Bali Pulendran, Ph.D.

Area of Research: Basic Immunology/Virology

In many ways the immune system can be described in anthropomorphic terms: Its memory allows it to remember and recognize pathogens after years or even decades; it can distinguish between the body’s own cells and those of another organism; and it makes decisions about how to response to particular pathogens. This last characteristic is the focus of Dr. Bali Pulendran’s research at the EVC. Central to the immune system’s decision-making process are dendritic cells, which command and orchestrate the immune system. Because the development of effective vaccines relies upon arousing the appropriate type of immune response, Dr. Pulendran aims to identify ways to stimulate dendritic cell production and activity.

TDr. Pulendran is a Professor in the Department of Pathology and Laboratory Medicine of the Emory University School of Medicine. He received his Ph.D. in immunology from the Walter & Eliza Hall Institute of the University of Melbourne, Victoria, Australia, and did his post-doctoral training at Immunex Corporation in Seattle, Washington.

Research

The immune system has evolved different classes of immune responses, each specialized for the elimination of particular types of pathogens. In response to intracellular microbes, CD4+ Th cells differentiate into Th1 (type 1) cells; in contrast, many extracellular parasites stimulate Th2 (type 2) responses, whose cytokines induce IgE- and eosinophil-mediated destruction of pathogens. The “decision-making mechanisms” that determine the class of the response are poorly understood. The two principle goals of our research are to: (i) understand how this decision making is made in the immune system, and (ii) use this information to design novel strategies to make the vaccines and drugs of the 21st century. Central to this issue is a system of rare but widely distributed cells known as dendritic cells (DCs), which have long been known to be pivotal in initiating immune responses. Their rarity in the body had posed an obstacle to their detailed study. Our recent work has demonstrated that:

• Cytokines such as Flt3-Ligand, GM-CSF and G-CSF profoundly increase the numbers of distinct subsets of DCs in mice, humans and macaques; and that these “dendritic cell-poietins [DC-Poietins],” can be used as vaccine adjuvants in promoting distinct classes of immune responses in vivo [reviewed in Pulendran et al, Trends in Immunology, 2001; Pulendran et al, Immunological Reviews 2004].
• DCs are not only important in initiating immune responses, but also in controlling the type and strength of immunity. In particular, different subsets of DCs direct qualitatively different types of immune responses in vivo [reviewed in Pulendran et al, Science 2001; Pulendran et al, Immunological Reviews 2004].
• Microbial stimuli exert potent influences on DCs to modulate the character of immune responses [Pulendran et al, J. Immunol, 2001; Pulendran et al, Science, 2001; Agrawal et al, Nature 2003; Agrawal et al, Cutting Edge, 2003]. In particular, our work suggests that microbial stimuli that activate DCs through different Toll-like receptors, elicit very different types of immune responses in vivo [Pulendran et al, J. Immunol, 2001; Pulendran et al, Science, 2001; Agrawal et al, Nature 2003; Agrawal et al, Cutting Edge, 2003].

Given their emergence as key regulators of the immune response, there is great enthusiasm for harnessing DCs as vectors and targets for the immune therapy of infectious diseases, autoimmunity, allergies, transplantation and cancer. Future work in our lab will concentrate on understanding basic mechanisms by which DCs control innate and adaptive immune responses, as well as in exploiting these in vaccinology and immune therapy. Our specific goals are:

1. To determine the molecular mechanisms and genomic networks by which different microbial stimuli modulate DC function so as to induce dramatically different classes of adaptive immune responses [Th1, Th2, Thn or tolerogenic, T regulatory]. Our preliminary data suggest that DC subsets, pathogen recognition receptors (e.g. Toll receptors), the microenvironment and cytokines all play important roles in this process. This question will be further explored using a combination of cellular and molecular immunological techniques, including transgenic and knockout mice, gene array and proteomic technologies, and in vivo models of immune response, using both mice and non-human primates.
2. To study how different pathogens, including certain agents of bioterrorism such as anthrax and Ebola, modulate DC function during pathogenesis. These projects are being pursued in collaboration with scientists at the Centers for Disease Control (CDC).
3. To explore the efficacy of Flt3-Ligand, GM-CSF, G-CSF, and other factors that modulate DC numbers or function, as immune modulators or vaccine adjuvants, in the context of HIV and other infectious diseases, in both non human primates in patients.

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