Resistance to Marek's Disease Herpesvirus-induced Lymphoma is Multiphasic and Dependent on Host Genotype

Abstract

Abstract. Genotype-dependent differences in Marek's disease (MD) susceptibility were identified using 14-day-old line N and 6 1 (resistant) and 15I and 7 2 (susceptible) inbred chickens infected with HPRS-16 MD virus (MDV). All line 7 2 chickens developed progressive MD. Line 15I had fluctuating MD-specific clinical signs and individuals recovered. A novel histologic scoring system enabled indices to be calculated for lymphocyte infiltration into nonlymphoid organs. All genotypes had increased mean lesion scores (MLSs) and mean total lesion scores after MDV infection. These differed quantitatively and qualitatively between the genotypes. Lines 6 1 and 7 2 had a similar MLS distribution in the cytolytic phase, although scores were greater in line 7 2 . At the time lymphomas were visible in line 7 2 , histologic lesions in line 6 1 were regressing. AV37 ϩ cells were present in similar numbers in all genotypes in the cytolytic phase, suggesting that neoplastically transformed cells were present in all genotypes regardless of MD susceptibility. After the cytolytic phase, AV37ϩ cell numbers increased in lines 7 2 and 15I but decreased in lines 6 1 and N. In the cytolytic and latent phases, in all genotypes, most infiltrating cells were CD4 ϩ . After this time, line 7 2 and 15I lesions increased in size and most cells were CD4 ϩ ; line 6 1 and N lesions decreased in size and most cells were CD8ϩ . In all genotypes, AV37 immunostaining was weak in lesions with many CD8 ϩ cells, suggesting that AV37 antigen expression or AV37 ϩ cells were controlled by CD8 ϩ cells. The rank order, determined by clinical signs and pathology, for MD susceptibility (highest to lowest) was 7 2 Ͼ 15I Ͼ 6 1 Ͼ N.

BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken

“…There is little evidence that MHC-B genotypeassociated differences exist during the initial phase of infection, aside from the slightly delayed appearance of splenomegaly in MHC-B-resistant birds and occasional subtle differences in cytokine profiles [reviewed by (21); see also (22)(23)(24)]. However, by the end of the first 7-10 days post inoculation (dpi), substantial differences in MD pathogenesis become clearly evident.…”

“…However, by the end of the first 7-10 days post inoculation (dpi), substantial differences in MD pathogenesis become clearly evident. There is an abrupt decrease in the viral load in the white cells in resistant birds (23) that is accompanied by lower levels of infected T cells (25), relatively higher levels of virus-neutralizing antibodies (26), fewer AV37ϩ cells (22), and the absence of induction of the proinflammatory cytokines IL-6 and IL-18, which in contrast occurs in susceptible birds during the same interval (23). In the absence of complicating stress or infection, the genetically resistant birds remain healthy, with the only sign of active infection being the shedding of virus from the feather follicle.…”

Identification of the Neoplastically Transformed Cells in Marek's Disease Herpesvirus-Induced Lymphomas: Recognition by the Monoclonal Antibody AV37

“…The inbred chicken lines have been selected over many generations for susceptibility (lines 7 2 and 15I) or resistance (lines 6 1 and N) to MD. Fourteen-day-old chickens were infected with HPRS-16 MDV exactly as described previously (14). All animal work was done under and complied with United Kingdom Home Office regulations.…”

“…MDV is an accepted and naturally occurring in vivo animal model of herpesvirus oncology (18,30,105), but in common with other animal models, a major impediment to its utility is that the neoplastically transformed cells in MD lymphoma have not been identified. Previous work has suggested that a monoclonal antibody (MAb), AV37, recognizing a novel surface antigen expressed by MDV-transformed cell lines (MDCC) in vitro, identifies the neoplastically transformed cells in MD lymphomas (14,15,85). However, AV37…”

“…ϩ cells are present not only within the developing lymphomas of genetically susceptible chickens but also in the organs of resistant genotypes of chickens up to 21 days post-MDV infection (14). This suggests that AV37 ϩ cells may not be neoplastically transformed; the antigen recognized might merely be expressed by lymphocytes that are part of the inflammatory response.…”