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Jenny Kim, M.D., Ph.D.
Stephan Krutzik, Ph.D.
Delphine Lee, M.D., Ph.D.
Roger Lo, M.D., Ph.D.
Lloyd Miller, M.D., Ph.D.
Robert L. Modlin, M.D.
Maria Teresa Ochoa, M.D.
Peter Allan Sieling, Ph.D.

Jenny Kim, M.D., Ph.D.
Dr. Kim's basic science research projects are funded by the National Institutes of Health, the Dermatology Foundation, and the American Society for Dermatologic Surgery. Dr. Kim's laboratory currently focuses on two specific areas:

Studying the mechanism of Toll-like receptor responses (innate immunity) in skin diseases.
Determining genes that are important in the development and progression of skin cancers.

Stephan Krutzik, Ph.D.
The primary objective of my research it to understand how the family of Toll-like receptors (TLRs) helps modulate the direct functions of the innate immune system such as phagocytosis, and the indirect functions such as T cell activation. Recently we discovered that activation of human peripheral blood monocytes through TLRs triggers their differentiation into distinct populations of DC-SIGN+CD16+ macrophages and CD1b+ dendritic cells. DC SIGN+CD16+ macrophages are phagocytic, capable of both the binding and uptake of mycobacteria. Therefore, DC-SIGN+ macrophages represent a population of cells capable of carrying out the direct function of the innate immune response. In contrast, CD1b+ dendritic cells express critical T cell co-stimulatory molecules, secrete cytokines such as the Th1 skewing IL-12 and potently trigger T cell activation. Therefore, CD1b+ dendritic cells represent a population of cells capable of carrying out the indirect function of the innate immune system, triggering T cell activation, and bridge the innate and adaptive immune responses. Current studies are aimed at further elucidating the distribution and function of DC-SIGN+ macrophages and CD1b+ dendritic cells in normal and diseased tissue and their role in combating microbial infections.

Delphine Lee. M.D., Ph.D.
Dr. Lee is primarily interested in autoimmunity and immune dysregulation. She is NIH funded and her studies involve 3 major areas:

1. Erythema nodosum leprosum as a model of type III immune complex hypersensitivity reactions
2. Leukocyte immunoglobulin-like receptors and their role in immune dysregulation
3. Gene expression profiles of lesional and non-lesional skin in vitiligo

Roger Lo, M.D., Ph.D.
My overall research objective is to gain a deeper understanding of the genetic underpinning of human melanoma, with an emphasis on malignant initiation in the skin and targetable molecular pathways. Numerous genetic, epigenetic and gene expression alterations have been identified in human melanoma cell lines and, in fewer instances, directly in tumor samples. However, deciphering whether these alterations represent true causative oncogenic events or mere epiphenomena remains a constant challenge. Functional analyses of these altered pathways in melanoma cell lines and in genetically engineered mice have met limitations that preclude a thorough delineation of the genetic and biochemical rules governing the malignant progression of human melanocytes. Furthermore, human melanoms have been found to be "addicted" to certain oncogenes and non-oncogenes for their survival. Harnessing effective targeted therapeutics requires an understanding of not just the molecular targets but also mechanisms of resistance as well as genetic modifiers of tumor escape.

Work is on-going (1) to study the oncogenic activities of defined genetic elements in human melanocytes by lentiviral gene transfers and incorporation of engineered human melanocytes into human skin reconstructs, (2) to identify novel targetable molecular vulnerabilities in metastatic disease, (3) to understand the mechanisms of resistance to targeted therapeutics, and (4) to define the functional genomic roadmap of modifiers to targeted therapeutic efficacy.

This work has been carried out during the post-doctoral training phase in the laboratory of Owen N. Witte, M.D., a Howard Hughes Medical Institute Investigator at UCLA and continued in the Lo Lab (Department of Medicine/Dermatology & Jonsson Comprehensive Cancer Center). Partial support for this work comes from the Dermatology Foundation, The American Skin Association, the American Society for Dermatologic Surgery, and the Los Angeles Metropolitan Dermatology Society, the Ian Copeland Melanoma Fund, and the California Institute of Regenerative Medicine. R.S. Lo holds a Career Award for Medical Scientists from the Burrough's Wellcome Fund.

Lloyd Miller, M.D., Ph.D.
My research interests involve the study of mechanisms of cutaneous host defense against bacterial skin pathogens. There are an increasing number of studies demonstrating that Toll-like receptors (TLRs) respond to components of bacteria and other microbial pathogens and subsequently initiate innate and adaptive immune responses. Our preliminary data is a mouse model system of Staphylococcus aureus induced skin ulceration suggest that TLRs and TLR signaling molecules are important in cutaneous host defense against bacterial skin infections. The hypothesis of these studies in that TLRs play a crucial role in initiating innate and adaptive immune responses that are important in controlling bacterial skin infections. My research involves the investigations of the role of TLRs and TLR related signaling molecules in an infection and to generate immune responses such as production of antimicrobial peptides, recruitment of immune system cells, and initiation of innate and adaptive immune. In addition, since cultured keratinocytes and epidermal keratinocytes from human skin specimens have been shown to express TLRs, we are investigating the functional role that human keratinocytes have in sensing and initiating cutaneous host defense mechanisms against Staphylococcus aureus in culture. We believe the insights obtained from the study of TLRs in bacterial skin infections will help broaden our understanding of cutaneous host defense and allow for much needed novel antibacterial therapies, which may be of particular importance since there are increasing numbers of bacterial strains that are resistant to conventional antibiotic therapy.

Robert L. Modlin, M.D.
Infectious disease poses a major health problem worldwide. Essential to control of these diseases is the elucidation of immune mechanisms which result in resistance versus susceptibility to infection. Our laboratory's focus is the identification of novel mechanisms by which the innate and adaptive immune system combat microbial pathogens. Mammalian Toll-like receptors comprise part of the innate response. Our group studies the microbial ligands that activate Toll-like receptors and the functional consequence of Toll activation.

We are interested in the mechanism by which Toll activation influences the adaptive T cell response, the mechanisms by which Toll activation leads to direct antimicrobial pathways and role of Toll-like receptors in causing tissue injury in disease. The adaptive T cell response recognizes peptide antigens in the context of MHC molecules and lipid antigens presented by CD1 molecules. We are identifying novel peptide and lipid antigens that are immunodominant in the human immune response to infection as well as mechanisms by which these T cells can directly kill the foreign invader. Using the knowledge of these antigen presentation pathways, we are engineering new vaccine strategies against these pathogens. It is hoped that the insights obtained from these studies will lead to better treatments and prevention of infectious diseases in humans.

Maria Teresa Ochoa, M.D.
Dr. Ochoa's research interest is the study of the immunologic mechanism of host response in infectious diseases of the skin, especially as it relates to the pathogenesis of leprosy and HIV. She recently established that the antimicrobial protein granulysin was present in leprosy lesions and found that CD4+ T cell lines derived from leprosy skin lesions were cytolytic and mediated an antimicrobial activity against infected targets. Studies with granulysin continues to draw attention over its possible use as a new drug for the treatment of infectious diseases. These investigations will contribute to the development of new immunomodulatory therapies for a variety of dermatologic diseases.

Peter Allan Sieling, Ph.D.
The overall research objectives in my laboratory are to identify basic mechanisms of innate and adaptive immunity to infection. One major research project concerns identifying mechanisms whereby dendritic cells (innate immune system) activate T cells (adaptive). Dendritic cells express pattern recognition receptors that allow the cells to recognize conserved microbial structures. Recognition of microbial patterns by pattern recognition receptors, in particular Toll-like receptors (TLRs) activates both direct antimicrobial activity and indirectly modulates the adaptive immune response of B and T cells. TLR1 and TLR2 combine to form a pattern recognition molecule for microbial lipoproteins. We found that TLR1 and TLR2 are co-expressed on dendritic cells in lymphoid tissue. The coexpression of TLR1 and TLR2 on dendritic cells provides the host with the ability to respond to a variety of microbial ligands at sites conducive to the generation of an immune response. We have also found that bacterial lipopeptides stimulate T helper 1 responses in an accessory cell-dependent manner in vitro. We are currently investigating the mechanism of adjuvant activity of TLR ligands and identifying the T cell subset that is responsive to TLR ligands.

The second major research topic of the laboratory is to define the role of T cells in response to infection. We have investigated the role of CD1-restricted T cells in mycobacterial disease for the past ten years. CD1 is an antigen presentation pathway similar to major histocompatibility (MHC) antigen presentation, but with a major distinction, that is the presentation of lipid antigens in contrast to the peptide antigens presented by MHC. We have identified glycolipid antigens of mycobacteria that activate CD1-restricted T cells and provided evidence suggesting that CD1-restricted T cells contribute to immune responses that limit mycobacterial infections. Currently we are investigating the precise chemical structures of the glycolipid antigens that activate CD1-restricted T cells. We are also expanding our investigations of CD1-restricted T cells to characterize their activity against non-mycobacterial human pathogens.

A third major area of investigation is to determine the mechanism of T cell help for auto-antibody production in systemic lupus erythematosus (SLE). The ability of T cells to provide help to B cells depends on their recognition of appropriately presented antigen on the surface of B cells. We have found that CD4-, CD8- double negative (DN) T cells in SLE patients promote IgG production in a CD1c-restricted manner, whereas DN T cells of healthy donors exhibited weak helper activity. Our data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c-expressing B cells for IgG production and could therefore promote pathogenic auto-antibody responses in SLE.