Individuals with one atopic disease are far more likely to develop a second. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. This association, suggesting a role for AD as an entry point for subsequent allergic disease, is a phenomenon known as the ‘atopic march’. While the underlying cause of the atopic march remains unknown, recent evidence suggests a role for the cytokine TSLP. We have established a mouse model to determine whether TSLP plays a role in this phenomenon, and in this study show that mice exposed to the antigen OVA in the skin in the presence of TSLP develop severe airway inflammation when later challenged with the same antigen in the lung. Interestingly, neither TSLP production in the lung nor circulating TSLP is required to aggravate the asthma that was induced upon subsequent antigen challenge. However, CD4 T cells are required in the challenge phase of the response, as was challenge with the sensitizing antigen, demonstrating that the response was antigen-specific. This study, which provides a clean mouse model to study human atopic march, indicates that skin-derived TSLP may represent an important factor that triggers progression from atopic dermatitis to asthma.

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has been associated with the promotion of type 2 inflammation and the induction of allergic disease. In humans TSLP is elevated in the lungs of asthma patients and in the lesional skin of individuals with atopic dermatitis, while mice lacking TSLP responses are refractory to models of Th2-driven allergic disease. While several cell types, including dendritic cells, basophils, and CD4 T cells, have been shown to respond to TSLP, its role in macrophage differentiation has not been studied. Type 2 cytokines (i.e. IL-4 and IL-13) can drive the differentiation of macrophages into alternatively activated macrophages (aaMΦ, also referred to as M2 macrophages). This population of macrophages is associated with allergic inflammation. We therefore reasoned that TSLP/TSLPR signaling may be involved in the differentiation and activation of aaMΦs during allergic airway inflammation. We report here that TSLP changes the quiescent phenotype of pulmonary macrophages toward an aaMΦ phenotype during TSLP-induced airway inflammation. This differentiation of airway macrophages was IL-13-, but not IL-4-, dependent. Taken together, we demonstrate here that TSLP/TSLPR plays a significant role in the amplification of aaMΦ polarization and chemokine production, thereby contributing to allergic inflammation.

The cytokine thymic stromal lymphopoietin (TSLP) functions as a regulator of bone marrow B-cell development and a key initiator of allergic inflammation. In the current study, we show that mature B cells, derived from transgenic mice with systemically elevated levels of TSLP (K5-TSLP mice), exhibit markedly enhanced mitogenic responses in vitro and that this enhanced responsiveness leads to polyclonal B-cell activation and development of autoimmune hemolytic anemia in vivo. In contrast, B cells derived from K5-TSLP mice lacking CD4(+) T cells failed to show polyclonal activation. Furthermore, neither mature B-cell activation nor hemolytic anemia occurred in IL-4-deficient K5-TSLP mice. Consistent with these findings, activation of mature B cells occurred independently of B-cell intrinsic TSLP signals. Taken together, our results demonstrate that systemic alterations in TSLP, through induction of IL-4 from CD4(+) T cells and other cell types, functions as an important factor in peripheral B-cell homeostasis and promotion of humoral autoimmunity.

mortality to female rats at 6 months (4/9, 44% vs. 5/11, 45%), as well as similar pericardial effusions and echocardiogram parameters. Conclusion: These results demonstrate that SS female rats exhibited greater sensitivity to image-guided cardiac RT compared to age-matched male rats treated with a 1.5 cm collimator, although volumes of lung receiving 5 and 20 Gy were much higher in female rats. Male rats treated with a 2.0 cm collimator had similar lung doses to the female rats treated with a 1.5 cm collimator, and had similar severity of RIHD as females treated with 1.5 cm collimator, as measured by mortality and echo parameters. This study adds to data suggesting the amount of lung tissue irradiated may be a predictor of morbidity and mortality in RIHD. This project has the potential to enhance the effectiveness and toxicity profile of RT.