Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) 6 and 11. These HPVs generate benign tumors in the airway, reduce """"""""quality of life"""""""" by requiring surgery as often as every two weeks to keep the airway open, and they can become malignant and cause mortality. However the immunologic mechanism(s) that governs disease predisposition and variation in RRP remains unknown. We have found RRP to be a TH2-like disease. The cytokine/chemokine milieu is enriched with IL-4, IL-10, but not IFN-g, and both T and non-T-cells express IL-10 after HPV-11 E6 exposure. In addition, the chemokine CCL18, expressed by alternatively activated macrophages (AAMPs) and immature dendritic cells (DCs), is increased in RRP plasma. We hypothesize that HPV-specific, TH2-like memory and regulatory T-cells (Tr1) express IL-4 and/or IL-10, that polarize resting macrophages (MP) to become AAMPs which also express IL- 10. This perpetuates a cycle of immunosuppressive cells that inhibit TH1-like T-cell responses to HPV proteins. Our long-term goal is to design a therapeutic vaccine to interrupt this cycle and support HPV- specific,TH1-like responses to HPV.
Specific aims are: 1) Characterize/quantitate HPV-specific, T-cells that express TH2 cytokines and IL-10 in response to HPV proteins, and correlate this with disease severity. T-cell and cytokine responses to E6/E2, and T-cell epitopes within HPV-11 E6/ E2 (mapped using E6/E2 peptide- loaded, class II MHC tetramers), will be identified by flow cytometry. 2) Determine if Tr1 cells can be generated from naTve T-cells in response to E6/E2 using flow cytometry. We will use Langerhans cells, E6/ E2 transduced keratinocytes, or DCs, as APCs to explore this conversion. 3) Characterize MP polarization in E6/E2-exposed PBMC, and identify AAMPs vs. classically activated MPs by CCL17, CCL18, and nitric oxide expression. 4) Determine if E6/E2-exposed APCs and TH2 cells can inhibit alloreactive T-cell killing. We will expose PBMC to E6/E2 and alloantigens, and test for alloreactivity in a MLR, and T-cell killing in a CML assay. We will determine if adding IFN-g or anti-IL-10 prevents this inhibition. 5) Determine if IL-10 promoter single nucleotide polymorphisms (SNPs) predict disease severity. We will identify and compare IL-10 SNPs in severe, vs. mild/moderate disease. These studies will identify immune system cells that inappropriately respond to HPV, help develop a therapeutic vaccine, and new strategies to treat patients with RRP. ? ? ?
|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|
|Rana, Ali A; Lucs, Alexandra V; DeVoti, James et al. (2015) Poly(I:C) induces controlled release of IL-36? from keratinocytes in the absence of cell death. Immunol Res 63:228-35|
|DeVoti, James; Hatam, Lynda; Lucs, Alexandra et al. (2014) Decreased Langerhans cell responses to IL-36?: 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|