Local and systemic mechanisms of allergen-induced airway inflammation

Abstract

Allergic asthma is associated with pronounced inflammatory changes in the airways, including increased numbers of lymphocytes, neutrophils and mast cells, but most strikingly increased number of eosinophils. The accumulation of eosinophils within the airways in allergic airway inflammation is very likely a combination of increased production, migration and a prolonged survival of these cells. Eosinophils develop from CD34+ progenitor cells within the bone marrow (BM) and allergen challenge causes enhanced BM eosinophilopoiesis in asthmatic subjects as well as in animal models of allergen-induced airway inflammation. In addition, recent studies show that allergic subjects have increased number of CD34+ cells in BM and the airways.The aims of the present thesis were A) to determine which chemotactic factors govern the traffic of both the newly produced and the CD34+ eosinophils to the airways following allergen exposure, B) to establish whether or not the newly produced CD34+ eosinophilic cells have a capacity to proliferate locally within the airways following allergen exposure, and C) to evaluate the role of T lymphocytes in allergen-induced BM eosinophilopoiesis. In order to assess this, we used mouse models of allergen-induced airway inflammation. Wild type mice, IL-5 transgenic mice (NJ. 1638; CD3IL-5+) and mice deficient in CD4+ (CD4-/-) or CD8+ (CD8-/-) T cells were studied. Cells produced during the allergen exposure period were identified using a thymidine analogue, bromodeoxyuridine (BrdU). Local treatment with neutralizing anti-eotaxin-1 or anti-eotaxin-2 of allergen sensitized/exposed mice caused a significant reduction in newly produced and CD34+ BAL eosinophils. Significant airway concentrations of the neutralizing antibodies had to be achieved before a reduction in the number of allergen-induced airway eosinophils could be obtained. The expression of chemokine receptor 3 (CCR3) was upregulated on CD34+ BM cells leading to a significant increase of CD34+/CCR3+ eosinophil-lineage committed cells in BM, blood and BAL following allergen exposure. A fraction of the CD34+/CCR3+ cells proliferated in situ in response to allergen. In addition, in vitro colony formation of lung CD34+ cells was increased by IL-5 or eotaxin-2.Naïve crossbred CD3IL-5+/CD8-/- mice showed a significant reduction in the number of BM eosinophils when compared to naïve CD3IL-5+ or naïve crossbred CD3IL-5+/CD4-/- mice. Allergen exposed CD4-/- and CD8-/- mice had a significantly reduced number of BM and BAL eosinophils compared to wild type mice. Furthermore, a significant reduction in newly produced BM eosinophils (BrdU+/MBP+ cells) was found in both knockout strains when compared to allergen-challenged wild type mice. Eotaxin-2 levels in BALF of allergen-challenged CD4-/- mice were similar to saline exposed wild type mice.In conclusion, this thesis shows that the CCR3/eotaxin pathway is intricately involved in the regulation of allergen-driven in situ hematopoiesis and the accumulation/mobilization of CD34+ eosinophil-lineage committed cells in the lung. Allergen-induced BM eosinopilopoiesis is partly regulated by CD4+ and CD8+ T cells. In addition, CD4+ T cells may regulate IL-5 dependent eosinophil maturation in allergen-induced bone marrow eosinophilia. The subsequent traffic of eosinophils to the airways is likely to be at least partly regulated by CD4+ T cell dependent local airway eotaxin-2 production.