Inflammatory cells and mediators in the pathogenesis of feline vaccine-associated sarcoma.

摘要

Feline vaccine-associated sarcomas (VAS) develop in 0.1 to 0.01 per cent of vaccinated cats in association with chronic inflammation after vaccination with killed, adjuvanted vaccines, especially those containing rabies and leukemia virus. Their exact mechanism of pathogenesis is unknown. Goals of the present study were to identify key cellular and biochemical factors in feline vaccine-site inflammation and to test for expression of a regulatory protein at vaccine sites, which may be important in tumorigenesis.; Histologic analysis of vaccine site tissue revealed that cats produce more lymphocytes at rabies vaccine sites and more eosinophils at some sites than mink or ferrets. An inflammatory cell influx time-line was established. More macrophages were produced at sites of adjuvanted vaccines than non-adjuvanted vaccines. Mink dermal lymph nodes were first described.; Immunofluorescence revealed that major histocompatibility complex (MHC) class II and CD11b are prominent cell surface markers in feline vaccine site tissue; CD3/CD4 were next in prevalence. A VAS was MHC Class II- and CD11b-positive. This was the first report of CD11b-positive fibroblasts and of CD11b-positive VAS cells.; Messenger RNA levels of interferon (IFN)-γ, tumor necrosis factor-α, interleukin-10 and transforming growth factor-β, wound-associated cytokines, were elevated in feline vaccine site tissue over normal dermis. Highest cytokine mRNA levels were at giardia vaccine sites. IFN-γ mRNA was elevated at 2 of 6 cats at non-adjuvanted rabies vaccine sites. Platelet-derived growth factor, basic fibroblast growth factor and epidermal growth factor stimulated DNA synthesis in vitro in normal and neoplastic feline fibroblasts. TGF-β stimulated or inhibited DNA synthesis depending on whether it preceded or followed PDGF-incubation. Supernatants from cultured adjuvanted rabies and leukemia vaccine-site tissue suppressed DNA synthesis in VAS cells and feline fibroblasts.; P53, a cell cycle regulator, was detected in 65% of 52 VAS tested. Cytoplasmic or nuclear P53 was detected in 13 vaccine-site tissues; location was antibody-dependent. Immunoblots showed P53 bands stronger at rabies and leukemia vaccine sites than in normal tissue. Phagocyte-produced reactive oxygen species and genetically determined cytokine levels at adjuvanted vaccine sites may result in increased expression, possibly signifying P53 mutation, which could contribute to multi-step tumorigenesis and vaccine-associated sarcoma.