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De Yang, M.D., Ph.D.
The immune system relies on highly orchestrated action of many cellular and humoral components to maintain homeostasis and to fend off immunologic non-self intruders. An intact layer of epithelium and skin acts as a mechanical barrier to separate the inner environment of an individual from outside environment. When the barrier is breached due to injury or infection, non-self substances including microorganisms enter the host and trigger immediately innate immune responses, including generation and/or mobilization of humoral mediators (e.g. cytokines, chemotactic factors, AMPs, complements, lipid metabolites, etc) and phagocytes (e.g. granulocytes, monocytes/macrophages, and DCs). These responses not only function to limit or eliminate non-self substances, but also set the stage for subsequent induction of adaptive immune responses by ensuring the transfer of antigenic information to naive lymphocytes through promoting the activation of antigen-presenting cells, particularly DCs. Induction of adaptive immune responses results in the generation of antigen-specific antibodies and effector T cells, which contribute the elimination of non-self substances, and immunological memory.
AMPs are endogenous peptides and proteins with direct anti-microbial effect. Chemotactic factors including classic chemoattractants and chemokines control the directional migration of cells including leukocytes using G-protein coupled seven-transmembrane domain receptors (GPCRs). Studies in the last couple of years have established that many AMPs, such as defensins, cathelicidins, eosinophil-derived neurotoxin and high mobility group proteins, are chemotactic for various leukocytes while many chemokines exhibit direct anti-microbial effect. In addition, certain AMPs and chemokines have been demonstrated to have the capacity to induce DC maturation and to enhance antigen-specific immune responses in mouse models. We have proposed to classify those endogenous mediators with dual DC-recruiting and activating effects as 'alarmins' and hypothesized that alarmins may play critical roles in alerting the adaptive immunity by enhancing the induction of antigen-specific immune responses through promoting antigen uptake, processing and presentation. We believe that extensive investigation on alarmins, including their number, generation, and mode of action, would help elucidate their roles immunity, with the hope of modulating immune responses using alarmins as targets. Dr. Yang's current research on alarmins is focusing on the following two three major areas.
1. Identification of additional alarmins
Alarmins have been identified from defensin, cathelicidin, chemokine, eosinophil-associated ribonuclease, and high mobility group protein families, however, it is currently unclear whether all the members of those protein famililies have the properties of an alarmin. Take defensin family (classified into , -, and - subfamilies) for example, only a number of -defensins have been characterized at the protein level despite the existence of up to 30 -defensin genes in either mouse or human genome. Members of defensin, chemokine, and high mobility group protein family are being screened for dual DC-chemotactic and DC-activating properties. Positive hits are tested for DC recruitment and enhancement of antigen-specific immune responses in mouse models for the identification.
2. Elucidation of the mechanism(s) by which various alarmins chemoattract and activate DCs
This includes identifying the receptors used by alarmins for the induction of DC migration and activation, and mapping the corresponding intracellular signal transduction pathways. The receptors responsible for mediating chemotacitc and DC-activating effects of a given alarmin can be different. We have reported that several alarmins induce leukocyte migration using GPCRs (e.g. CCR6 for -defensin-2, FPRL1 for human cathelicidin), whereas the receptors mediating the DC-activating effect of mouse -defensin-2 and high mobility group box-1 protein are reported to be Toll-like receptor (TLR) 4, TLR2 and/or receptor for advanced glycation endproduct (RAGE). The receptors of several alarmins such as eosinophil-derived neurotoxin and defensin-3 are under current investigation.
3. Testing the potential use of alarmins as adjuvants for experimental tumor immunotherapy
Tumor-bearing individuals, despite the existence of tumor-associated antigen (TAA), often lack a generation of effective TAA-specific anti-tumor immune responses due to low number of TAA-specific T cells, deficient or suboptimal initiation TAA-specific immune response to generate effector and memory T cells, or insufficient migration of effector T cells to tumor sites. One potential reason for inadequate initiation of TAA-specific T cells response may be due to the lack of alarmin(s) at the tumor tissue so that tumor-infiltrating DCs do not receive a strong maturational signal, resulting in the formation of lymphoid-homing DCs that can not present TAA to trigger T cell proliferation and clonal expansion. Based on the capacity of alarmins to enhance antigen-specific immune response, several alarmins are currently investigated and compared in mouse tumor models to 1) ensure if they can promote anti-tumor immune response, and 2) sort out the more potent Th1-polarizing alarmin(s).
This page was last updated on 2/23/2009.