Malignant Rabbit Fibroma Virus Research Articles

Immunologic dysfunction during viral oncogenesis. I. Nonspecific immunosuppression caused by malignant rabbit fibroma virus.

Malignant rabbit fibroma virus (MV) is a potent oncogenic poxvirus that produces a rapidly progressive syndrome of disseminated myxosarcoma, immunosuppression, and fatal gram-negative infection. MV is probably a recombinant between Shope fibroma virus (SFV) and rabbit myxoma virus, and is capable of preventing or aborting the in vitro proliferative responses of rabbit lymphocytes to B and T lymphocyte mitogens. Proliferative responses to sheep erythrocytes (SRBC) are similarly affected, although MV does not alter ongoing antibody responses to SRBC. Splenic lymphocytes from MV tumor-bearing rabbits suppress antibody and proliferative responses to SRBC when added to lymphocytes from SRBC-primed rabbits. Finally, lysates of cultured splenic lymphocytes from rabbits given MV suppress both proliferative and antibody-forming responses to SRBC. When MV is removed from these lysates by UV inactivation or by centrifugation, the suppressive activity remains. We therefore conclude that MV induces immunologic unresponsiveness in rabbits by at least two mechanisms. First, a direct suppressive effect of added virus on in vitro lymphocyte proliferation is seen. There is no effect in this situation if an antibody response is already in progress. Second, spleen cells exposed to MV in vivo produce one or more soluble factors capable of suppressing both proliferative and antibody responses of normal lymphocytes.

Malignant Rabbit Fibroma Virus: Observations on the Culture and Histopathologic Characteristics of a New Virus-Induced Rabbit Tumor<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>

The clinical, histopathologic, and cultural characteristics of a newly isolated poxvirus, malignant rabbit fibroma virus (MV), were investigated. MV was isolated from tumors induced by an uncloned stock of Shope fibroma virus (SFV). MV, SFV, and rabbit myxoma virus were compared. Similarly to myxoma virus, MV grew to higher titer in vitro than did SFV and produced plaques rather than foci on rabbit kidney cell monolayers. Unlike the local, self-limited fibroblastic proliferations observed in SFV recipients, MV and myxoma caused a fulminant clinical syndrome characterized by malignant histology, metastases, and supervening fatal gram-negative infection with Pasteurella multocida. MV induced a large, protuberant local tumor and discrete metastases histologically resembling myxosarcomas. Draining lymph nodes contained metastases and showed diffuse cortical hyperplasia. Kupffer's cells were prominent in the liver, and macrophages were abundant in the splenic sinusoids. The lungs and trachea were spared, but the conjunctiva and nasal mucosa showed squamous metaplasia and atypia, with overlying Pasteurella infection and underlying tumor. Myxoma virus infection produced similar mucosal changes, but both of these as well as the epidermis overlying the myxomas showed cytoplasmic virus inclusions. Neither the skin nor the epithelial surfaces overlying MV-induced tumors nor the tumors themselves contained virus inclusions. Thus the tumor syndrome caused by MV differed from other known rabbit tumors. Endonuclease restriction digests showed that the MV genome resembled, but was distinct from, rabbit myxoma virus. Opportunistic infection associated with MV-induced disseminated tumor may be an experimental model for the infectious complications that often supervene in host-tumor relationships.

Immunohistology of Malignant Rabbit Fibroma Virus—a Comparative Study With Rabbit Myxoma Virus<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>

Malignant rabbit fibroma virus (MV) causes a syndrome that consists of disseminated malignant tumors and immunosuppression complicated by severe Pasteurella multocida infection and death. Tissues from rabbits given MV and rabbit myxoma virus were examined by direct immunofluorescence with the use of antibody against virus antigens. Primary and metastatic tumors caused by MV and rabbit myxoma virus were composed of soft tissue cells containing virus antigens. Skin appendages and epidermis overlying the respective tumors showed scant MV but abundant myxoma virus antigen. Both viruses were present systemically in the reticuloendothelial system. Epithelial cells from the liver, kidney, and lung of myxoma virus-infected rabbits contained virus, whereas in MV tumor-bearing rabbits, these cells were uninvolved. However, nasal mucosal and conjunctival epithelia, the locations of Pasteurella infection, showed squamous metaplasia and contained large amounts of MV and myxoma antigens. By analogy to other respiratory tract pathogens, these epithelial changes were probably etiologically significant for development of pasteurellosis in rabbits bearing virus-induced tumors. Thus by immunopathologic as well as clinical examination, MV produces a syndrome distinct from that seen with rabbit myxoma virus. MV induced severe immunosuppression despite T-lymphocyte hyperplasia in the lymphoid tissues observed. The combination of a systemic virus infection, epithelial alterations that impaired clearance mechanisms, and immunologic dysfunction is likely to contribute to the inability of rabbits given MV to survive their gram-negative infection.

Malignant rabbit fibroma virus causes secondary immunosuppression in rabbits.

Shope fibroma virus (SFV) causes a localized, self-limited, fibroblastic proliferation in adult rabbits. Extracts of Shope fibroma tumors were found to contain a second virus that induces a rapidly progressive disseminated tumor. Dissemination of this malignant fibroma is associated with activation of commensal mucosal infection with Pasteurella multocida, causing purulent conjunctivitis and rhinitis and resulting in death from nasal obstruction. We have isolated this new agent by two cycles of plaque purification. It is a poxvirus that is antigenically virtually identical to SFV as measured by a plaque reduction assay, but behaves differently both in vivo and in vitro. We have called this virus malignant rabbit fibroma virus (MV). Electrophoresis of restriction digests made with HIND III indicates that despite the antigenic similarity of SFV and MV, the locations of HIND III sites in the two viral genomes are quite different. These experiments have enabled us to determine that MV was present in small quantities in our initial uncloned stock of Patuxent strain SFV. Lymphocytes from rabbits bearing MV-induced tumors responded poorly to both B and T lymphocyte mitogens. This nonspecific immunologic dysfunction is evident at or before the time when metastases and Gram-negative infection develop, and it becomes more profound as the disease progresses. MV-induced tumors may provide a model for Gram-negative infection and decreased immunologic responsiveness associated with malignancies.