Research Interests: "My laboratory is interested in understanding the regulation of cytotoxic T-lymphocyte (CTL) activation, proliferation and survival during viral infection. Of particular interest is the role of CTL functional avidity." In the news... Dr. Alexander-Miller is part of a team of researchers at WFUBMC in the discovery and development of a colony of cancer-resistant mice. Their research suggests a genetic basis for resistance to certain types of cancer, and sheds light on the immune system's mechanism for fighting cancer. Click here for more information. Current Research: My laboratory is interested in understanding the activation and regulation of CD8+ cytolytic T lymphocytes (CTL) during the course of viral infection. One critical attribute of CD8+ T cells is their functional avidity, e.g. their sensitivity to peptide antigen. Cells of high functional avidity are known to be more efficacious for viral clearance compared with those of low functional avidity. An unanswered question with regard to functional avidity is the molecular mechanism responsible for conferring this attribute and whether it is an inherent property of a cell or can be induced as a result of antigen encounter. The findings from our studies are consistent with the ability of naive cells to regulate their avidity as a result of the amount of peptide antigen encountered in the early rounds of stimulation. Modulation of CD8, both the overall level and the ratio of CD8alpha:alpha homodimers to CD8alpha:beta heterodimers appear to be mechanisms by which this modulation can occur. Further studies are underway to identify additional mechanisms involved in the regulation of avidity and the duration of the window in which cells are capable of avidity modulation. My lab is also investigating the potential use of the paramyxovirus simian virus 5 as a vaccine delivery vector. While this virus is immunogenic in humans, it is not associated with disease. Our laboratory has developed a mouse model to analyze the immune response to this virus. In so doing we have made two novel and critical findings with regard to the generation of anti-viral responses following respiratory infection: 1) the initial response is comprised almost exclusively of high avidity cells and 2) immunodominance is not present at the initiation of the anti-viral response, but emerges over time. In addition our analyses of the cells present at the site of infection have revealed an unexpected negative regulation of virus-specific cells. Over time these cells increasingly lose effector function, suggesting that their ability to clear virus in vivo is impaired. Our future studies in this model will seek to determine the mechanisms responsible for the control of CTL during the initiation of the anti-viral response as well as their regulation in the specialized micro-environment of the lung. Identification of these mechanisms may allow us to develop more effective vaccines. Finally my lab is utilizing respiratory infection with vaccinia virus as a model for smallpox. We have found that high, but sublethal doses of vaccinia virus result in a loss of lymphocytes. This occurs not only for virus-specific cells but in naïve cells of heterogeneous specificity. This is a previously unknown immunosuppression associated with high vaccinia virus burden. Surprisingly it appears to be specific for respiratory tract infection, as infection with a similar dose delivered via an alternative route does not result in lymphocyte loss. Current studies are focused on understanding the mechanism responsible for lymphocyte loss with the goal of developing therapeutics that can maintain optimal T cell responses to improve viral clearance and decreased disease severity. Publications Dillon PJ, Wansley EK, Young VA, Alexander-Miller MA, Parks GD. Exchange of P/V genes between two non-cytopathic simian virus 5 variants results in a recombinant virus that kills cells through death pathways that are sensitive to caspase inhibitors. J Gen Virol. 2006 Dec;87(Pt 12):3643-8. Yates NL, Alexander-Miller MA. Vaccinia virus infection of mature dendritic cells results in activation of virus-specific naive CD8(+) T cells: A potential mechanism for direct presentation. Virology. 2007 Mar 15;359(2):349-61. Epub 2006 Oct 20. Pejawar-Graddy S, Alexander-Miller MA. Ligation of CD80 is critical for high-level CD25 expression on CD8+ T lymphocytes. J Immunol. 2006 Oct 1;177(7):4495-502. Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJ, Old LJ, Cui Z. Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7753-8. Epub 2006 May 8. Arimilli S, Alexander-Miller MA, Parks GD A simian virus 5 (SV5) P/V mutant is less cytopathic than wild-type SV5 in human dendritic cells and is a more effective activator of dendritic cell maturation and function. J Virol. 2006 Apr;80(7):3416-27. Publications:
For a listing of additional publications, refer to PubMed, a service provided by the National Library of Medicine |