Intrapulmonary targeting of RANTES/CCL5‐responsive cells prevents chronic fungal asthma

Abstract

Regulated upon activation in normal T cells, expressed, and secreted (RANTES)/CCL5 is abundantly expressed during atopic asthma, suggesting that it is an important mediator of this disease. The contribution of intrapulmonary RANTES/CCL5-sensitive cells during Aspergillus fumigatus-induced airway disease in mice was assessed in this study. The intranasal delivery of a chimeric protein comprised of RANTES/CCL5 and a truncated version of Pseudomonas exotoxin A (RANTES-PE38) significantly attenuated serum IgE, peribronchial eosinophilia, and airway hyperreactivity when it was administered from day 0 to 15 after intratracheal conidia challenge in A. fumigatus-sensitized mice but had little effect when delivered from day 15 to 30 after conidia challenge. Intranasal RANTES-PE38 treatment enhanced macrophage recruitment and accelerated fungal clearance in the lungs of RANTES-PE38-treated mice. These data reveal a major role for RANTES/CCL5 and its receptors in the development of fungal asthma yet reveal only a modest role in the chronic remodeling of the allergic airway in this disease.

Toll like receptor-2 modulates both innate and adaptive immune responses during chronic fungal asthma in mice

“…Airway hyperresponsiveness is a hallmark of many models of allergic and asthmatic airway disease, but this physiologic change persists during fungal asthma due to the retention of fungal material in the lungs of A. fumigatus-sensitized mice challenged with conidia [32][33][34]. Our histological analysis of whole lung samples at various days after conidia suggested that there was increased abundance of fungal material in the lungs of A. fumigatus-sensitized TLR2 -/-mice versus the wildtype group.…”

The link between fungi and severe asthma: a summary of the evidence

“…Elimination of this fungal material from these mice reverses these major features. Experimental strategies that have been successfully employed to eliminate fungal material from the lungs of Aspergillussensitised mice include genetic deletion of CC chemokine receptor (CCR)1 [93], CXCR2 [94] or CCR4 [95], or eradication of IL-13 [96] or RANTES/CCL5-responsive cells [97]. All of these approaches also result in resolution of allergic airway inflammation and airway hyperreactivity, and enhancement of the pulmonary innate immune response through macrophages and/or neutrophils.…”

Infectious disease, the innate immune response, and fibrosis

“…Experimentally, the allergic responseto A. fumigatus, which is dominated by Th2 cytokines and chemokines, markedly compromises neutrophil and macrophage function, allowing intact conidia and degraded fungal components to persist for many weeks in M2 macrophages from allergic mice (91). Strategies directed toward the elimination of fungal material in the lungs of allergic mice through attenuation of the Th2 inflammatory response (92)(93)(94)(95)(96) or promotion of M2 macrophage apoptosis (97,98) have proved very effective at reversing established experimental fungal asthma and the airway remodeling associated with this model. Therefore, the allergic responses to A. fumigatus conidia observed in atopic individuals and asthmatics seems to promote chronic airway remodeling through a skewed immune response that fails to adequately clear this pathogen from the pulmonary system.…”