Synergistic therapeutic effects of combined adenovirus-mediated interleukin-10 and interleukin-12 gene therapy on airway inflammation in asthmatic mice.
BACKGROUND
Asthma is a chronic disease characterized by airway inflammation caused by the dysregulated production of cytokines secreted by allergen-specific type 2 T helper (Th2) cells. Although the Th1-promoting cytokine, interleukin (IL)-12, is capable of inhibiting Th2-driven allergen-induced airway changes in mice, IL-12 also aggravates the Th1-driven inflammatory pulmonary pathology. Further, IL-10 was found to exert both anti-inflammatory and immunoregulatory activities. To avoid the side-effects of IL-12, we hypothesized that the low-dose expression of IL-10 with concomitant IL-12 administration in the airway may represent a more effective therapy for allergic airway diseases. Thus, the present study explored the immunomodulatory and therapeutic effects of IL-10 combined with IL-12 in airway inflammation in allergic asthma.


METHODS
Adenovirus-expressing murine IL-10 (Ad-IL-10) and IL-12 (Ad-IL-12) were co-administrated in an established murine model of ovalbumin (OVA)-induced asthma.


RESULTS
We found that a single combined treatment of low doses of Ad-IL-10 and Ad-IL-12 efficiently inhibited the development of airway hyper-responsiveness compared to Ad-IL-10 or Ad-IL-12 treatment alone. Moreover, both Ad-IL-10 and Ad-IL-12 treatment reduced pulmonary infiltration of eosinophils and neutrophils. In addition, histological studies showed that combined treatment was able to reduce tumor necrosis factor-alpha-mediated airway inflammation induced by IL-12 treatment. Suppression of IL-4, IL-5, Keratinocyte-derived chemokine (KC) and eotaxin in bronchoalveolar lavage fluid was also noted in OVA-immunized mice with combined Ad-IL-10 and Ad-IL-12 treatment.


CONCLUSIONS
Taken together, the results obtained in the present study indicate that co-administration of IL-12 and IL-10 may have therapeutic potential for the immunomodulatory treatment of allergic asthma.
Hsu
Chih-Yu
CY
Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, Republic of China.
Liu
H Eugene
HE
Sheu
Feei-Yi
FY
Leu
Sy-Jye
SJ
Chiang
Bor-Luen
BL
Hsiao
George
G
Lee
Yueh-Lun
YL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001249:Asthma / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004804:Eosinophils / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016753:Interleukin-10 / Q000008:administration & dosage / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D016753:Interleukin-10; D018664:Interleukin-12