RESUMO
Certain inbred mouse strains display progression to lymphoma development after infection with E-55+ murine leukemia virus (E-55+ MuLV), while others demonstrate long-term nonprogression. This difference in disease progression occurs despite the fact that E-55+ MuLV causes persistent infection in both immunocompetent BALB/c-H-2(k) (BALB.K) progressor (P) and C57BL/10-H-2(k) (B10.BR) long-term nonprogressor (LTNP) mice. In contrast to immunocompetent mice, immunosuppressed mice from both P and LTNP strains develop lymphomas about 2 months after infection, indicating that the LTNP phenotype is determined by the immune response of the infected mouse. In this study, we used bone marrow chimeras to demonstrate that the LTNP phenotype is associated with the genotype of donor bone marrow and not the recipient microenvironment. In addition, we have mapped a genetic locus that may be responsible for the LTNP trait. Microsatellite-based linkage analysis demonstrated that a non-major histocompatibility complex gene on chromosome 15 regulates long-term survival and is located in the same region as the Rfv3 gene. Rfv3 is involved in recovery from Friend virus-induced leukemia and has been demonstrated to regulate neutralizing virus antibody titers. In our studies, however, both P and LTNP strains produce similar titers of neutralizing and cytotoxic anti-E-55+ MuLV. Therefore, while it is possible that Rfv3 influences the course of E-55+ MuLV infection, it is more likely that the LTNP phenotype in E-55+ MuLV-infected mice is regulated by a different, closely linked gene.
Assuntos
Vírus da Leucemia Murina/imunologia , Leucemia Experimental/genética , Infecções por Retroviridae/genética , Animais , Células da Medula Óssea , Progressão da Doença , Suscetibilidade a Doenças , Ligação Genética , Imunidade Inata , Endogamia , Leucemia Experimental/imunologia , Leucemia Experimental/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologiaRESUMO
We have previously demonstrated a genetic predisposition among mice regarding their ability to be protected against vaginal candidiasis after peripheral immunization. Both BALB/c and (BALB/cx C57BL/6) F1 mice are protected against vaginal candidiasis after subcutaneous immunization with Candida albicans extract and C57BL/6 mice are not protected by this immunization. In the present study, the ability of F1-derived immune cells to transfer protection to naive parental strains was observed in BALB/c recipient mice, but not apparent in B6 recipient mice. This result is highly suggestive that the microenvironment of the B6 mouse is responsible for the susceptible phenotype. Genetic studies using (BALB/cx C57BL/6)F1x C57BL/6 backcross mice demonstrated that two genes appeared to regulate the protective effect of peripheral immunization to vaginal challenge. Microsatellite mapping indicated that candidate loci involved in controlling the immune response to vaginal candidiasis after peripheral immunization included the intercellular adhesion molecule-1 (ICAM-1), the Icam-1 related sequence 1, and the Fc epsilon RII (P<0.01). Thus, the ability of cells to bind to vaginal endothelial cells may play an important role in protection against vaginal candidiasis mediated by peripheral immunization.
Assuntos
Antígenos de Fungos/imunologia , Candida albicans/imunologia , Candidíase Vulvovaginal/prevenção & controle , Quimiotaxia de Leucócito , Imunização/métodos , Camundongos Endogâmicos BALB C/imunologia , Camundongos Endogâmicos C57BL/imunologia , Subpopulações de Linfócitos T/citologia , Vagina/imunologia , Animais , Antígenos de Fungos/administração & dosagem , Candidíase Vulvovaginal/imunologia , Cruzamentos Genéticos , Feminino , Predisposição Genética para Doença , Injeções Subcutâneas , Molécula 1 de Adesão Intercelular/genética , Camundongos , Camundongos Endogâmicos BALB C/genética , Camundongos Endogâmicos C57BL/genética , Repetições de Microssatélites , Mucosa/imunologia , Receptores de IgE/genética , Subpopulações de Linfócitos T/imunologiaRESUMO
In these studies, significant protection against experimental vaginal candidiasis after a subcutaneous immunization with Candida albicans extract was achieved in BALB/c mice but not in C57BL/6 (B6) mice. Protection from vaginal candidiasis was transferred to naive BALB/c mice by a population of spleen cells derived from immunized BALB/c mice. Removal of CD3 or CD4 but not CD8 T cells before transfer completely abrogated resistance to vaginal candidiasis. Recombinant inbred (RI) strains of mice derived from BALB/c and B6 strains were used for mapping loci that might be responsible for regulating vaginal protection after subcutaneous immunization. Linkage analysis using microsatellite-based genome mapping in these RI strains revealed four candidate loci on chromosomes 3, 7, 8, and 18 that exhibit statistically significant linkage to the strain distribution pattern. These results may contribute to the understanding of host genetic factors controlling the immune response to vaginal infections.
Assuntos
Candida albicans/imunologia , Candidíase Vulvovaginal/prevenção & controle , Vacinas Fúngicas/imunologia , Transferência Adotiva , Animais , Candidíase Vulvovaginal/imunologia , Feminino , Imunidade Inata/genética , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Especificidade da Espécie , Subpopulações de Linfócitos T/imunologia , VacinaçãoRESUMO
E-55+ murine leukemia virus infection of both progressor (BALB) and long term nonprogressor (C57BL) mouse strains is characterized by an acute and a persistent phase of infection. During the acute phase, progressor strains require CD8+ T cells to decrease virus burden, whereas the long term nonprogressor strains do not. In the present studies the immune response in BALB and C57BL mice during the acute phase of E-55+ murine leukemia virus infection was examined. The results demonstrate that BALB mice produce both IL-4 and IFN-gamma, in contrast to C57BL mice, which produce only IFN-gamma. In BALB mice, IL-4 production results in the absolute requirement for CD8+ T cells to reduce the virus burden during the acute phase of infection. The anti-virus immune response in these mice is IFN-gamma dependent. On the other hand, C57BL mice do not produce IL-4 and, in the absence of both CD8+ T cells and IFN-gamma, still generate an effective anti-virus immune response. Genetic studies suggest that these distinct immune responses are regulated by more than one non-MHC-linked gene. Two candidate regions that may encode this gene(s), located on chromosomes 7 and 19, respectively, were identified by recombinant inbred strain linkage analysis.
Assuntos
Vírus da Leucemia Murina/imunologia , Infecções por Retroviridae/imunologia , Infecções Tumorais por Vírus/imunologia , Doença Aguda , Animais , Citocinas/biossíntese , Suscetibilidade a Doenças , Ligação Genética , Imunidade Inata , Interferon gama/fisiologia , Interleucina-4/biossíntese , Interleucina-4/fisiologia , Leucemia Experimental/genética , Leucemia Experimental/imunologia , Leucemia Experimental/metabolismo , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Retroviridae/genética , Infecções por Retroviridae/metabolismo , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/metabolismoRESUMO
Previous studies from this laboratory have demonstrated that E-55+MuLV-infected BALB/c-H-2k (BALB.K) mice progress to develop thymic lymphoma about 7 months after infection whereas infected C57BL/10-H-2k (B10.BR) mice are long-term nonprogressors that fail to develop disease even after 2 years of infection. Both resistant long-term nonprogressor (B10.BR) and progressor (BALB.K) mice generate an early immune response that results in a dramatic decrease in the number of virus-infected cells. Despite this early immune response, mice from both strains become persistently infected. However, resistant B10.BR mice also demonstrate a late T-cell-mediated response that may be causally related to long-term nonprogression whereas susceptible BALB.K mice fail to demonstrate this late T-cell response. In the present studies, the T-cell subsets involved in the effective early immune response in both B10.BR and BALB.K mice as well as the late T-cell response in B10.BR mice were determined by in vivo antibody-mediated depletion. Results from these studies demonstrate that during the early acute phase of infection, elimination of CD4+ T cells ablated the ability of both BALB.K and B10.BR mice to decrease the burden of virus-infected cells. However, elimination of CD8+ T cells ablated this result in BALB.K but not B10.BR mice. Thus, despite the fact that both immunocompetent B10.BR and BALB.K mice are able to decrease the number of virus-infected cells during the early acute phase of infection, there is a difference in the T-cell subsets that mediate this effect in these strains of mice. In addition, characterization of the late immune response that keeps virus at very low levels during the persistent stage of virus infection in resistant B10.BR mice demonstrated that simultaneous elimination of both CD4+ and CD8+ T cells allowed the emergence of virus-infected cells whereas the elimination of either subset alone showed no effect compared to untreated control mice that are immunologically intact. Since B10.BR and BALB.K are identical with respect to their H-2k-haplotypes, it appears that the differences between these strains with respect to the generation of effective early and late anti-virus immune responses are regulated by a non-H-2-linked gene(s).
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vírus da Leucemia Murina/imunologia , Leucemia Experimental/imunologia , Infecções por Retroviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Infecções Tumorais por Vírus/imunologia , Doença Aguda , Animais , Feminino , Imunidade Inata/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
We have previously demonstrated that BALB/c-H-2k (BALB.K) mice are susceptible to the development of thymic lymphoma induced by E-55+ murine leukemia virus (MuLV). In the present studies, C57BL/10-H-2k (B10.BR) mice were found to be resistant to E-55+ MuLV-induced lymphoma despite the fact that these mice become persistently infected. This resistance to lymphomagensis is mediated by the anti-virus immune response since immunosuppressed mice progress to develop disease. The protective immune response in B10.BR mice is bimodal with respect to time after virus infection. The early immune response results in a dramatic decrease in the number of virus-infected cells within 4-8 weeks after infection. This decrease in virus-infected cells occurs in immunocompetent mice from strains that are either resistant (B10.BR) or susceptible (BALB.K) to E-55+ MuLV-induced disease. Subsequently, susceptible mice develop an increase in infected cells, whereas no increase in infected cells occurs in resistant mice despite the fact that they are persistently infected. This later phase of resistance in B10.BR appears to be mediated by T cells. Since B10.BR and BALB.K both express the H-2k haplotype, resistance appears to be mediated by a non-H-2-linked gene(s). (BALB.K x B10.BR)F1 mice are resistant to disease development, indicating resistance is a dominant trait.
Assuntos
Antígenos H-2/genética , Vírus da Leucemia Murina , Leucemia Experimental/imunologia , Infecções por Retroviridae/imunologia , Infecções Tumorais por Vírus/imunologia , Animais , Sequência de Bases , Primers do DNA , Feminino , Ligação Genética , Imunidade Inata/genética , Imunocompetência , Imunoterapia Adotiva , Vírus da Leucemia Murina/isolamento & purificação , Leucemia Experimental/genética , Leucemia Experimental/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Infecções por Retroviridae/genética , Infecções por Retroviridae/mortalidade , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/mortalidadeRESUMO
Although most inbred strains of mice contain endogenous retroviral sequences, these sequences are usually not capable of producing infectious retroviruses. In some cases, the retroviral sequences are small fragments of viral genomes. In a few cases the sequences for complete retroviruses exist, but contain small defects which prevent the production of infectious virus. While the ability of reversions of these defects to produce retroviruses has been studied by site-directed mutagenesis and chemical-mediated mutagenesis, the presence of spontaneously occurring reversions has not been completely evaluated. We characterized an infectious ecotropic retrovirus spontaneously expressed in aged DBA/2 mice, which carries the complete but defective Emv-3. Although this endogenously produced retrovirus was related to the endogenous Emv-3 sequence, it had undergone recombination with another retroviral sequence to correct the defect which resided in the gag of Emv-3. Thus, recombination of endogenous ecotropic retroviral sequences may be a mechanism to produce infectious retroviruses in adult animals that contributes to pathologic disease.
Assuntos
Genes gag , Vírus da Leucemia Murina/genética , Camundongos Endogâmicos DBA/microbiologia , Provírus/genética , Recombinação Genética , Células 3T3 , Envelhecimento , Sequência de Aminoácidos , Animais , Sequência de Bases , Masculino , Camundongos , Dados de Sequência MolecularRESUMO
The role of T lymphocytes in disseminated candidiasis in a mouse model of irradiation-induced immunosuppression was investigated. A continuously cultured Candida albicans-specific T-cell line mediated protection of sublethally irradiated mice from disseminated candidiasis as measured by both the fungal load in the kidneys and mortality. These results are the first to demonstrate directly a role for antigen-specific T cells in the protective immune response against murine disseminated candidiasis.