Showing papers by "Herbert C. Morse published in 1995"

Cells and cytokines in the pathogenesis of MAIDS, a retrovirus-induced immunodeficiency syndrome of mice

Abstract: MAIDS is a retrovirus-induced immunodeficiency syndrome of mice that develops as a consequence of multiple interactions between T and B cells. The disease develops in response to infection with a defective virus encoding a Pr60gag protein that is myristylated and binds to cell membranes. T cells, B cells, and macrophages are all targets for infection by the defective virus, and some direct effects of infection have been demonstrated for T cells in the absence of other cell types. It is not known if the defective virus has direct effects on B cells and macrophages. It is clear, however, that an unusually vigorous response of the immune system to the inciting virus elicits deregulated expression of numerous cytokines. This response is antigen driven, as it does not develop in mice lacking MHC class II molecules, but the nature of the antigenic molecule is not known. Other T cell-B cell interactions of major importance to induction of disease include those mediated by ligation of CD40/CD40L and CD11a/CD54. It would appear that a significant component of the abnormal response is due to stimulation of T cells through the TCR in the absence of efficient co-stimulation, resulting in generalized anergy. The pattern of cytokine expression in MAIDS-susceptible mice — high IL-4, IL-10, and IFN-γ and low IL2 — is consistent with this model. By further increasing IFN-γ expression through treatment of mice with IL-12, it is possible to inhibit induction of disease and to reverse many manifestation of established disease. Disease inhibition by IL-12 can be ascribed in part to effects in limiting expression of the etiological virus. IL-12 may prove to be an effective treatment for other retrovirus infections with similar immunopathogenesis.

Modulation of specific T cell responses by concurrent infection with Leishmania major and LP-BM5 murine leukemia viruses

Abstract: C57BL/6 mice infected with a murine leukemia virus (MuLV) mixture designated LP-BM5 develop an immunodeficiency syndrome termed MAIDS, characterized by a variety of T and B cell abnormalities, including elevated levels of IgE, suggesting that IL-4 expression is increased in these animals. It has been suggested that the immunodeficiency associated with MAIDS is caused by a conversion of immune responses normally characterized by Th1 development towards a Th2-dominated response. Mice of the same strain, infected with Leishmania major, mount a protective Th1 response with the induction of high levels of IFN-gamma and undetectable IL-4. We therefore infected mice with L. major at differing time points before and after virus infection and assessed the effects on T cell responsiveness, cytokine production and survival to L. major, as well as the effect on MAIDS-associated pathology. We have also immunized C57BL/6 mice with trinitrophenol-keyhole limpet haemocyanin (TNP-KLH), which leads to a predominantly Th2 response, and compared the effects of MAIDS on the response to TNP-KLH with the effect of MAIDS on L. major infection. Our results show that significant immunodeficiency with regard to infection by L. major is only apparent after 8 weeks of LP-BM5 MuLV infection, by which time T and B cell defects are well advanced. Further, we have found that the strongly polarized Th1 response stimulated by L. major infection can modulate the effect of MAIDS on T cells, leading to the survival of antigen-specific T cells. Our results suggest that the impairment of immune responses to either TNP-KLH or L. major is due not to an alteration of the balance of Th1/Th2 subsets but to a general loss of reactivity in antigen-specific CD4+ cells. However, prior activation of Th1 but not Th2 cells can inhibit the development of lymphoproliferation and immunodeficiency caused by MAIDS.

Classification of mouse lymphomas.

Abstract: We have applied the Kiel Classification of human lymphomas (Lennert and Feller 1992) to a series of mouse lymphomas (Table 1). In our survey, some came from other sources but most were from mice congenic for ecotropic murine leukemia virus induction loci and expressing high levels of endogenous leukemia viruses. Although such expression is associated with lymphoma development (Fredrickson et al. 1984), the proposed classification is considered generally applicable irrespective of etiology, since thymic lymphomas induced chemically with virus (Joshi and Frei 1970) or occurring in transgenic mice (Pattengale 1994) are morphologically similar. The classification attempts to provide a diagnosis based on morphology supported by molecular and immunologic analysis.

Effects of exogenous, nonleukemogenic, ecotropic murine leukemia virus infections on the immune systems of adult C57BL/6 mice.

Abstract: Mouse AIDS (MAIDS) develops in mice infected with a mixture of replication-competent ecotropic and mink lung cell focus-inducing murine leukemia viruses and an etiologic replication-defective virus. Helper viruses are not required for induction of MAIDS, but the time course of disease is accelerated in their presence. To understand the possible contributions of ectropic murine leukemia viruses to MAIDS pathogenesis, we biologically cloned a series of viruses from the MAIDS-inducing LP-BM5 virus mixture. These viruses were examined for replication in tissues of infected mice and for effects on the immune system. All virus stocks replicated efficiently in mice. Infected animals showed slight lymphadenopathy and splenomegaly due primarily to B-cell proliferation associated with differentiation to immunoglobulin secretion resulting in twofold increases in serum immunoglobulin M levels; however, B-cell responses to helper T-cell-independent antigens were increased rather than decreased as in MAIDS. Analyses of CD8+ T-cell function showed that cytotoxic T-lymphocyte responses to alloantigens were comparable in control and infected mice. Finally, we showed that infection resulted in enhanced expression of transcripts for interleukin-10, interleukin-4, and gamma interferon. These cytokines can all contribute to B-cell activation and may promote the expansion of a target cell population for the MAIDS defective virus.

Impact of mhc class i gene on resistance to murine aids

Abstract: Development of murine AIDS in mice following infection with LP-BM5 murine leukaemia virus (MuLV) is highly strain dependent, with strain differences determined by genes within and outside H-2. Among H-2 genes, the Dd gene is the most closely associated with resistance to LP-BM5 MuLV infection. However, the Dd-mediated resistance is highly influenced by outside H-2 genes, i.e. A lineage strains are more resistant than mice strains of B6/B10 lineage. In this study, the mice having BALB background were analysed and, similarly to A lineage mice, only Dd gene products were found to be required to provide resistance to LP-BM5 MuLV infection. Furthermore, BALB/c Kh mice bearing both Dd and Ld genes clearly showed obviously higher resistance than BALB/c-H-2dm2 mice solely having the Dd gene. In addition, in the long-term observation of the effect of the Dd gene on B6/B10 background mice, D8 mice having the Dd gene as a transgene and expressing a high level Dd gene product showed higher resistance than naturally recombinant B10.A(18R) mice. These results suggest that the MAIDS resistance associated with the D end loci is dependent on the level of expression of an MHC class I gene.