The immune response to bacteria and to a soluble protein was compared in germfree and conventionalized mice. Sixty germfree and 59 conventionalized mice received a suspension of killed Serratia marcescens into one front foot-pad and sterile horse ferritin into the other and were sacrificed in groups from 2 hr to 14 days after inoculation. All mice had no pre-existing antibody to either antigen and the flora of the conventionalized mice never contained Serratia. Lymphatic tissue changes and the fate of the antigens were followed in axillary lymph nodes and the spleens by histologic, fluorescent antibody, and autoradiographic techniques after tritiated thymidine injection. Individual serum antibody titers for both antigens were determined at each time period. The cellular and serologic responses were slightly delayed in the germfree mice but later equaled and sometimes exceeded those of the conventional animals. In all animals, lymph nodes draining the site of Serratia injection showed a more vigorous response than those on the ferritin-injected side but the reaction was qualitatively the same for both antigens. All lymph nodes contained the antigens by 2 hr after foot-pad injection. With time, both antigens lost their particulate nature sooner in conventionalized than in germfree macrophages. In the latter, both antigens persisted throughout the study while no longer demonstrable with fluoresceinated antiserum in conventional macrophages after the first week. While phagocytosis is equal in germfree and conventional mice, a greater digestive capacity of macrophages for antigens seems to result from the continuous exposure of conventional animals to the immunologic effects of the microbial flora. Conversely, the lack of substantial antigenic stimulation of lymphatic tissue in germfree animals fails to develop these macrophage functions beyond their basic ability to degrade foreign substances. Although the onset of the immune response is delayed in germfree mice, the relatively prolonged antigen digestion and the presumably slower release of immunogenic antigen fragments result in a more sustained and sometimes greater response than in conventional animals. This modifying effect of the microflora on the function of macrophages during the immune response is independent of previous experience with, or the nature of, the antigen.
For many decades, investigators have intensively studied the responses of animals rendered uremic by a variety of experimental means, and have extensively speculated on the importance to these responses of the uremic animal's so called "normal" indigenous flora (1, 2). Much of the discussion has centered on the retention by the uremic host of "toxic" substances which are known or postulated to derive from microbial activity in its intestine and to be normally excreted by the kidneys. However, despite the reiteration of these concepts, we are unaware of any systematic exploration of the extent and nature of the contribution of the indigenous flora and its various components to the pathogenesis of renoprival states. As a first step in this direction, we removed both kidneys from germ free rats and from such rats previously contaminated intentionally with one or more intestinal microorganisms and compared their responses. In this paper, we show that the microbial status of the rat significantly influences its ability to endure the lethal sequelae of acute anuria and of food and water deprivation. We will present the histopathology of these and other rats as well as some biochemical alterations in the communication that follows (3). Materials and MethodsGeneral.--To determine whether microbial status influences survival time in uremia, three separate series of experiments (Experiments I, II, and III) were conducted in which bilateral nephrectomy was performed on healthy rats. The groups in each experiment were studied concurrently to enable direct comparison of performance.Fischer rats, of either sex, were received germfree from the Charles River Breeding Laboratories, North Wilmington, Massachusetts, at 4 to 5 wk of age and used as described below. All rats were continuously maintained in isolators from birth to death. The standard procedures used in this laboratory for maintaining and monitoring these animals have been detailed (4-6).
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