Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV) types 6 and 11, is characterized by repeated growth of pre-malignant tumors, with significant morbidity and mortality. Standard treatment is surgical removal but patients can require >100 surgical procedures to maintain their airway, at a cost of >$100 million U.S. dollars yearly. The major question driving our studies is: what prevents RRP patients from mounting an effective immune response to HPV? These HPVs induce extremely high levels of the pro-inflammatory cytokine IL-36? in papilloma tissues, which paradoxically fails to trigger an effective activating innate response and the subsequent immune clearance of these lesions. We are currently conducting a phase IIB clinical trial of celecoxib in RRP, and this proposed study will permit us to address this mechanism in vivo. Our long-term goal is to use our knowledge of the immune response in RRP to develop better therapies for this disease. These studies may also provide critical insight into why some patients with high risk HPV infections of the oropharynx fail to clear the infection and ultimately develop cancer.
Specific Aims :
Three aims will test the hypothesis that RRP patients have a defect in IL-36? mediated activation of the innate immune response caused, at least in part, by expression of PGE2 in the airway are: 1A) Determine the effect of IL-36? on the expression and release of cytokines/chemokines by laryngeal keratinocytes from RRP patients, and the effects of elevated COX-2/PGE2 on this modulation;1B) Determine the effect of both IL-36? and exogenous PGE2 on maturation and the expression of pro/anti-inflammatory cytokine/chemokines by Langerhans cells;2): Determine the signal transduction pathways that mediate expression and release of IL-36? in laryngeal keratinocytes and Langerhans cells, and the impact of concurrent PGE2 signaling on those pathways;and 3). Determine if patterns of altered pro/anti-inflammatory cytokine/chemokine expression in Aim I parallel those in serum and laryngeal tissue from RRP patients enrolled in an ongoing, phase IIB clinical trial of celecoxib therapy. Innovation: We will test for the first time, the novel concept that a host-specific, constitutive, and elevated expression of PGE2 suppresses the local HPV-induced inflammatory response and contributes to a bias in innate immune signaling in RRP patients. We have the unique opportunity through our clinical trial of celecoxib to compare our in vitro studies with in vivo responses. These studies should identify novel targets that could change the existing surgical approach to treat RRP patients to medical immune-based therapies that would be less costly, reduce morbidity, have the potential to cure this disease, and also provide critical and much needed insight into why some patients with high risk HPV infection develop cancer of the oropharynx.

Public Health Relevance

Recurrent respiratory papillomatosis (RRP) is a rare chronic disease that causes the relentless recurrence of benign tumors that occlude the airway, requiring patients to have more than 100 surgical procedures in a lifetime at a public health cost of more than $100 million dollars annually. Our ongoing clinical trial using a novel medical treatment showed clinical improvement and restoration of normal immune function;however, the mechanism that caused this is unknown. Our project will identify this mechanism, potentially shifting the current surgical management of RRP to a medical one that improves quality of life, reduces the cost of treatment, and has the potential to cure this disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE017227-07
Application #
8735124
Study Section
Immunity and Host Defense (IHD)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Rana, Ali A; Lucs, Alexandra V; DeVoti, James et al. (2015) Poly(I:C) induces controlled release of IL-36γ from keratinocytes in the absence of cell death. Immunol Res 63:228-35
Lucs, Alexandra V; DeVoti, James A; Hatam, Lynda et al. (2015) Immune Dysregulation in Patients Persistently Infected with Human Papillomaviruses 6 and 11. J Clin Med 4:375-88
DeVoti, James; Hatam, Lynda; Lucs, Alexandra et al. (2014) Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis. Mol Med 20:372-80
Hatam, Lynda J; Devoti, James A; Rosenthal, David W et al. (2012) Immune suppression in premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression. Clin Cancer Res 18:1925-35
Rosenthal, David W; DeVoti, James A; Steinberg, Bettie M et al. (2012) T(H)2-like chemokine patterns correlate with disease severity in patients with recurrent respiratory papillomatosis. Mol Med 18:1338-45
James, Eddie A; DeVoti, James A; Rosenthal, David W et al. (2011) Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis. J Immunol 186:6633-40
Bonagura, Vincent R; Hatam, Lynda J; Rosenthal, David W et al. (2010) Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human papillomavirus-6 and -11. APMIS 118:455-70
Bonagura, Vincent R; Du, Zeying; Ashouri, Elham et al. (2010) Activating killer cell immunoglobulin-like receptors 3DS1 and 2DS1 protect against developing the severe form of recurrent respiratory papillomatosis. Hum Immunol 71:212-9
DeVoti, James A; Rosenthal, David W; Wu, Rong et al. (2008) Immune dysregulation and tumor-associated gene changes in recurrent respiratory papillomatosis: a paired microarray analysis. Mol Med 14:608-17