A novel approach to restore lung immunity during systemic immunosuppression

Abstract

Systemic immunosuppression accounts for significant morbidity and mortality worldwide. Pulmonary infections represent the most common cause of death in these patients. The resident inflammatory cell in the lung is the alveolar macrophage (AM) and its function is markedly diminished by immunosuppression. We hypothesized that AMs from normal mice with or without gene transfer of the gamma interferon gene inside the macrophages, can restore alveolar immunity in immunosuppressed mice with severe combined immunodeficiency syndrome (SCID). To test this hypothesis we intratracheally instilled normal and IFN-gamma activated macrophages to the lungs of SCID mice. We demonstrated that airway delivery of macrophages results in widespread alveolar distribution, improved phagocytic function and ability to clear opportunistic infections such as Pneumocystis carinii. Airway delivery of IFN-gamma expressing macrophages further increased the function of alveolar macrophages. Reconstitution of the lungs of immunosuppressed mice with normal or activated AMs can restore alveolar immunity despite ongoing systemic immunosuppression.