Editorial: leukocyte-targeting toxins as therapeutics in allergic asthma.

Asthma is a prevalent inflammatory disorder of the airway, characterized by immune cell infiltration, epithelial barrier defects, mucous hypersecretion, and obstruction of airflow [1]. In allergic asthma, patients are sensitized to inhaled allergens in a Th2-driven process of allergen-specific IgE production. Subsequent exposures to inhaled allergens result in inflammatory mediator release from mast cells and basophils that enhance blood vessel permeability, leukocyte recruitment, and chronic inflammation [2]. Current therapies largely target the symptoms of this disease and are not effective for all allergic asthma patients [3]. New targets that are fundamentally involved in allergic asthma are being pursued to block more effectively early events in the pathogenesis of allergic asthma. In this issue of the Journal of Leukocyte Biology, Gupta et al. [4] report that LFA-1 is a promising target in human allergic asthma patient samples. They test this by use of a mouse model of allergic asthma and an experimental toxin directed against LFA-1, called LtxA (Leukothera). Integrins form heterodimers on the cell surface that regulate cell adhesion and motility through interactions with ligands expressed on activated endothelium or within the extracellular matrix. Leukocyte integrins play key roles in leukocyte adhesion to blood vessel walls, spreading, and transendothelial migration (Fig. 1) [5]. Relevant integrins include VLA-4 (or a4b1), macrophage 1 antigen (aMb2), and LFA-1 (aLb2, or CD11a/CD18). In asthmatic airways, ligands for these integrins are expressed at high levels, including VCAM-1 and ICAM-1 [6]. This promotes firm adhesion and tissue invasion by immune cells expressing VLA-4 and LFA-1 and has led research into therapeutic blockade of these integrins in asthma and autoimmune disorders. Efalizumab (Raptiva) is an inhibitory LFA-1 antibody that was approved by the U.S. Food and Drug Administration in 2003 for treatment of an autoimmune disease but was withdrawn in 2009 as a result of risk of developing fatal brain infections [7]. One potential drawback with Efalizumab is that it targets all LFA-1-positive cells, whereas targeting only activated LFA-1 would be preferable for therapeutic applications. LtxA is a toxin secreted by the gramnegative bacterium Aggregatibacter actinomycetemcomitans that binds activated LFA-1 on leukocytes leading to cell death [8]. The therapeutic potential of LtxA was first demonstrated in a leukemia model, showing that LtxA preferentially targets leukemic cells expressing activated LFA-1 compared with normal leukocytes [8]. Moreover, LtxA treatment was effective in treating leukemias that had relapsed on standard chemotherapy [9]. In addition, LtxA was tested in a xenograft model of human psoriasis and shown to allow resolution of disease by preferential targeting of proinflammatory leukocytes [10]. In this issue of the Journal of Leukocyte Biology, Gupta et al. [4] have now extended studies of LFA-1 expression in allergic asthma patient samples and effects of LFA-1 blockade with LtxA in a mouse model of allergic asthma [4]. They identified a circulating cell population with elevated levels of LFA-1 (CD11a) in asthma patients that were not found in healthy controls. This population was composed of CD14CD4 CD11a monocytes and CD3CD4 CD11a non-Th cells. The authors went on to show that these CD11a cells undergo apoptosis upon LtxA treatment ex vivo, whereas CD11a cells within the same samples were unaffected. These findings were tested further in mice chronically exposed to HDM extract. The authors validate high expression of LFA-1 in leukocytes from broncheoalveolar lavage fluid of allergic mice compared with control mice. This provides further evidence for the potential targeting of LFA-1 cells in allergic asthma. The authors go on to compare treatment of HDM mice directly with LtxA or dexamethasone, the current gold standard corticosteroid used as a general immunosuppressant. Importantly, the authors demonstrate that LtxA outperforms dexamethasone by several metrics. LtxA-treated mice were protected from airway infiltration of all major leukocyte subtypes, including neutrophils, eosinophils, macrophages, and B and T cells. LtxA-treated mice were protected from airway remodeling induced by HDM exposure and had reduced expression of several cytokines implicated in asthma pathogenesis within the lung. LtxA treatment was more effective than dexamethasone in blocking neutrophil