Adenovirus-Mediated Interleukin-10 Gene Transfer Inhibits Post-Transplant Fibrous Airway Obliteration in an Animal Model of Bronchiolitis Obliterans

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Abstract
Bronchiolitis obliterans, a form of chronic allograft rejection characterized by progressive fibrous obliteration of the airways, is the major obstacle limiting prolonged survival of lung transplant recipients. To date, no effective therapy against this fatal complication exists. Interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, inhibits various T cell and antigen-presenting cell functions. We examined the effect of IL-10 in an animal model for bronchiolitis obliterans. A heterotopic tracheal transplant model was used. IL-10 was administered to the recipient either in its recombinant form by osmotic minipump or by adenoviral-mediated IL-10 gene transfer (Ad5E1mIL-10). Successful gene transfection and expression was confirmed by measuring circulating IL-10 protein. Tracheal allografts were assessed histologically based on a scoring system. IL-10 administration (in recombinant form or by gene transfer) inhibited the development of fibrous airway obliteration 3 weeks after transplantation in comparison to untreated controls (p < 0.05). This was demonstrated only if the delivery was initiated 5 days after transplantation and not if it was started at the time of transplantation. A single administration of the gene construct was sufficient to achieve the desired effect. We have shown that IL-10 can prevent the development of airway fibro-obliteration in this model. Gene transfection at a site distant from a graft can be used to produce a desired effect on the graft. IL-10 may be of major importance in the control of post-transplant bronchiolitis obliterans. The timing of its administration is critical and further studies are required to determine the mechanisms underlying the observed effects of IL-10. Expression of Interleukin-10 (IL-10) in the setting of allotransplantation might be beneficial in preventing acute allograft rejection and has recently been associated with stabilization of polarized Th2-type gene expression and thereby preventing Th1-type activation. To explore the effect of IL-10 on bronchiolitis obliterans, a form of chronic allograft rejection after lung transplantation, we used a replication-defective type-5 adenovirus encoding murine IL-10 under the control of a cytomegalovirus promoter (AdE1mIL-10). A replication-defective adenovirus (Ad5d170-3) served as control vector. In this paper we show, using a rat model of bronchiolitis obliterans, that IL-10 administration was able to inhibit airway fibro-obliteration. The effect of IL-10 in this process was confirmed by the replication of the results with the administration of recombinant IL-10 and adenoviral-mediated IL-10 gene transfer. These data suggest that AdE1mIL-10 may be useful for further study of the mechanisms underlying the observed effects of IL-10.

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