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Genetic Immunization with Lung-Targeting Macroaggregated Polyethyleneimine-Albumin Conjugates Elicits Combined Systemic and Mucosal Immune Responses¹

Frank M. Orson^2,*,,,§, Berma M. Kinsey^*,, Pascal J. Hua^*,, Balbir S. Bhogal^*,, Charles L. Densmore^¶ and Michael A. Barry^§,||

^* Veterans Affairs Medical Center, Center for AIDS Research, and the Departments of Internal Medicine, ^§ Microbiology and Immunology, ^¶ Molecular Physiology and Biophysics, and ^|| Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

Genetic immunization is a novel form of vaccination in which transgenes are delivered into the host to produce the foreign protein within host cells. Although systemic immune responses have been relatively easy to induce by genetic immunization, the induction of regional and mucosal immunity has often been more challenging. To address the problem of eliciting mucosal immunity in the lung, we utilized macroaggregated albumin to target plasmid DNA to the lung. Macroaggregated albumin is trapped in the lung after i.v. injection, and it is routinely used in radiolabeled form as an imaging modality to evaluate pulmonary blood flow. To couple DNA to this targeting agent, polyethyleneimine (a polycation that binds DNA and enhances transfection) was conjugated to serum albumin, and the conjugate was aggregated by heating to produce particles of 25–100 µm. The resulting particles bound plasmid DNA avidly, and when injected i.v. in mice, the particles distributed in the peripheral lung tissue in the alveolar interstitium. Particle-bound luciferase plasmid transfected a variety of cell lines in vitro, and after i.v. injection, gene expression was detected exclusively in the lung. Using human growth hormone as the encoded foreign Ag for immunization, i.v. injection of the particle-bound plasmid elicited both pulmonary mucosal and systemic immune responses, whereas naked DNA injected either i.v. or i.m. elicited only systemic responses. Thus, particle-bound plasmid DNA may have utility for genetic immunization by intravascular delivery to the lung and potentially to other organs and tissues.

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