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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Genetically engineered macrophages expressing IFN-gamma restore alveolar immune function in scid mice
1Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Summary
Gene therapy for lung immunodeficiency faces challenges in delivering genes to lung cells. This study shows that delivering engineered macrophages expressing the murine interferon-gamma gene directly to the airways can restore immune function in immunodeficient mice.
Area of Science:
- Immunology
- Gene Therapy
- Respiratory Medicine
Background:
- Gene therapy for lung immunodeficiency is hindered by difficulties in in vivo lung cell transfection.
- Existing in vitro transfection methods are not easily applicable to in vivo conditions.
Purpose of the Study:
- To overcome in vivo lung cell transfection challenges.
- To develop a method for expressing murine interferon-gamma (mIFN-gamma) in vivo using engineered macrophages.
Main Methods:
- Engineered macrophages using a modified pSF91 retroviral vector to express mIFN-gamma and enhanced green fluorescent protein (EGFP).
- Intratracheal instillation of transduced macrophages into mechanically ventilated severe combined immunodeficient (scid) mice.
- Quantification of mIFN-gamma levels in bronchoalveolar lavage fluid and assessment of EGFP expression in lavaged cells.
Main Results:
- Transduced macrophages secreted high levels of mIFN-gamma in vitro (131.6 μg/ml).
- Intratracheal delivery resulted in detectable mIFN-gamma levels in mouse lungs (158.8 pg/ml at 48h).
- Partial restoration of immune function observed, including enhanced MHC class II expression, increased phagocytosis, and elevated tumor necrosis factor alpha.
Conclusions:
- Airway delivery of genetically engineered macrophages expressing mIFN-gamma can partially restore immune activity in the lungs of immunodeficient mice.
- This approach offers a potential strategy for treating lung immunodeficiencies.
- Direct airway delivery is more effective than intraperitoneal administration for achieving therapeutic mIFN-gamma levels in the lungs.
