The objectives of this program focus on the cellular, molecular and biochemical characterization of the underlying pathologic events in inflammatory, infectious, neoplastic and autoimmune diseases, with the long-term intent to develop novel approaches to therapeutic intervention. Our basic research program fuels this clinical focus based on our characterization of in vitro immunoregulatory pathways and animal model studies in disease pathogenesis. Nonhealing mucosal and cutaneous lesions due to infection, inflammation or neoplasia can become chronic and debilitating. Despite the profound health effects that chronic wound healing problems and excessive scarring pose, the mechanisms underlying normal and pathologic healing are little understood. Moreover, mucosal epithelial healing is typically more rapid and nearly scarless, prompting a comparison of cutaneous and oral mucosal wound inflammation and repair to identify controlling factors which may be of benefit in clinical delayed healing responses. In recent studies, not only were the kinetics, cellular composition, and outcome of the healing response found to be substantially altered between cutaneous and oral wounds, but secretory leukocyte protease inhibitor (SLPI) was identified as a pivotal regulatory factor in cutaneous and mucosal wounds using pre-clinical models, setting the stage for determining clinical efficacy. In clinically-derived chronic inflammatory lesions, perpetuated by bacteria and/or their products (periodontal tissues, etc.), viruses (HIV-1), other pathogens, or autoimmune responses (Sjogren's Syndrome), our characterization of the systemic immune response, as well as the local lesion cellular constituents and their products, using laser capture microdissection, proteomic and transcriptome profiles, offers new insight into targets for amelioration of tissue degradation and delayed repair. Traumatic and infectious tissue inflammation and injury in oral mucosa: Tissue injury in the oral mucosa of humans activates a cascade of transcriptional events important during inflammation and the healing process that are not yet clearly defined. To characterize these events and identify potential gene targets for clinical intervention strategies, we used cDNA expression arrays in a clinical model of tissue injury. Mucosal biopsies were taken before 3rd molar extraction, 2-4 hours post-operatively, or at 48 hours. Hybridization patterns were analyzed and validated using real-time PCR. Prior to extraction, the biopsied mucosal tissues were characterized by a panoply of genes that were constitutively expressed. After injury, analysis revealed differential expression of genes involved in transcription, inflammation and remodeling. Early after injury, genes such as Fos, Jun and early growth response protein were upregulated, while genes responsible for inter-cellular adhesion were downregulated. At later time points after injury, the gene profile had shifted towards tissue remodeling. In these studies, we began to identify genes constitutively expressed in normal oral mucosa and transcriptional events following traumatic mucosal tissue injury, which will offer insight into differences between physiologic and pathologic pathways. To extend these studies to infectious pathogen-mediated inflammation and tissue injury, we collaborated with the University of MD Dental School and the National Naval Medical Center to study subjects with chronic periodontal lesions and a subset of patients with clinically defined chronic aggressive periodontal disease. Therapeutic approaches to Sjogren?s Syndrome: Sjogren?s Syndrome (SS) is a common autoimmune disorder affecting primarily females in the fourth and fifth decade of their life. The autoimmune hallmarks of the disease are attested by the focal lymphoid cell infiltration of the exocrine glands and the production of autoantibodies. The clinical spectrum extends from an exocrine gland specific disorder which compromises quality of life to a systemic process with increased morbidity and mortality, mainly due to the increased risk of developing B cell lymphomas. In addition, features of SS are frequently encountered in patients with nearly all autoimmune rheumatic disorders. The etiology of the syndrome remains largely unknown and therapy is empirical and mainly symptomatic. In an effort to address the immune-mediated destruction observed in SS, immunomodulatory drugs such as thalidomide and anti-TNFa have recently been evaluated for potential effectiveness in controlling the hyperimmune phenotype of the disease. In the last decade, thalidomide has been reinvented as a potential anti-inflammatory, immunomodulatory and anti-angiogenic agent for the treatment of a variety of conditions ranging from dermatological disorders and autoimmune diseases to cancer. The beneficial effects on conditions such as Behcet?s disease, systemic lupus erythematosus and rheumatoid arthritis have been attributed to multiple immune regulatory actions of thalidomide. Thalidomide has been shown to suppress chemotaxis and phagocytosis of polymorphonuclear cells without producing cytotoxic cell effects and to selectively inhibit TNF production by human monocytes. Given the central role of TNF in immune and inflammatory conditions, the ability of thalidomide to down-regulate TNF may, in large part, explain its clinical usefulness in other immune-mediated disorders. To this end, thalidomide was tested as a potential therapy for SS and its clinical efficacy was monitored together with an evaluation of systemic immunological parameters that may serve as potential prognostic markers of treatment outcome. A 12-week randomized, double-blind, placebo-controlled pilot clinical trial was designed to evaluate efficacy, safety and potential side effects of thalidomide in patients with primary SS. In addition to clinical parameters, characterized by significant adverse effects, we monitored changes in systemic immune parameters. Prior to treatment, HLA-DR, TNFRI, CXCRI and CXCRII were elevated in the patients compared to healthy controls. After three weeks of thalidomide treatment, phenotypic changes began to emerge in the patient peripheral blood mononuclear cells. Although no significant changes were evident in multiple PBMC subsets, the number of B cells decreased after treatment, which may be attributed to a differential pattern of trafficking of this population, or an actual population decrease. HLA-DR expression decreased on PBMC of treated patients. In addition, cell surface expression of the adhesion molecule L-selectin decreased. Interestingly, a reduction in TNFRI was not accompanied by changes in levels of TNFRII in the periphery, although this may not be the case in the inflammatory lesion of the gland. Finally, expression of CXCRI and II chemokine receptors was reduced in the treated patients, possibly reflecting reduced recruitment potential to areas of disease. Evidence of multiple systemic immunological consequences within weeks after the onset of thalidomide treatment, despite lack of quantifiable clinical efficacy during this short treatment interval, may offer insight into the immunoregulatory actions of thalidomide. The systemic response in SS patients may underlie the beneficial role of thalidomide in other disorders and may aid in the understanding of thalidomide?s mechanisms of action in vivo. Moreover, in the case of SS, the elevated levels of TNF as well as the evidence of systemic immune activation may support the use of thalidomide or other TNF inhibitors in a modified regimen. The use of a low dose treatment or a local delivery system may maximize the benefits of thalidomide, while minimizing the possibility of adverse outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Intramural Research (Z01)
Project #
1Z01DE000691-08
Application #
7146123
Study Section
(OIIB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Dental & Craniofacial Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Wahl, Sharon M; Chen, Wanjun (2005) Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases. Arthritis Res Ther 7:62-8

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