The Cellular and Molecular Bases of Inflammation
Dr. Peter Weller has many active areas of basic laboratory research centered around understanding basic mechanisms of leukocyte functioning in forms of inflammation. The two principal areas of investigation are:
1) the immunobiology of eosinophilic leukocytes and
2) the intracellular regulation and compartmentalization of inducible mediators of inflammation in neutrophils and other leukocytes.
Studies of human eosinophils are aimed at defining mechanisms whereby eosinophils may collaboratively interact with other cellular elements of the immune system. These studies include investigations of the mechanisms whereby eosinophils may function as antigen-presenting cells in governing T-lymphocyte dependent immune responses, and include investigations of the in vivo migration and function of eosinophils and of the regulated expression of cell surface proteins involved in collaborative interactions between eosinophils and other cell types.
Additional studies are focused on defining the molecular mechanisms governing the synthesis, granule storage and release mechanisms of eosinophil derived cytokines. The roles of eosinophils in wound healing and fibrosis and the activities of chemokines and cytokines released by eosinophils that contribute to tissue remodeling are being studied. The second area of research involves the molecular and cellular biologic bases of inducible responses of leukocytes participating in host defense and other forms of inflammation. These are centered on a unique intracellular compartment, termed the lipid body, whose formation is rapidly inducible in leukocytes. The intracellular signaling mechanisms responsible for lipid body induction and especially the roles of lipid bodies as distinct sites of cytokine and eicosanoid mediator formation are being studied.
In addition to investigating previously undefined pathways of leukocyte responses to inflammation, these studies also offer the potential to identify novel anti-inflammatory therapeutic targets. Our research indicates that lipid bodies in leukocytes have roles as sites of regulated formation of eicosanoids and as distinctextranuclear sites of translation. The biology of these structures is intimately related to the roles of leukocytes in acute inflammation.
Study of Viruses Associated with Human Cancer
Dr. Joyce Fingeroth studies herpesviruses that are causally associated with human cancer. These studies include basic, translational and clinical research. In the laboratory Dr. Fingeroth inveestigates the Epstein-Barr virus (EBV) receptor. This 140 Mr glycoprotein is expressed on human B lymphocytes, some T lymphocytes and rarely other hematopoietic lineage, epithelial and smooth muscle cells. It is the cellular attachment protein for EBV and also for complement fragments. The spectrum of EBV-related neoplasms reflects the cellular distribution of this receptor. The function of this receptor is studied using the tools of molecular biology, protein biochemistry and cellular immunology to relate the regulation and structure of the molecule to its function as a virus receptor. HHV-8 or KSHV (Kaposi's sarcoma-associated herpesvirus), the most recently discovered member of the human herpesvirus family, appears to have a limited tropism similar to EBV. Preliminary experiments are underway to determine whether specific cellular attachment proteins can be identified. Translational studies in the laboratory have focused on characterizing the EBV and KSHV thymidine kinases as a targets for antiviral and antitumor therapy.
The Barouch Laboratory:
Dr. Barouch's laboratory focuses on studying the immunology and virology of HIV-1 infection and developing novel vaccine strategies. They have demonstrated that humoral and cellular immune responses elicited by adenovirus and poxvirus vectors can partially protect against acquisition of infection and can control viral replication following pathogenic virus challenges in rhesus monkeys. They have also developed a series of alternative serotype and chimeric adenovirus vector-based vaccines that are designed to circumvent the high titers of neutralizing antibiotides to the common adenovirus serotype 5 (Ad5) vector in the developing world. They have constructed a variety of novel vaccine vectors, explored their immunogenicity and protective efficacy in preclinical studies, and advanced optimal vaccine candidates into clinical trials. Four phase 1 clinical trials with these novel HIV-1 vaccine vectors are currently in progress in the United States and sub-Saharan Africa. Dr. Barouch's group is a key part of the Bill and Melinda Gates Foundation Collaborative for AIDS Vaccine Discovery (CAVD), the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI), and the Ragon Institute of MGH, MIT, and Harvard. Dr. Barouch currently serves at the Chief of the Division of Vaccine Research at Beth Israel Deaconess Medical Center.
The Koralnik Laboratory:
This laboratory, under the direction of Dr. Igor Koralnik, is investigating Progressive Multifocal Leukoencephaloathy (PML). PML is a deadly demyelinating disease of the central nervous system caused by JC virus (JCV) in immunosuppressed individuals. JCV infects most healthy adults without causing any disease, but its reactivation leads to a productive and lytic infection of oligodendrocytes, the myelin producing cells in the central nervous system. This laboratory is currently studying the cellular immune response against JCV mediated by both CD8+ and CD4+ T lymphocytes in patients with PML, and they are characterizing genetic markers of the host associated with clinical outcome of PML. They are using MR spectroscopy and advanced imaging techniques to understand the immunopathogenesis of the immune reconstitution inflammatory syndrome (IRIS) in the context of PML. In addition, they are also studying JCV variants infecting cerebellar granule cell neurons and cortical pyramidal neurons, and have characterized two novel clinical entities called JCV granule cell neuronopathy (JCV GCN) and JCV encephalopathy (JCVE). Furthermore, they are using a humanized mouse model to decipher early events of JCV infections, latency, and reactivation. Since there is no cure for PML, this laboratory is now developing a dendtritic cell-based immunotherapy for this disease.
The Dolin Laboratory:
Laboratory and Clinical Studies of HIV Vaccines and Biodefense Vaccines: Dr. Raphael Dolin and colleagues have a major interest in the development and evaluation of HIV vaccines. As part of the NIH sponsored Harvard HIV Vaccine Trials Unit, studies of candidate HIV vaccines are carried out in normal volunteers for safety and immunogenicity. Recent vaccines which have been studied include DNA vaccines which code for HIV-1 envelope genes, and genes for gag, pol, and nef proteins. Studies of candidate vaccines based on adenovirus vectors are also underway. Laboratory investigation of immune responses also has been undertaken, including studies of both humoral and cell-mediated immune responses. The latter employ techniques to measure T-cell responses by ELISPOT, intracellular cytokine staining, and tetramer assays. Establishment of highly sensitive, specific neutralization antibody assays is a particular interest of the group.
Dr. Dolin and colleagues are also interested in the development of safe and more tolerable smallpox vaccines, as part of the NIH sponsored Translational Immunology Center. Clinical studies of vaccinia and Modified Vaccinia Ankara (MVA) vaccines in human volunteers are being undertaken along with measurement of humoral and cell mediated immune responses in vaccines. The goal of the studies is to develop a new generation of genetically modified and defined vaccines for biodefense uses.