Alarming increases in the incidence, morbidity and mortality of allergic asthma have been noted over the last few decades. Although it is well established that allergic asthma is a Th2 cell dependent process, the molecular mechanisms underlying the development of pathogenic Th2 cells and the mechanisms by which they confer disease are currently unknown. Recent studies in murine models of asthma provide compelling evidence that mediators of the innate immune response, the anaphylatoxins (AT) C3a and C5a, play important roles in the pathophysiology of experimental asthma. Both ATs are long recognized as mediators of proinflammatory functions and inductors of smooth muscle contraction, features that are both relevant to the allergic phenotype. However, recent data suggest novel opposing immunoregulatory roles for the ATs at the level of T-cell polarization. Specifically, genetic deletion of the C3a receptor attenuates the allergic phenotype associated with diminished Th2 cytokine production, while genetic deficiency of C5 or blockade of the C5a/C5aR interaction has the opposite effect. The exact mechanisms underlying the pivotal roles of these ATs in allergic responses remain unknown. Our preliminary data strongly suggest that C5a regulates Th differentiation by the induction of the Th1-promoting cytokine IL-12 from antigen presenting cells. Thus the central goal of the proposed studies is to define the complex role of ATs in the pathogenesis of allergic asthma. Specifically, we will test the hypotheses that ATs regulate the allergic response at two levels: (A) the initiation and maintenance of T cell polarization; and (B) the regulation of the allergic effector mechanisms by direct and indirect effects on airway smooth muscle activation.
The specific aims are: (1) to determine the kinetics and dynamics of the mechanistic roles played by C3a and C5a in regulating allergic asthma in vivo; (2) to define the mechanisms by which C3a and CSa bias T cell differentiation during the sensitization phase; and (3) to determine downstream mechanisms of C3a- and C5a mediated airway contraction and inflammation during the effector phase. The results of these studies should provide valuable insight into the immunopathogenic mechanisms involved in the development of allergic asthma and may lead to the development of novel immunotherapeutic strategies for the treatment of this ever-increasing disease.
| Zhang, Xun; Kohl, Jorg (2010) A complex role for complement in allergic asthma. Expert Rev Clin Immunol 6:269-77 |
| Weaver Jr, Donald J; Reis, Edimara S; Pandey, Manoj K et al. (2010) C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. Eur J Immunol 40:710-21 |
| Zhang, Xun; Schmudde, Inken; Laumonnier, Yves et al. (2010) A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol 185:6741-52 |
| Khodoun, Marat; Strait, Richard; Orekov, Tatyana et al. (2009) Peanuts can contribute to anaphylactic shock by activating complement. J Allergy Clin Immunol 123:342-51 |
| Zhang, Xun; Lewkowich, Ian P; Köhl, Gabriele et al. (2009) A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol 182:5123-30 |
| Klos, Andreas; Tenner, Andrea J; Johswich, Kay-Ole et al. (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46:2753-66 |
| Rittirsch, Daniel; Flierl, Michael A; Nadeau, Brian A et al. (2008) Functional roles for C5a receptors in sepsis. Nat Med 14:551-7 |
| Reis, Edimara S; Barbuto, J A M; Kohl, Jorg et al. (2008) Impaired dendritic cell differentiation and maturation in the absence of C3. Mol Immunol 45:1952-62 |
| Kohl, Jorg; Wills-Karp, Marsha (2007) A dual role for complement in allergic asthma. Curr Opin Pharmacol 7:283-9 |
| Kohl, Jorg; Wills-Karp, Marsha (2007) Complement regulates inhalation tolerance at the dendritic cell/T cell interface. Mol Immunol 44:44-56 |
Showing the most recent 10 out of 15 publications
