thymic-factor--circulating and Asthma

Despite long-standing efforts to enhance care for chronic asthma, symptomatic treatments remain the only option to manage this highly prevalent and debilitating disease. We demonstrate that key pathology of allergic asthma can be almost completely resolved in a therapeutic manner by inhaled gene therapy. After the disease was fully and stably established, we treated mice intratracheally with a single dose of thymulin-expressing plasmids delivered via nanoparticles engineered to have a unique ability to penetrate the airway mucus barrier. Twenty days after the treatment, we found that all key pathologic features found in the asthmatic lung, including chronic inflammation, pulmonary fibrosis, and mechanical dysregulation, were normalized. We conducted tissue- and cell-based analyses to confirm that the therapeutic intervention was mediated comprehensively by anti-inflammatory and antifibrotic effects of the therapy. We believe that our findings open a new avenue for clinical development of therapeutically effective gene therapy for chronic asthma.

Topics: Animals; Asthma; Disease Models, Animal; Genetic Therapy; Lung; Mice; Mice, Inbred BALB C; Nanoparticles; Thymic Factor, Circulating

Thymulin has been shown to present anti-inflammatory and anti-fibrotic properties in experimental lung diseases. We hypothesized that a biologically active thymulin analog gene, methionine serum thymus factor, delivered by highly compacted DNA nanoparticles may prevent lung inflammation and remodeling in a mouse model of allergic asthma. The DNA nanoparticles are composed of a single molecule of plasmid DNA compacted with block copolymers of poly-L-lysine and polyethylene glycol (CK30PEG), which have been found safe in a human phase I/II clinical trial. Thymulin plasmids were detected in the lungs of ovalbumin-challenged asthmatic mice up to 27days after administration of DNA nanoparticles carrying thymulin plasmids. A single dose of DNA nanoparticles carrying thymulin plasmids prevented lung inflammation, collagen deposition and smooth muscle hypertrophy in the lungs of a murine model of ovalbumin-challenged allergic asthma, leading to improved lung mechanics. In the present model of chronic allergic asthma, highly compacted DNA nanoparticles using thymulin analog gene modulated the inflammatory and remodeling processes improving lung mechanics.

Topics: Airway Remodeling; Animals; Asthma; DNA; Genetic Therapy; Lung; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Plasmids; Thymic Factor, Circulating

Topics: Adjuvants, Immunologic; Asthma; Chronic Disease; Drug Evaluation; Humans; Immune Tolerance; Prognosis; Remission Induction; Thymus Hormones; Time Factors

In asthma, it has been hypothesized that suppressor T-lymphocytes play a protective role and have been reported to be functionally abnormal. Thymic hormone thymulin plays a role in the differentiation of T-lymphocytes and plasmatic thymulin concentration and is related to the functional state of the thymus. To assess the participation of the thymus in the impairment of T-lymphocyte function, we measured plasma thymulin activity in children with allergic asthma (N = 40). The plasma thymulin activity was compared with plasma thymulin activity of children with nonallergic asthma (N = 6), children with atopic dermatitis (N = 9) or allergic rhinitis (N = 7), and in age-matched healthy control children (N = 18) (age range of children studied, 2 to 19 years). Thymulin activity was found within the normal range (1/16 to 1/64) in all control children and in all children with allergic asthma and allergic rhinitis, as well as in all children with intrinsic asthma and atopic dermatitis. Our findings are at variance with the low thymulin activity previously reported in allergic asthma, and we could not explain these discrepancies. (Both studies used the same bioassay, and the population studied did not appear to be different.) T-lymphocyte abnormalities in subjects with asthma must be assessed by other means than measurement of thymic function.

Topics: Adolescent; Animals; Asthma; Child; Child, Preschool; Female; Humans; Immunoenzyme Techniques; Immunoglobulin E; Infant; Male; Mice; Mice, Inbred C57BL; Skin Tests; T-Lymphocytes; Thymic Factor, Circulating; Thymus Hormones

Topics: Adjuvants, Immunologic; Adult; Asthma; Cell Differentiation; Female; Humans; Male; Middle Aged; T-Lymphocytes; Thymus Hormones

Topics: Adjuvants, Immunologic; Adolescent; Antibody Formation; Asthma; Child; Child, Preschool; Drug Evaluation; Female; Humans; Immunity, Cellular; Male; Thymus Hormones