Angela Haczku, M.D., Ph.D.
Research Associate Professor of Medicine and Pharmacology
University of Pennsylvania Medical Center
Pulmonary, Allergy, & Critical Care Division
Translational Research Laboratories (TRL)
125 South 31st Street, TRL Suite 1200
Philadelphia, PA 19104-3413
tel.: (215) 573-4718
fax: (215) 746-1224
Education: M.D., University Medical School of Debrecen, Hungary
Ph.D., National Heart and Lung Institute, University of London, United Kingdom
Residency: University Medical School of Debrecen, Hungary
Postdoctoral Fellowship: National Jewish Medical and Research Center, University of Colorado, Denver, CO
Our research focuses on how the innate and adaptive immune systems cooperate during development and resolution of airway inflammation. In my PhD and early postdoctoral studies, I concentrated on demonstrating that T lymphocytes (Th2 cells in particular) are essential in regulation of the inflammatory changes in the lung. These cells, however, cannot exert a proper function by themselves. The pulmonary innate immune system both cells and released epithelial products, play a very important role in shaping the direction and extent of the adaptive immune changes and the consequent inflammatory airway response. Research fellows in my laboratory are involved in projects studying asthma exacerbation by environmental exposures (cigarette smoke and ozone inhalation or psychosocial stress). We investigate the role of lung collectins, IgE-mediated immune mechanisms, promoter regulation of the surfactant protein D gene and mechanisms of corticosteroid resistance. My laboratory is involved in multiple collaborations with the Airways Biology Initiative, the Center of Excellence in Environmental Toxicology and the Allergy & Immunology Section. Our projects are funded by the NIH and also supported by grants from the American Lung Association and the pharmaceutical industry. We work in a lively, highly collaborative laboratory setting and have one of the best animal facilities at UPenn for our transgenic mice. The main techniques include lung physiology (pulmonary function testing), the use of specifically designed animal exposure and plethysmography chambers and state of the art setups for a wide spectrum of immunological, cell and molecular biology techniques.
Current basic research projects open to fellow participation:
Innate immune regulation of ozone-induced exacerbation of asthma.
The surface area of an adult lung has approximately the same size as a football field. This area is constantly bombarded by inhaled foreign particles and yet it normally remains inflammation and infection free. The mechanisms that ensure both the elimination of inhaled toxic, infectious or allergenic material and protection from an ensuing inappropriate immune response are unclear but we know that the resident innate and adaptive immune mechanisms play a key function. This project aims to unravel dendritic cell-mediated regulatory pathways during development of inflammatory airway changes. My laboratory was one of the few that originally raised the importance of the lung collectin, SP-D in allergen-induced airway inflammation and the one that discovered a feedback regulation between Th2 cytokines (IL-4/IL-13) and IL-6 with the SP-D gene. Our current studies support a novel concept that lectin-like modulation of the innate and the adaptive immune responses in the lung facilitates resolution of the inflammatory airway changes and is necessary to prevent chronic damage. These studies are important because they will provide us with unique, novel opportunities to control and manipulate the pulmonary immune system.
Social stress and steroid resistance in allergic airway inflammation.
Psychosocial stress has a severe impact on the course of chronic asthma but the mechanisms are poorly defined. Altered innate immune cell-T cell interactions may play a role in stress-induced enhancement of the allergic immune response. This project will study the importance of altered glucocorticoid responsiveness by immune and epithelial cells and the role of the innate immune lung collectins in the impact of psychosocial stress on allergic airway inflammation. We developed a unique mouse model to mimic these conditions in order to unravel the cellular and molecular regulatory pathways.
Role of TSLP in allergic airway inflammation.
Air pollution, particularly O3, induces exacerbations of asthma that substantially worsen morbidity and mortality. Regulation of pulmonary dendritic cell maturation and migration is important in protection from development of chronic damage. Currently, neither the effects of O3 on dendritic cells nor the consequent alterations in the pulmonary immune system are understood. We hypothesize here that a protective presence of SP-D in the normal airways inhibits activation of the thymic stromal lymphopoietin (TSLP). This gene encodes a hemopoietic cytokine proposed to signal through a heterodimeric receptor complex composed of the TSLP receptor and the IL-7R alpha chain. It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells. Alternative splicing of this gene in humans results in two transcript variants and has been shown to be strongly associated with predisposition to asthma. This project will unravel the importance of TSLP in ozone-induced exacerbation of the asthmatic changes using mouse models.
- Myint M, Limberis MP, Bell P, Somanathan S, Haczku A, Wilson JM, Diamond SL. In Vivo Evaluation of Adeno-Associated Virus Gene Transfer in Airways of Mice with Acute or Chronic Respiratory Infection. Hum Gene Ther. 2014 Sep 22. [Epub ahead of print]
- Adam VS, Crosariol M, Kumar S, Ge MQ, Czack SE, Roy S, Haczku A, Tretiakova A, Wilson JM, Limberis MP. AAV9-mediated airway expression of antibody protects old and immunodeficient mice against influenza. Clin Vaccine Immunol. 2014 Sep 10. [Epub ahead of print]
- Kim WK, Jain D, Sanchez MD, Koziol-White CJ, Matthews K, Ge MQ, Haczku A, Panettieri RA Jr, Frieman MB, Lopez CB. Deficiency of MDA5 Results in Exacerbated Chronic Post-Viral Lung Inflammation. Am J Respir Crit Care Med. 2014 Jan 13.
- Yang Q, Monticelli LA, Saenz SA, Chi AW, Sonnenberg GF, Tang J, De Obaldia ME, Bailis W, Bryson JL, Toscano K, Huang J, Haczku A, Pear WS, Artis D, Bhandoola A. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity. 2013 Apr 18; 38(4):694-704.
- Jordan M, Haczku A. Autoreactive bronchus-associated lymphoid tissue in interstitial lung disease: friend or foe? Am J Respir Cell Mol Biol. 2013 Apr;48(4):397-8.
- Jiang Z, Fehrenbach M, Ravaioli G, Ducka B, Redai IG, Sheardown SA, Wilson S, Macphee C, Haczku A. The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in aspergillus fumigatus sensitized mice. Respir Res. 2012 Nov 12; 13(1):100. [Epub ahead of print]
- Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, Krymskaya VP. Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse Model of Pulmonary Lymphangioleiomyomatosis (LAM). Sci Transl Med. 2012 Oct 3;4(154):154ra134.
- Haczku A. The dendritic cell niche in chronic obstructive pulmonary disease. Respir Res. 2012 Sep 19;13(1):80. [Epub ahead of print]
- Sziksz E, Vannay A, Haczku A. Galectin-9: a suppressor of food allergy? Allergy. 2012 Mar;67(3):293-5.
- Anderson AL, Zheng Y, Song D, Larosa D, Van Rooijen N, Kierstein G, Kierstein S, Haczku A, Levinson AI. The B-cell superantigen Finegoldia magna protein L causes pulmonary inflammation by a mechanism dependent on MyD88 but not B cells or immunoglobulins. Inflamm Res. 2012 Feb; 61(2):161-9.