Natural killer T cells are not the predominant T cell in asthma and likely modulate, not cause, asthma.

Asthma is a multifactorial disease of the airways characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Conventional MHC class II-restricted CD4(+) T cells are considered a key cell in asthma pathogenesis because they have a broad T-cell receptor repertoire, providing specificity and reactivity to diverse protein allergens. This notion was challenged when a study found that invariant Natural Killer (NK) T cells were the predominant T cells in the lung and bronchoalveolar lavage fluid of all asthmatic subjects studied. This finding was provocative because invariant NKT cells have a very limited T-cell receptor repertoire and are specific for a restricted set of lipid antigens that bind to CD1d, a nonpolymorphic MHC-like molecule. However, multiple subsequent studies failed to replicate the initial study and instead found that invariant NKT cells are present as a small fraction of the total T cells in the asthmatic lung. Thus, we believe that although CD1d-restricted NKT cells might play a role in modulating the asthmatic phenotype, they are not the critical drivers of the asthmatic response, a role we believe is still held by conventional MHC class II-restricted CD4(+) T cells.

System for simultaneous tissue-specific and disease-specific regulation of therapeutic gene expression.

Gene therapy has been proposed as an alternative strategy for treating nongenetic disorders, such as cancer and coronary artery disease. However, for many of these types of diseases, the therapeutic genes must be tightly regulated, as extensive toxicity and pathology can result if their expression is not adequately controlled. Toward this end, we have developed a regulatory system in which the expression of a therapeutic transgene is controlled simultaneously by both a tissue-specific promoter and a disease-specific promoter. Thus, the transgene of interest will be expressed in a given cell only if both of these promoters are active. Unlike many other transgene-regulatory systems that have been previously developed, this system does not require the persistent expression of any foreign genes that could provoke an immune response or lead to toxicity. As proof of concept, we synthesized a construct harboring the lacZ transgene that is under the control of both the hepatocyte-specific human alpha(1)-antitrypsin promoter and the zinc-inducible mouse metallothionein promoter. We show that reporter gene expression from this construct is regulated in both a hepatocyte-specific and zinc-regulated manner, as reporter gene expression occurs only in hepatocyte-derived cells that have been exposed to zinc. The improved regulation offered by our system would facilitate the targeting of transgene expression to sites of disease in the body and spare healthy tissue, thereby considerably enhancing the therapeutic window of gene therapy.