Publications

Experimental infection with the intracellular protozoan Leishmania major constitutes a particularly versatile model for assessing the role of CD4+ subset development in the host response to infectious disease. The association of Th1 development with control of infection, and of Th2 cell development with progressive disease, has been well established. The capacity to manipulate the outcome, using distinct immunologic interventions, in both genetically resistant and susceptible mice has identified key effector cytokines that must be present during the time of initial priming of T cells in order to affect the CD4 switch phenotype. Roles for interferon-gamma (IFN-gamma), interleukin 12 (IL-12), and IL-4 in Th1 and Th2 maturation have been demonstrated, although additional undefined signals are required. Study of the genetically susceptible BALB/c mouse has shown failure to downmodulate IL-4 production in response to infection, a response that is critically associated with the failure to develop appropriate Th1 responses. Use of the murine L. major model continues to elucidate new methods for vaccine development and suggests a promising system for identification of genes that determine susceptibility to infection.

Leishmania major infection has proven an exceptional model for CD4+ subset development in inbred mice. Most strains contain infection coincident with the appearance of T helper 1 (Th1) cells that produce gamma-interferon (IFN-gamma) required for macrophage activation. In contrast, mice on the BALB background are unable to control infection due to the development of Th2 cells that produce counter-regulatory cytokines, particularly interleukin 4 (IL-4), capable of abrogating the effects of IFN-gamma. Selective gene disruption studies in mice have illustrated critical components of the host response to L. major. Mice deficient in beta 2 microglobulin, which have no major histocompatibility complex (MHC) class I or CD8+ T cells, control infection as well as wild-type mice, whereas mice deficient in MHC class II (and CD4+ T cells) suffer fatal infection. Mice with disruption of the gene coding IFN-gamma are also incapable of containing infection, reflecting absolute requirements for this cytokine. A number of interventions have been demonstrated to abrogate Th2 cell development in BALB mice, enabling these mice to control infection. Each of these--IL-12, anti-IL-4, anti-IL-2, anti-CD4 and CTLA4-Ig--has in common the capacity to make IL-4 rate limiting at the time of CD4+ cell priming.

The practice of medicine is information-intensive. From reviewing the literature to formulating therapeutic plans, each physician handles information differently. Yet rarely does a representation of the user's information needs and preferences--a user model--get incorporated into information management tools, even though we might reasonably expect better acceptance and effectiveness if the tools' presentation and processing were customized to the user. We developed the Physician's Information Customizer (PIC), which generates a shareable user model that can be used in any medical information-management application. PIC elicits the stable, long-term attributes of a physician through simple questions about her specialty, research focus, areas of interest, patient characteristics (e.g., ages), and practice locale. To show the utility of this user model in customizing a medical informatics application, PIC custom-filters and ranks articles from Medline, using the user model to determine what would be most interesting to the user. Preliminary evaluation on all 99 unselected articles from a recent issue of six prominent medical journals shows that PIC ranks 66% of the articles as the user would. This demonstrates the feasibility of using easily acquired physician attributes to develop a user model that can successfully filter articles of interest from a large undifferentiated collection. Further testing and development is required to optimize the custom filter and to determine which characteristics should be included in the shareable user model and which should be obtained by individual applications.