Immunomodulatory Effects of CpG DNA
Members of the University of Iowa Environmental Health Sciences Research Center have been at the forefront of investigating the immunomodulatory effects of CpG motif (bacteria-like) DNA. DNA (native or oligodeoxy-nucleotides) containing the dinucleotides CG within specific base sequence contexts have been shown to induce patterns of immune stimulation including, among others, activation of dendritic cell subtypes, Th1-deviated cytokine responses, and suppression of atopic responses such as B-cell secretion of IgE, eosinophil chemotaxis, and airway inflammation. This is relevant to the relative protection against atopic disorders (though not of all airway inflammation) seen in agricultural populations. In addition, CpG oligonucleotides may prove to be a novel disease-modifying pharmacotherapeutic approach to asthma and atopic diseases.
EHSRC investigators have been particularly interested in the effects of CpG DNA on the innate and acquired immune responses. These studies have resulted in seminal observations relating to the pathogenesis of asthma and airway inflammation, and appeared to provide the scientific basis for the observation that individuals whose childhood is spent in agricultural environments have a reduced expression of atopy and allergic asthma compared to urban inhabitants. This has led to the development of the “hygiene hypothesis” which holds that the current epidemic of asthma and allergic disease in the developed world is due to an inadequate exposure to microbial products. One of the most immunopotent microbial products is bacterial DNA, which differs from mammalian DNA in its content of CpG motifs. Members of the EHSRC have explored the effects of CpG DNA on the immune response, and have found that it can both prevent and treat established atopic airway inflammation; these responses are mediated through multiple cells including B-cells, dendritic cells, and (at least indirectly) T-lymphocytes.
EHSRC investigators evaluated the effect of bacterial-like DNA (CpG oligonucleotides) on manifestations of asthma in a murine model. They found and were the first to report that airway eosinophilia, bronchial hyperresponsiveness, IgE antibodies, and Th2 cytokine expression were prevented by the administration of CpG oligonucleotides at the time of sensitization to experimental allergen. Subsequent studies demonstrated that induction of Th1-type immune responses was associated with protection against Th2-driven inflammation, but that these responses were not required.
Implications and Public Health Impact
CpG DNA can both prevent and reverse already-established eosinophilic inflammation. The protection is offered against both asthma and other forms of atopic disorders, such as allergic rhinitis. Not only inflammation, but also remodeling of the airways is prevented. Future studies are needed to establish if CpG oligonucleotides can be used to treat atopic asthma in humans.
Center Contribution
Studies of CpG DNA originated at the University of Iowa with Dr. Arthur Krieg and were introduced to EHSRC investigators by Dr. David Schwartz through the Pulmonary Biology Research Core. In 1996, Dr. Joel Kline was awarded an EHSRC pilot grant to perform animal studies of CpG Dna and inflammation. This research received facility support from the EHSRC Molecular Immunology and Cell Biology Facility Core, the Inhalation Toxicology Facility and the Clinical Exposure Facility.
Key Researchers and Support
Joel N. Kline, Associate Professor, Internal Medicine, Occupational & Environmental Health, 1R01HL059324, 5M01RR000059, 5P30ES005605;
Iftikar Hussain, Assistant Professor of Clinical Medicine, Internal Medicine, 5P30ES005605;
Zuhair Ballas, Professor, Internal Medicine, 5P30ES005605;
Patrick O’Shaughnessy, Assistant Professor, Occupational & Environmental Health, Civil & Environmental Engineering, 5P30ES005605;
Bradley Britigan, Professor, Internal Medicine, 5P30ES005605
References
Ballas ZK, Krieg AM, Warren T, Rasmussen W, Davis HL, Waldschmidt M, Weiner GJ. Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs. J Immunol 167:4878-4886, 2001.
Britigan, BE, Lewis, T.S., Waldschmidt, M., McCormick, M.L., and Krieg, A.M. Lactoferrin binds CPG-containing oligonucleotides and inhibits their immunostimulatory effects on human B cells. J. Immunol. 167:2921-2928, 2001.
Chen Y, Zhang J, Moore SA, Ballas ZK, Portanova JP, Krieg AM, Berg DJ. CpG DNA induces cyclooxygenase-2 expression and prostaglandin production. Int Immunol 13:1013-1020, 2001.
Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis HL, and Krieg AM. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617-1624, 2000.
Hussain I, Jain VV, Kitagaki K, Businga TR, O’Shaughnessy PO, Kline JN. Modulation of eosinophilic inflammation by CpG oligodeoxynucleotides in a murine model of allergic rhinosinusitis. Laryngoscope, 112:1819-26, 2002.
Hussain I, Kline JN. DNA, the immune system, and atopic disease. J Investig Dermatol Symp Proc. 9(1):23-28, 2004.
Hussain I, Kline JN. CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders. Curr Drug Targets Inflamm Allergy 2(3):199-205, 2003.
Jain VV, Businga TR, Kitagaki K, George CL, O’Shaughnessy PT, Kline JN. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. Am J Physiol Lung Cell Mol Physiol 285(5):L1137-1146, 2003.
Jain VV, Kitagaki K, Businga TR, Hussain I., George C., O’Shaughnessy P., Kline J.N. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J All Clin Immunol, 110(6):867-72: 2002
Jain VV, Kitagaki K, Kline JN. CpG DNA and immunotherapy of allergic airway diseases. Clin Exp Allergy 33(10):1330-1335, 2003.
Kitagaki K, Jain VV, Businga TR, Kline JN. Immunomodulatory effects of CpG oligodeoxynucleotides on established Th2 responses. Clin Diag Lab Immunol, 9:1260-1269, 2002.
Kline JN, Kitagaki K, Businga TR, Jain VV. Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am J Physiol Lung Cel Mol Physiol, 283:L170-L179, 2002.
Kline JN, Krieg AM, Waldschmidt TA, Ballas ZK, Jain V, Businga TR. CpG oligonucleotides do not require Th1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma. J Allerg Clin Immunol 104:1258-1264, 1999.
Kline JN, Waldschmidt TA, Businga TR, Lemish JE, Weinstock JV, Thorne PS, Krieg AM. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 160:2555-2559, 1998
Krieg AM, Kline JN. Immune effects and therapeutic applications of CpG motifs in bacterial DNA. Immunopharmacology 48(3):303-305, 2000.
Krug A, Rothenfusser S, Hornung V, Jahrsdörfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G. Identification of CpG oligonucelotide sequences with high induction of IFN-alpha/beta in pasmacytoid dendritic cells. Eur J Immunol 31:2154-2163, 2001.
Vollmer J, Janosch A, Laucht M, Ballas ZK, Schetter C, Krieg AM. Highly immunostimulatory CpG-free oligodeoxynucleotides for activation of human leukocytes. Antisense Nucleic Acid Drug Dev. 2002 Jun;12(3):165-75.