200 r aufwrts erhhen auerdem nachweislich die Grewebspermeabilitt. Da auch eine Permeabilittssteigerung durch Vorbehandlung der Infektionsfelder mit Hyaluronidase die Papillomentwicklung deutlich frdert, lt sich die sekundr infektionsfrdernde Wirkung der Rntgenstrahlen mglicherweise ebenfalls auf die Steigerung der Gewebspermeabilitt zurckfhren.
Chapter
Diese spontane seuchenhafte Erkrankung wurde erstmalig durch Sanarelli (1898), dann durch Splendore (1909) bei kleinen Ausbrüchen in Südamerika beschrieben. Kessel u. Mitarb. (1931) beobachteten sie 1930 als Spontanerkrankung in kalifornischen Kaninchenbeständen. Aragao (1927) und Martin (1934/35) machten Vorschläge zur Bekämpfung der australischen Wildkaninchenplage mit Hilfe dieser Seuche. Nach vorbereitenden Arbeiten, besonders von Bull und Mules (1944), setzte diese Aktion 1950/51 ein und führte in den Jahren 1952–1954 zu einer äußerst starken Dezimierung der Bestände [Lines (1952), Fenner (1952), Fenner und Woodroofe (1953), Bull, Ratcliffe und Edgar (1953), Brereton (1953) u. v. a.]. 1952 nahm dann von Frankreich aus infolge fahrlässiger experimenteller Infektion von 2 Wildkaninchen die Seuche ihren Ausgang und hatte bis Ende 1955 praktisch ganz Westeuropa einschließlich der Britischen Inseln sowie Teile Mittel- und Südeuropas ergriffen [Jacotot und Vallée (1953), Ramon (1953a, b), Devis (1953), Akkermans (1953), Siegmann und Woernle (1954), Zureck (1956) u. v. a.].
Chapter
Den Kliniker weisen ungezählte Beobachtungen am Krankenbett, insbesondere bei Kranken mit Berufskrebsen darauf hin, daß Krebs in der großen Mehrzahl der Fälle ein örtliches Leiden, ausgelöst durch exogene Faktoren, darstellt. Darin liegt bei aller scheinbaren Trostlosigkeit des Krebsproblems doch ein gewisser Trost: Krebs ist nicht ohne weiteres ein unentrinnbares Fatum, sondern als örtlich verursachtes Leiden in einem beachtlichen Prozentsatz durch örtliche Maßnahmen heilbar und mit forschreitender Kenntnis der exogenen Krebsursachen in steigendem Maße vermeidbar.
Chapter
Die Fähigkeit, aus der Umwelt aufgenommene Substanzen unter Angleichung zum eigenen Aufbau zu benutzen (Stoffwechsel und Wachstum, Bedingungen des individuellen Lebens) und die eigene Art durch Bildung neuer, gleichartiger Lebewesen zu erhalten und zu vermehren (Fortpflanzung, Bedingung des Lebens der Art), ist allen belebten Organismen gemeinsam. Wir finden sie beim primitivsten Einzeller nicht weniger als bei Pflanze, Tier und Mensch. Diese „vegetativen Funktionen“ gelten deshalb mit Recht als Kriterium des Lebens.
Chapter
It is conventional, and convenient, to recognise both antibody-mediated and cell-mediated immune responses to viral infections. Both processes are complex, and there are complex interactions between them, but detailed descriptions of the immune response to some viral infections are available. The antigenic targets are both virions and virus-infected cells that are marked with viral products. The immune response acts to combat initial lodgement of the virus and to prevent reinfection, to modulate the clinical response during an episode of acute infection, and to influence the development of persistent infection. Events that impair immune responsiveness modify the course of infections; sometimes the infecting virus itself contributes to immunosuppression. We understand no infectious disease unless we understand the immune events that determine the clinical outcome. Immune responsiveness is exploited in the diagnosis of viral disease and in the induction of immunity with viral vaccines.
Article
The two groups of viruses to be discussed in this chapter are apparently dissimilar, although they do share DNA as their essential component. The papilloma viruses belong to the papovavirus group and are included in the medium-sized DNA viruses, while myxoma virus and its allied agents belong to the larger DNA viruses of the pox group. Nevertheless, an acceptable basis for bringing them together may derive from the fact that they both are literally the most “classical” tumor viruses (Shope, 1932, 1933). Two viruses representing these groups, Shope papilloma and myxoma, have played a very important role in setting the stage for the earliest identification of tumor viruses in mammalian species; they were first reported by the pioneering investigator in the field, Richard Shope. The other feature common to them is that the tumors they induce are benign in the sense that the tumor cells rarely metastasize to remote tissues and organs. In many cases, even spontaneous regression is not uncommon. However, myxoma virus as an infectious agent can be lethal to the host.
Chapter
Most genital human papillomavirus (HPV) infections are benign. Subclinical genital infections with HPV are extremely common. Genital HPV infections cause a spectrum of diseases, ranging from asymptomatic infection to invasive cervical cancer. The HPV types are divided into low- and high-risk viruses, based on their association with cervical cancer. When the low-risk HPV infections are clinically expressed, they produce external genital warts. Once clinically apparent, they may persist, spread, grow, spontaneously regress, and/or recur. The high-risk HPV types cause abnormal Pap smears, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), atypical squamous cells of uncertain significance (ASCUS), and atypical glandular cells of uncertain significance (AGUS). When the high-risk HPV types are clinically recognized on the external genital area, they cause formation of papular lesions. A useful strategy for HPV control is immunotherapy. Adoptive cellular transfers involve collection of the cells involved in host defenses from patients with cervical cancer; then growing these cells; activating them ex vivo by cytokines, such as the recombinant IL-2; and transferring them back to the cancer patient as therapy.
Article
To the busy, practicing dermatologist, an animal model system may appear to offer little benefit to patient diagnosis or management; however, animal model systems often can provide answers to vexing clinical problems that cannot be approached in patient studies because of ethical restrictions or logistic problems. Animal models are imperfect substitutes for human diseases; but because they share similar mechanisms, an animal model can provide an opportunity to test hypotheses that contribute to an understanding of the human counterparts.The Shope rabbit papilloma is remarkably similar in etiology and mechanism to many naturally occurring lesions induced by human papillomaviruses. In that sense, the Shope system can contribute to an understanding of human wart-virus infections. In a broader context, the Shope papilloma-carcinoma complex can provide an understanding of the determinants of neoplastic progression and of host interactions with neoplastic tissue.The purpose of this report will be to review some of the more important aspects of this experimental tumor system, especially those that are relevant to clinical situations. This review will be limited in scope. For more detailed coverage, the reader is referred to another article which we published elsewhere.1
Chapter
Weit vor der Zeitrechnung wurde der Begriff Carcinoma von Hippokrates für eine Geschwulstkrankheit des Menschen eingeführt, die nach wie vor den Arzt und die Patienten gleichermaßen beunruhigt. Gestützt auf die Beobachtung erneut auftretender Tumoren im Operationsbereich entfernter Krebsgeschwülste, drängte sich schon früh die Frage nach den Bedingungen und nach der Natur der Faktoren auf, die eine Übertragbarkeit des Krebses möglich machen. Engel-Reimers und Reincke teilten 1870 Befund und Verlauf zweier Fälle von Impfrezidiven in Punktionskanälen bei carcinomatöser Peritonitis mit. E. Hahn (1888) transplantierte bei einer Frau mit einem inoperablen Mamma-Carcinom gesunde Haut und verpflanzte auf die Entnahmestelle die exstirpierte carcinomatöse Haut und mußte nach 6 Wochen feststellen, daß die Geschwulstknötchen in das gesunde Gewebe hineinwucherten. Über zwei ähnliche Versuche eines anonymen Chirurgen berichten Cornil (1891) unter berechtigtem Protest vieler Mitglieder der Akademie der Wissenschaft in Paris.
Article
Vascular puncture inoculation (VPI) of plant viruses previously has been conducted either manually or by use of a commercial engraving tool and laboratory-fabricated needle arrays. In an effort to improve this technique, a linear-motion tattoo machine driving industry-standard needle arrays was tested as a means of delivering plant viruses into maize and small grain seed embryos. The new method was applied in the successful transmission of maize rayado fino virus (MRFV), the type member of the genus Marafivirus, from an archived sample to maize. Subsequent transfer of MRFV from the sap of an infected plant using the method produced an average infection rate in maize of 70% (range 39–93%). Maize, oat, and triticale were successfully infected with oat blue dwarf virus (OBDV) using the method; similar infection rates were observed between maize seeds inoculated with the tattoo machine and those inoculated with the engraving machine when using prefabricated needle arrays. No infection was obtained in repeated tests with barley yellow dwarf virus (BYDV-PAV) or cereal yellow dwarf virus (CYDV-RPV) using either sap or RNA from infectious cloned cDNA. Replacement of the original engraving-tool with a linear-motion tattoo machine in VPI provides greater flexibility and convenience in a quiet, readily-available instrument, while improving reproducibility through the use of prefabricated needle arrays. KeywordsLuteovirus–Marafivirus–Mechanical inoculation
Article
1. A report is given of a malignant tumor in tropical cultivated fish which is not yet described in the literature and which is apparently caused by a virus, since it can be transferred by cell-free extracts. 2. The infectious parcticles can be centrifuged out at 40,000 to 50,000 rev. |min. from the tumor extract, and are rapidly inactivated in 50% glycerine and by drying. 3. Out of 9 types of fish tested, 4 became infected while 5 other nearly related types were resistant. Of the sensitive sorts, lebistes reticulatus is the most predisposed although the embryos and young fish are resistant. After the first 2 to 4 weeks of life, this juvenile resistance is completely lost. 4. The latent period is individually different, but in the majority of experimental animals it was found to be between 25 and 40 days. 5. The tumors occur most frequently in the kidneys, and then wander through the body cavities and destroy the musculature, heart and intestine. The liver, spleen, ovaries and brain are not attacked. According to the histological picture, it appears to be a largely undifferentiated, mesenchymal tumor, which can evidently occur in different organs. 6. Since the tumors often wander into the bloodstream and their cells possess only a slight degree of cohesion, spreading of the tumor by way of the bloodstream (metastase formation) is very probable.
Article
The application of methylcholanthrene and tar to virus-induced papillomas of the domestic rabbit caused them to become carcinomatous with great rapidity, and the malignant changes were frequently multiple. In bringing on the cancers the chemical agents acted in their specific capacity as carcinogens, not as ordinary stimulants of cell proliferation. The cancers derived from the virus-infected cells and were of the same types as arise from these elements spontaneously after a much longer time. The evidence would seem to indicate that the chemical carcinogens acted by way of the virus.
Article
The virus-induced papillomas of cottontail as well as domestic rabbits regress completely within a few weeks when exposed to 5,000 r of x-ray irradiation. The x-rays do not immediately kill the papilloma cells, but lead to death by inhibiting cellular division and producing pathological changes in the cells which then continue to differentiate. The virus associated with the growths, however, not only persists in undiminished amount during regression, but often an increased yield of it can be obtained on extraction. The fibroma virus in crude extracts or in vivo is inactivated by far less irradiation than the papilloma virus. 10,000 r destroys 90 per cent or more of the infectivity of the fibroma virus, whereas at least 100,000 r is required to inactivate 50 per cent of the papilloma virus in extracts containing about the same amount of protein. No variant of the papilloma virus or fibroma virus has been encountered as a result of the irradiation.
Article
Papillomas occur frequently on the oral mucosa of domestic rabbits procured in the metropolitan area of New York. They are small and benign, and are situated mostly on the under side of the tongue. A filtrable virus can be extracted from them with which growths can be reproduced in the oral mucosa of several species of rabbits and hares but which fails to cause lesions when inoculated into other rabbit tissues and into the oral mucosa of other species. The virus differs notably from the Shope virus, which causes cutaneous papillomas in rabbits but proves innocuous to oral mucosa: rabbits solidly immune to the oral papilloma virus are fully susceptible to the Shope virus and vice versa. The oral papillomas are not highly contagious, for susceptible animals kept in individual cages in the same rooms with others carrying the growths, fed the same kind of food, and cared for by the same attendants, do not "catch" them. They are found much more frequently in the offspring of dams that carry the growths than in those of mothers free from them, and the causative virus can be recovered from the mouth washings of rabbits having no growths. The observations indicate that the virus may be spread by transfer from the mother to the young during the period of suckling, and that it may lie latent in the mouth, doing no harm unless the mucous membrane is injured. The slight trauma occurring now and then when coarse foods are chewed may furnish the required tissue nidus under natural conditions, for papillomas occasionally appear after virus has been dropped into the mouths of uninoculated rabbits; but the more extensive injury and healing resulting from experimental tattoo inoculations proves regularly effective in this respect. Tar can also act as an efficient adjuvant to the virus, the incidence of "spontaneous" oral papillomas being much higher in domestic rabbits that had had the opportunity to lick tar from their ears and paws during long periods than in normal control animals. The virus is recoverable in quantity from the oral papillomas of tarred domestic rabbits, and the findings indicate that it is their essential cause, the tar acting merely to prepare the tissue for the virus' action. For the same tar does not elicit oral papillomas in wild cottontail rabbits, which do not carry the causative virus though fully susceptible to it. The implications of the findings are discussed.
Article
Continued serological investigations of the sedimentable constituents of normal and neoplastic tissues have shown that the blood serum of normal rabbits will fix complement in mixture with saline extracts of normal rabbit tissues. The phenomenon has proved referable, not to anticomplementary effects of serum or antigen nor to so called non-specific complement fixation, but to a naturally occurring serum principle, hitherto unrecognized, which reacts specifically in vitro with a sedimentable constituent of normal tissue cells. The principle exists in the blood of nearly all adult rabbits but is absent from that of rabbits less than 1 month old. It can be salted out from serum with ammonium sulfate and is destroyed when heated at 65 degrees C. for 20 to 30 minutes. Its titer was found to run parallel in general with that of two natural antibodies also present in normal rabbit's blood (natural Wassermann reagin, natural anti-sheep hemolysin); but absorption tests showed it to be distinct from these. Because of its properties, the serum principle has been termed the natural tissue antibody. The substance with which the natural tissue antibody reacts is regularly present in saline extracts of many normal tissues,-those of rabbits and of other species as well. Kidney and liver tissues always yield it in abundance, while spleen, brain, and testicle provide somewhat less; heart and voluntary muscle extracts contain relatively little, and non-nucleated erythrocytes and skin are practically devoid of it. The results of affinity and absorption tests indicate that it is nearly or quite the same from whatever tissue or species derived. It is readily sedimentable in the high-speed centrifuge, little or none remaining in the supernatant liquid of potent suspensions spun at 25,000 R.P.M. (45,400 g) for 1 hour. It either does not come away into alcohol or is inactivated thereby, is readily destroyed by heat (56-70 degrees C. for 30 minutes), and diminishes notably in antigenic potency upon standing overnight in saline suspension or when the tissues containing it are kept in glycerol. Its properties suggest that it may be a protein. The implications of the findings are discussed in relation to the formation of the natural antibody and its place amongst serological phenomena, to so called "non-specific" fixation of complement and other serological complexities, and with particular reference to the character of the sedimentable constituents of normal and neoplastic tissue cells.
Article
The V2 carcinoma-a transplanted rabbit cancer derived originally from a virus-induced papilloma and carrying in masked or altered form the virus primarily responsible for it-was propagated in five successive groups of animals all previously hyperimmunized against the papilloma virus. The cancer grew as well in the hyperimmunized hosts as in normal animals implanted during the same months; and serological tests, made when the tumor was eventually returned to ordinary hosts, proved that the virus was still associated with the carcinoma cells: it had increased to the usual extent as the tumor grew in the hyperimmune animals. The continued increase of the neoplastic virus during propagation of the V2 carcinoma in hyperimmunized hosts contrasts sharply with the elimination of certain extraneous passenger viruses when the tumors they ride upon are grown in hosts previously immunized against them. The facts as a whole would seem to warrant a distinction between the enduring partnership of a neoplastic virus and carcinoma cells on the one hand and the casual association of passenger viruses with tumor cells on the other.
Article
The foregoing experiments have shown that the causative virus is usually "masked" in the large, disorderly, fissured and inflamed papillomas of cottontails when antiviral antibody is present in quantity in their blood, though virus can be recovered as a rule from the smaller, discrete, well ordered papillomas of these rabbits, almost irrespective of the amount of antibody in the blood of the individuals bearing them. Other findings are described which indicate that the masking of the virus in the large fissured growths is due to serum antibody present in them as result of exudation or hemorrhage, which neutralizes the virus when the growths are extracted or preserved in vitro. The local conditions that favor extravasation of serum (and the accumulation of antibody) prevail as a rule in the large, confluent growths arising after virus has been sown broadcast on scarified skin, but to lesser extent or not at all in the discrete papillomas that occur naturally or as result of tattoo inoculation. The state of affairs is notably different in the papillomas of domestic rabbits. The virus is regularly masked in these, and usually masked completely, even when there is little antibody in the blood and the local conditions do not favor its extravasation into the growths. The findings indicate that something other than antibody is primarily responsible for the masking in this species.
Article
All the strains of the Shope virus thus far tested which give rise to vigorous, progressively enlarging papillomas in domestic rabbits, function as carcinogenic agents by way of these growths. The more pathogenic the virus as evidenced by the brevity of its incubation period and the vigor of the papillomas produced, the sooner and oftener does cancer occur. The number of virus entities contained in the inoculum notably influences the outcome, cancer appearing most frequently in those confluent, papillomatous masses which have resulted from the greatest concentration of the virus material under test. The papillomas experimentally induced by the ordinary inoculation methods are essentially aggregates of proliferating cell families, each the outcome of some primary cell-virus association. Some of these associations are followed more frequently by cancer than others are in the same animal. Cottontail rabbits, the natural hosts of the virus, are notably resistant to its sustained activity, as compared with domestic rabbits. Though often growing rapidly at first, the papillomas of cottontails soon become relatively inert in most cases, and they usually retrogress, and rarely undergo malignant change. In an instance here reported both a squamous cell carcinoma and a metastasizing sarcoma appeared at the base of some papillomas due to experimental inoculation, which had existed on the ears of a cottontail for nearly 2 years. The meaning of the phenomena is discussed.
Article
Methods were developed for a study of the relations existing between viruses and living cells. It was found that vaccinia and the virus causing the infectious fibroma of rabbits (Shope) rapidly become fixed upon tissue cells freed as individuals and submitted to virus in suspension. This happens whether the cells are alive or have been killed with heat or ultraviolet light. The virus does not come away during agitation of the cells with Tyrode solution and repeated washings with large amounts of it. The exposure to neutralizing antisera of cells carrying virus fails to affect this latter significantly if the cells are alive, whereas if they are dead the activity of the virus is nullified. Cells freed as individuals from tissue cultures of vaccinia and the Shope tumor carry these viruses in abundance through repeated washings, and, if living, protect them from the influence of a neutralizing serum, whereas killed cells exert no such protection. The findings would appear to throw light on the way in which viruses gain a foothold in the host; and they suggest reasons for the persistence of some viruses in recovered animals and for the unsatisfactory results of serum treatment instituted during the course of virus diseases. The virus causing the Shope fibroma has been successfully maintained in cultures of the growth. It is closely associated with the cells, almost none being present in the culture fluid. Certain of its other attributes have been determined. Vaccinia greatly damages the cells of cultures of rabbit embryo in which it is under propagation.
Article
Rabbit papillomas developing on the skin as the result of virus inoculation can be readily transferred to the inner organs of favorable hosts by implanting bits of the living tissue. The growths thus produced proliferate actively as a rule and frequently cause death. Often they are markedly invasive and destructive; and they tend to recur after excision. Bacterial infection may greatly enhance their malignancy. Accidental dissemination may occur during operation, and distribution to the peritoneal surface has been repeatedly noted. There may be no cellular reaction whatever about the invading epithelium of interior growths, but usually some new formation of connective tissue takes place, its amount varying inversely with the rate of epithelial proliferation. An immediate reason exists for the inflammatory changes and scarring found beneath long-established skin papillomas, in the trauma and secondary infection to which the projecting, necrotizing masses have been subjected. In animals dying of progressively enlarging interior growths the skin papilloma may long have been stationary in size. The growths appearing after the transfer of papillomatous tissue to the inner organs are due to the survival and multiplication of transplanted cells. However, the virus can be readily recovered from them, in the case of wild rabbits. No distinctive changes in the blood of the host have been found. The virus itself is highly specific for the epithelium of the skin, failing to act not only upon that of the other organs thus far tested but even upon embryonic skin. The papilloma frequently penetrates into the blood and lymph vessels, especially at the edge of implantation growths. The intravascular injection of fragments of it sometimes results in pulmonary nodules of characteristic morphology. These are due to survival and proliferation of the injected cells. Secondary nodules have been encountered at autopsy in a lymph gland and in the lungs, but under conditions more suggestive of operative dissemination of the growth than of true metastasis. Implantation growths of the papilloma in favorable hosts have the morphology of epidermoid tumors of greater or less malignancy. They behave as these do and elicit similar changes in the surrounding tissue. The attributes and potentialities of the papilloma will be further considered in Papers II and III.
Article
A papilloma has been observed in wild cottontail rabbits and has been found to be transmissible to both wild and domestic rabbits. The clinical and pathological pictures of the condition have been described. It has been found that the causative agent is readily filtrable through Berkefeld but not regularly through Seitz filters, that it stores well in glycerol, that it is still active after heating to 67 degrees C. for 30 minutes, but not after heating to 70 degrees C., and that it exhibits a marked tropism for cutaneous epithelium. The activities and properties of the papilloma-producing agent warrant its classification as a filtrable virus. Rabbits carrying experimentally produced papillomata are partially or completely immune to reinfection and, furthermore, their sera partially or completely neutralize the causative virus. The disease is transmissible in series through wild rabbits and virus of wild rabbit origin is readily transmissible to domestic rabbits, producing in this species papillomata identical in appearance with those found in wild rabbits. However, the condition is not transmissible in series through domestic rabbits. The possible significance of this observation has been discussed. The virus of infectious papillomatosis is not related immunologically to either the virus of infectious fibroma or to that of infectious myxoma of rabbits.
Article
The phenomena of natural and acquired resistance to transplanted chicken tumors strikingly resemble those observed in the case of transplanted mammalian growths; and no more than those do they suggest that the tumors have an extrinsic cause. That there may exist in fowls implanted with a chicken tumor a resistance directed against the tumor-causing agent distinct from the resistance manifested against the alien tumor cells has been shown in a previous article. Both sorts of resistance are present in a fowl in which a tumor has retrogressed, the resistance in such an instance being acquired. That directed against the agent is largely specific, giving little if any protection against the agents causing other tumors. There is some evidence that the conditions upon which a fowl's natural resistance depends are the same for the agents causing different chicken tumors. It has proved impossible to protect chickens against the agent causing the simple sarcoma by injecting them with dried tumor material in which this agent has been attenuated by heat. The transfer of blood from resistant fowls to fowls with growing tumors is in our experience void of effect on the tumors.
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