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Joost J. Oppenheim, M.D.

Portait Photo of Joost Oppenheim
Laboratory of Molecular Immunoregulation
Head, Cellular Immunology Group
Laboratory Chief
Center for Cancer Research
National Cancer Institute
Building 560, Room 21-89A
Room 31-19 (Lab)
P.O. Box B
Frederick, MD 21702-1201
Phone:  
301-846-1551/1347
Fax:  
301-846-7042
E-Mail:  
oppenheJ@mail.nih.gov

Biography

Dr. Oppenheim obtained his M.D. degree from the Columbia College of Physicians and Surgeons, New York, trained as a clinical associate at the National Cancer Institute (NCI), Bethesda, Maryland, and was a postdoctoral fellow at the University of Birmingham, England, in immunology. He returned to the National Institute of Dental Research and subsequently headed the Section of Cellular Immunology there and, since 1983, has been head of the Laboratory of Molecular Immunoregulation, NCI-Frederick.

Research

The Role of Cytokines in Host Defense and Repair

Based on our findings that the antimicrobial defensins are chemotactic for host cells that express chemokine receptors (CCR6 or CCR2) our laboratory has changed its emphasis considerably from studies of chemokines to studies of chemokine mimics and other endogenous molecules that are rapidly released by cellular degranulation or cell necrosis in response to infectious or injurious danger signals. These molecules rapidly initiate host defense based on their interaction with chemotactic as well as activating receptors on host cells. We have termed them 'alarmins' based on their capacity to rapidly mobilize and activate innate as well as subsequent adaptive host immune defense mechanisms. This alarmin concept was conceived based on our earlier studies of antimicrobial proteins such as defensins and cathelicidin (LL37) that we identified as having the capacity to use both chemoattractant receptors on as well as activating receptors on host antigen-presenting cells. This idea led us to identify other antimicrobial proteins as having similar properties including eosinophil-derived neurotoxin (EDN), lactoferrin, granulysin, high mobility group (HMG) box 1 protein (HMGB1), and more recently HMG nucleosome-binding protein 1 (HMGN1). All of the alarmins identified so far have the capacity to activate dendritic cells and promote adaptive immunity. Since radiotherapy, chemotherapy and growing tumors themselves certainly cause extensive tissue injuries and increased susceptibility to infections, they undoubtedly induce the release of alarmins. Consequently, alarmins participate in the host response to cancer, and they can also potentially be used as immunoadjuvants in tumor vaccines. The alarmin concept has enabled us to identify a previously unidentified subset of Danger Associated Molecular Patterns (DAMPs) with the capacity to rapidly mobilize and activate host defense with potential anti-tumor activities.

In our second project entitled, 'Role of Suppressive Immune Cells in Cancer, we are investigating a) suppressive regulatory T cells (Tregs), b) myeloid derived suppressor cells (MDSC) and c) suppressive DC'. We have found that the prototypic proinflammatory cytokine, TNF also induces the proliferative expansion and activation of Tregs. TNF activates Tregs subsequent to T effector cells (Teff) by interacting with the TNFR2 receptor. This pathway serves as a feedback down regulator of inflammation. The majority of tumor infiltrating T cells (TILs) are actually Tregs, most of which express TNFR2. We have found them to be 'super' suppressive promoters of tumor immune evasion. Thus, means of countering these Tregs need to be identified to optimize antitumor responses.

In order to contend with other immunosuppressive pathways, we recently also initiated studies of myeloid derived immunosuppressive cells (MDSC) and suppressive dendritic cells (sDC), which also enable tumors to evade immune responses. Overall, we propose to promote protective antitumor immune responses utilizing the more potent Th1-polarizing alarmins as tumor vaccine adjuvants in conjunction with inhibition of suppressive cells to achieve more effective treatment of tumors.

Our third project, 'Consequences of receptor cross talk and algesia', is aimed at identifying novel pathways resulting in painful inflammatory reactions. We have shown that chemokine interactions with chemokine receptors cross desensitize opioid receptors and also sensitize vanilloid (TRPV1) receptors, both resulting in enhanced pain. We have been funded by an intramural grant from the NCI and NIAID to collaborate with Dr. Jeffrey Cohen (NIAID) to investigate the painful effects of herpes virus in cotton rats, a model for Herpes Zoster. We have found that peripheral neurons present in the dorsal root ganglia of rodents express many receptors including functional TLR3, 7 and 9. Furthermore, TLR ligands generated by herpes virus infections up-regulate the expression of TLR's and of TRPV1 on dorsal root ganglia neurons. Thus, herpes infections by inducing TLR signals may promote TRPV1 pain receptor responses resulting in neuralgia. We have tested these possibilities in an in vivo sarcoma tumor model injected near the sciatic nerve. Administration of a suppressive olignucleotide resulted in both slowing the tumor growth and reducing the pain sensitivity of the treated mice. In vivo evaluation of pain induction by herpes infection is being investigated in another animal model.

This page was last updated on 6/7/2013.