Autoimmunity and Sjogren's syndrome (SS) (55%) An important objective of our studies is to define the underlying mechanisms by which inflammatory and immune responses go awry, resulting in autoimmune pathogenesis, as exemplified by Sjogren's syndrome. The autoimmune hallmarks of SS include focal lymphoid cell infiltration of exocrine glands (focus score) and production of autoantibodies. The etiology of SS remains largely unknown and a conundrum is presented by the failure of many drugs that are effective in other autoimmune disorders, particularly TNF antagonists. At the cellular level, we showed that expression of IL-17 and also TGFbeta progressively increases with higher biopsy focus scores, connecting IL-17 to SS tissue pathology. Locally involved innate immune defense populations include macrophages, and in our microarray analysis of SS tissues, we focused on disease related overexpressed genes. Among the most highly expressed genes were members of the mammalian chitinase family. Both chitinase-3-like-1 (CHI3L1/YKL-40) and chitinase 1 (CHIT1), highly conserved members of the mammalian chitinase-like glycoprotein family were evident at the transcriptome levels, as well as detected as glycoproteins within inflamed salivary glands. Since the elevated expression of these and other macrophage-derived molecules, including components of the fibrinolytic pathway, corresponded with more severe disease in SS, these observations implicate a potential immunopathologic macrophage involvement and furthermore, that chitinases and/or other macrophage products may provide a diagnostic tool. SLPI regulation of proteolytic cascade in inflammation and cancer (30%) Enhanced inflammation, delayed healing and susceptibility to infection in the absence of SLPI suggested a link between SLPI and regulation of inflammatory responses. In SLPI null mice, macrophages process unregulated levels of plasmin, which contributes to excess tissue degradation, increased inflammation and failed healing following tissue injury. By inhibiting plasmin, which has a myriad of downstream consequences relative to complement activation, fibrinolysis, cytokine regulation, TGF-beta activation and other inflammatory sequelae, SLPI can exert control over proteolytic and inflammatory activation networks. Because fibrinolytic processes are fundamental not only to inflammation, coagulation and tissue repair, but growing evidence highlights their dysregulation in the pathogenesis of multiple chronic inflammatory disorders, cardiovascular disease and malignancy, further defining and regulating these pathways is of major significance. Relevant to these findings, we have explored the role of SLPI in metastatic head and neck squamous cell carcinoma (HNSCC), one of the 10 most frequently occurring cancers worldwide with a very poor prognosis, with investigators at UMD. SLPI expression was higher in noninvolved than in malignant tissue, and levels significantly inversely correlated with HNSCC stage and pattern of invasion. Moreover, our data demonstrate cytokine regulation of these invasive pathways suggesting a strategy to modulate tumor invasive potential in oral cancer. TNFalpha as a therapeutic target for aberrant cutaneous wound healing (15%) Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the USA. Both chronic and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, related to increased local and systemic TNF levels. Moreover, we used the SLPI null mouse model of impaired wound healing, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNF neutralizing antibodies blunts leukocyte recruitment and NFkB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Our data suggest that inhibiting TNF is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.

Project Start
Project End
Budget Start
Budget End
Support Year
41
Fiscal Year
2012
Total Cost
$806,588
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
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Hubbard, Jonathan J; Greenwell-Wild, Teresa; Barrett, Lisa et al. (2012) Host gene expression changes correlating with anti-HIV-1 effects in human subjects after treatment with peginterferon Alfa-2a. J Infect Dis 205:1443-7
Moutsopoulos, Niki M; Kling, Heather M; Angelov, Nikola et al. (2012) Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. J Autoimmun 39:294-303
Ashcroft, Gillian S; Jeong, Moon-Jin; Ashworth, Jason J et al. (2012) Tumor necrosis factor-alpha (TNF-?) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen 20:38-49
Smith, P D; Smythies, L E; Shen, R et al. (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4:31-42
Vázquez, Nancy; Schmeisser, Hana; Dolan, Michael A et al. (2011) Structural variants of IFN? preferentially promote antiviral functions. Blood 118:2567-77
Greenwell-Wild, Teresa; Moutsopoulos, Niki M; Gliozzi, Maria et al. (2011) Chitinases in the salivary glands and circulation of patients with Sjögren's syndrome: macrophage harbingers of disease severity. Arthritis Rheum 63:3103-15
Wahl, Sharon M; Redford, Maryann; Christensen, Shawna et al. (2011) Systemic and mucosal differences in HIV burden, immune, and therapeutic responses. J Acquir Immune Defic Syndr 56:401-11
Wen, Jie; Nikitakis, Nikolaos G; Chaisuparat, Risa et al. (2011) Secretory leukocyte protease inhibitor (SLPI) expression and tumor invasion in oral squamous cell carcinoma. Am J Pathol 178:2866-78
Challacombe, S J; Fidel Jr, P L; Tugizov, S et al. (2011) HIV infection and specific mucosal immunity: workshop 4B. Adv Dent Res 23:142-51
Malamud, Daniel; Wahl, Sharon M (2010) The mouth: a gateway or a trap for HIV? AIDS 24:5-16

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