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In Vivo Responses to Inhaled Proteins

I. Quantitative Analysis of Antigen Uptake, Fate, and Immunogenicity in a Rabbit Model System¹

Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Case Western Reserve University, Cleveland, Ohio 44106

Abstract

Quantitative studies describing the in vivo behavior of an inhaled protein antigen are presented. Aerosol mists were generated from bovine serum albumin (BSA) solutions without detectable alteration in the physical or antigenic properties of the protein molecule. The fate of inhaled ¹²⁵I-BSA in vivo was studied in rabbits by using a paired-isotope technique to quantitate antigen sequestration within organs, as distinct from circulating antigen label present within the plasma compartment of such organs. Total body uptake could be controlled and averaged 3.20 ± 0.26% of the protein introduced into the aerosol chamber. Accessibility of such aerosolized antigen to the alveolar sacs was confirmed by ultraviolet microscopy with fluorescein-tagged BSA. Immediately after a 90-min aerosol exposure, over 90% of the in vivo label was localized within organs (stomach, 72%; lungs, 4%; intestine, 7%). Maximal concentrations of antigen in the intestines occurred 30 min later. The subsequent decline in gastrointestinal antigen concentrations was accompanied by the appearance of degraded antigen peptides in the serum, peaking at 24 hr. By 48 hr, over 99% of the inhaled antigen had been degraded, and the radiolabel excreted into the urine (93%) or incorporated into the thyroid (6%); less than 0.1% remained in the lung. Similarly, with repeated daily administrations the antigen was rapidly degraded, and no accumulations of antigen in the lung were observed. The presence of humoral immunity induced by systemic immunization did not affect the fate of inhaled antigen. Biweekly exposures of previously unimmunized animals to BSA aerosols resulted in vigorous humoral antibody responses representing IgG and IgM immunoglobulin classes. Despite the presence of good Arthus skin reactivity in animals immunized by systemic depot injections or by inhalation routes, subsequent repeated challenges with antigen aerosol failed to induce Arthus-like injury in the lung. This study suggests that antigen inhalation may function primarily as an important physiologic means by which natural immunity to environmental antigens is established. Humoral antibody, although capable of readily mediating cutaneous Arthus reactions, appears to require an initiating event or mechanism, as yet undefined, before it can interact with inhaled antigen to form pathogenic immune complexes.

Footnotes

¹ This work was supported in part by Grant HL 19819-01 from the National Institutes of Health and a grant from the Tuberculosis and Respiratory Disease Association.

² Requests for reprints should be addressed to W. F. Willoughby, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.