Clifford J. Bellone, Ph.D.
Clifford J. Bellone, Ph.D.
Doisy Research Center
Clifford J. Bellone, Ph.D.
Many immunological diseases are the result of the combined activities of both the adaptive and innate systems. The immunopathology of these diseases is generally a direct consequence of the cytokines that are produced under the conditions surrounding a particular disease. Cytokines are produced in many tissues by a variety of cell-types and have a broad range of biological activities, including inflammation when produced in aberrant amounts. My laboratory studies two immune mediated diseases at the cellular and molecular levels. Our goals are to understand the mechanisms which activate both the adaptive and innate immune responses that lead to disease.
Allergic bronchopulmonary aspergillosis (ABPA) is an immune hypersensitivity disease that is a complication in patients with either asthma or cystic fibrosis. It results from the allergic response to Aspergillus antigens that colonize the respiratory tracts in patients compromised by either of the above mentioned diseases. Our studies focus on the HLA class II molecules and associated Af antigens that activate and direct CD4+ T cells to produce the cytokines IL-4, IL-5, and IL-13 which lead to an allergic response and disease. A major goal of this work is to understand how the HLA class II molecules in association with antigen trigger intracellular signals that program T cells to produce particular cytokine profiles.
Identification and characterization of the immune response to the smallpox vaccine. Bioterrorism has been pushed to the forefront by the tragic events of September 11, 2002. Smallpox is a likely candidate virus to be used by terrorists because of the lack of immunity in a large number of the global population. In the event of a bioterrorist attack mass vaccination would have to take place using the best possible vaccines that are safe and rapidly effective. It is not clear that the existing smallpox vaccines meet these requirements. Because of historical reasons little is known regarding the cellular and molecular mechanisms that underlie the immune response to the smallpox virus. Our laboratory studies this response in lymphocytes derived from vaccinated volunteers. Our focus is to map the critical viral epitopes that immune T cells target in successful immune responses. In addition we identify and characterize the phenotype and function of the T cells that are directed to these epitopes. Ultimately this information is needed for the design of new safe and effective smallpox vaccines.
Regulation of IL-1ß in keratinocytes. Chloracne is a severe debilitating inflammatory skin disease that is promoted by the dysregulated production of the cytokine, IL-1. A number of agents, most prominently bacterial components, are responsible for the production and release of IL-1. Although not well studied, there are several reports that halogenated aromatic hydrocarbons (HAHs), which are implicated in some inflammatory diseases, also stimulate IL-1 in several different tissues. The most recognizable and potent member of this class of compounds is 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD). Our work has shown that TCDD triggers IL-1 production in differentiated keratinocytes, a major cell type in skin, and this response is mediated by the aryl hydrocarbon receptor (AhR). This signaling pathway acting on the IL-1 gene to promote transcription appears to be through a novel mechanism. Our goals are to identify and characterize the transcription factors responsible for the activation of IL-1 transcription through this novel mechanism.
Publications (1997 to present):
Nguyen TL, Khurana SS, Bellone CJ, Capoccia BJ, Sagartz JE, Kesman RA, Mills JC, DiPaolo RJ..
Autoimmune gastritis mediated by CD4+ T cells promotes the development of gastric cancer.
Cancer Research, 2013, Feb. 1. Epub ahead of print.
Pubmed Abstract Link: 23378345
Handley L, Buller RM, Frey SE, Bellone C, Parker, S.
The new ACAM2000 vaccine and other therapies to control orthopoxvirus outbreaks and bioterror atttacks.
Expert Rev Vaccines. 2009 Jul;8(7):841-50. Review.
Pubmed Abstract Link: 19538111
Lawrence SJ, Lottenbach KR, Newman FK, Buller RM, Bellone CJ, Chen JJ, Cohen GH, Eisenberg RJ, Belshe RB, Stanley SL Jr, Frey SE. Antibody responses to vaccinia membrane proteins after smallpox vaccination. J Infect Dis. 2007 Jul 15;196(2):220-9.
Pubmed Abstract link: 17570109
Liu B, Yang Y, Chernishof V, Loo RR, Jang H, Tahk S, Yang R, Mink S, Shultz D, Bellone CJ, Loo JA, Shuai K.
Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell. 2007 Jun 1;129(5):903-14.
Pubmed Abstract Link: 17540171
Koehm S, Slavin RG, Hutcheson PS, Trejo T, David CS, Bellone CJ.
HLA-DRB1 alleles control allergic bronchopulmonary aspergillosis-like pulmonary responses in humanized transgenic mice. J Allergy Clin Immunol. 2007 Jun 8.
Pubmed Abstract link: 17561243
Henley DV, Bellone CJ, Williams DA, Ruh MF. MAPK signaling pathways modulate IL-1beta expression in human keratinocytes. Arch Biochem Biophys. 2004 Apr 1;424(1):112-8.
PubMed Abstract link: 15019843
Henley DV, Bellone CJ, Williams DA, Ruh TS, Ruh MF. Aryl hydrocarbon receptor-mediated posttranscriptional regulation of IL-1beta. Arch Biochem Biophys. 2004 Feb 1;422(1):42-51.
PubMed Abstract link: 14725856
Chauhan B, Hutcheson PS, Slavin RG, Bellone CJ. MHC restriction in allergic bronchopulmonary aspergillosis. Front Biosci. 2003 Jan 01;8:s140-8. Review.
PubMed Abstract link: 12459546
Chauhan B, Hutcheson PS, Slavin RG, Bellone CJ. T-cell receptor bias in patients with allergic bronchopulmonary aspergillosis. Hum Immunol. 2002 Apr;63(4):286-94.
PubMed Abstract link: 12039410
Chauhan B, Santiago L, Hutcheson PS, Schwartz HJ, Spitznagel E, Castro M, Slavin RG, Bellone CJ.
Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis.
J Allergy Clin Immunol. 2000 Oct;106(4):723-9.
Ndengele MM, Bellone CJ, Lechner AJ, Matuschak GM.
Brief hypoxia differentially regulates LPS-induced IL-1beta and TNF-alpha gene transcription in RAW 264.7 cells. Am J Physiol Lung Cell Mol Physiol. 2000 Jun;278(6):L1289-96.
Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription.
J Immunol. 1999 May 1;162(9):5367-73.
Hu W, Bellone CJ, Baldassare JJ.
RhoA stimulates p27(Kip) degradation through its regulation of cyclin E/CDK2 activity.
J Biol Chem. 1999 Feb 5;274(6):3396-401.
1 Ruh MF, Bi Y, Cox L, Berk D, Howlett AC, Bellone CJ. Effect of environmental estrogens on IL-1beta promoter activity in a macrophage cell line. Endocrine. 1998 Oct;9(2):207-11.
Ruh MF, Bi Y, D'Alonzo R, Bellone CJ. Effect of estrogens on IL-1beta promoter activity.
J Steroid Biochem Mol Biol. 1998 Aug;66(4):203-10.
Chauhan B, Santiago L, Kirschmann DA, Hauptfeld V, Knutsen AP, Hutcheson PS, Woulfe SL, Slavin RG, Schwartz HJ, Bellone CJ. The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis.
J Immunol. 1997 Oct 15;159(8):4072-6.
Godambe SA, Chaplin DD, Takova T, Bellone CJ. Molecular Dissection of the Murine IL-1beta Promoter.
Am J Ther. 1995 Sep;2(9):677-686.
NIH/NIAID N01 AI15436.
Small animal models of human orthopoxvirus infections for evaluation of experimental therapies.
Sympathetic regulation of endotoxemia in drug abuse.
HLA and pulmonary inflammation in an ABPA transgenic animal model.
NIH R01 GM43153.
Liver-lung interactions during gram-negative endotoxemia.
NIH R21 AI53346.
Immunodominant epitopes of a smallpox vaccine in humans.