Biomedical subjects
Publications and source records attributed to R van Furth.
A β-lactamase-producing strain of Neisseria gonorrhoeae with nutritional requirements for arginine, hypoxanthine, and uracil was isolated from the knee-joint fluid, the genital tract, and the sexual partner of a woman presenting with gonococcal arthritis.
Studies dealing with the concept of the mononuclear phagocyte system are described, and the origin of synovial type A cells and osteoclasts is discussed in some detail. All of the available evidence indicates that both derive from precursor cells in the bone marrow. It seems justifiable to conclude that monocytes transform into type A synovial cells and fuse to form osteoclasts.
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Research on phagocytosis is often hampered by the inability to distinguish whether (opsonized) particles have been ingested by phagocytes or are only attached to the surface of these cells. Treatment of the cells after phagocytes to remove all extracellular particles makes it possible to evaluate phagocytosis with certainty by light microscopy. Opsonized erythrocytes attached to the macrophage surface are usually removed by hypotonic lysis. The present report describes the advantages of the use of lysostaphin to lyse Staphylococcus aureus and of xylene, chloroform or dioxane to dissolve polystyrene latex beads on the surface of peritoneal macrophages and embryonic fibroblasts. This procedure facilitates differentiation between professional and facultative phagocytes.
To demonstrate local synthesis of anti-Mycobacterium leprae antibodies, biopsies from skin lesions of leprosy patients were cultured in vitro in a medium containing 14C-labeled lysine and isoleucine, and the culture fluids were analyzed by crossed immunoelectrophoresis with intermediate gel and autoradiography. The results show that anti-M. leprae antibodies were synthesized in vitro in the biopsies from the skin lesions of leprosy patients and that the specificity of the locally produced antibodies varied from patient to patient.
The effects of immunization and anticoagulation in experimental Escherichia coli endocarditis were studied. Immunization of rabbits with E. coli resulted in the development of specific agglutinating and opsonic activity of the serum, but not in bactericidal activity. These antibody activities also developed in nonimmunized rabbits during the course of bactericidal endocarditis. Immune serum promoted phagocytosis in vitro but did not enhance intracellular killing of E. coli by elicited rabbit peritoneal macrophages. The presence of specific antibodies in rabbits after immunization had no effect on the induction or course of E. coli infection of endocardial vegetations. Anticoagulation was found to affect the induction of the infection. In anticoagulated rabbits, larger bacterial inocula were needed to induce an infection, but in animals with bacterial endocarditis the number of bacteria in the vegetations did not differ significantly from that of the control animals.
This study shows that the intracellular killing of Streptococcus pyogenes, Streptococcus faecalis, and Streptococcus pneumoniae by human monocytes is stimulated by the extracellular presence of both heat-stable and heat-labile serum factors. A similar kind of stimulation of monocytes has been described in respect of catalase-positive microorganisms. However, killing of these bacteria is negligible in the absence of extracellular serum factors, whereas a large proportion of the ingested catalase-negative bacteria are killed in the absence of such extracellular stimuli. Monocytes from patients with chronic granulomatous disease, which are unable to kill Staphylococcus aureus even in the presence of extracellular serum, killed S. pyogenes equally effectively whether serum was present or absent. This index proved to be the same as that for killing by monocytes of healthy subjects in the absence of serum. Taken together, these results indicate that catalase-negative microorganisms possess some kind of suicide mechanism that leads to the death of these bacteria after their ingestion by monocytes in the absence of an extracellular stimulus. Furthermore, the mechanism by which extracellular serum stimulates intracellular killing probably involves enzymes of the O2-dependent bactericidal mechanisms of the monocytes.
Human phagocytic cells are of crucial importance in the early responses to infection. However, tests of their function have been somewhat neglected in immunological screening. This paper summarises briefly our techniques for studying neutrophils and monocytes in skin abrasions and a simple assay of phagocytic and bactericidal function. These techniques use small volumes of blood and are suitable for inclusion in the early screening of individuals who have repeated bacterial infections.
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Pulmonary macrophages of mice in the steady state were isolated by lavage with PBS containing EDTA and subsequent enzymatic digestion of tissue with pronase and DNA-ase. By this method, the total pulmonary macrophage population was obtained in two cell suspensions, one with a pure population of pulmonary alveolar macrophages (PAM) and the other with a mixed population of pulmonary alveolar and pulmonary tissue macrophages (PTM). The morphological, cytochemical, and functional characteristics of both PAM and PTM were like those of mature tissue macrophages except for the presence of C3 receptors. These receptors were almost absent on PAM and present on a larger number of cells in the mixed population of PAM and PTM. The total pulmonary macrophage population of mice in the steady state is approximately equal to 2 x 10(6), of which about 93% are PAM and about 7% are PTM. In labeling experiments with 3H-thymidine, the low in vitro labeling indices (less than 3%) for both PAM and the mixture of PAM and PTM, showed that both are essentially nondividing cells. In vivo labeling studies showed an increase in the number of labeled macrophages that can only be attributed to labeled monocytes migrating into the lungs. Additional evidence was provided by a decrease in the labeling indices of pulmonary macrophages when mice were treated with hydrocortisone acetate, which causes a severe monocytopenia, thus preventing monocyte influx into the lungs. Confirmation of the bone marrow origin was obtained in mice labeled after x-irradiation with partial bone marrow shielding: labeled pulmonary macrophages were found in the exposed lungs. In all experiments, the labeling indices were identical in the two macrophage populations isolated. These results show that the influx of monocytes is the source of cell renewal for the pulmonary macrophages. No indications for an interstitial division or maturation compartment in the lung were found. Quantitation of the efflux of labeled monocytes from the blood, and the number of labeled pulmonary macrophages, showed that in the steady state about 15% of the monocytes leaving the circulation become pulmonary macrophages and that the turnover time of pulmonary macrophages is approximately equal to 27 d.
Monoblasts, promonocytes, and macrophages in in vitro cultures of murine bone marrow were studied ultrastructurally, with special attention to peroxidatic activity. Monoblasts show peroxidatic activity in the rough endoplasmic reticulum and nuclear envelope as well as in the granules. The presence of peroxidatic activity in the Golgi apparatus could not be determined. Promonocytes have peroxidase-positive rough endoplasmic reticulum, Golgi apparatus, nuclear envelope, and granules, as previously reported. During culture, cells are formed with peroxidatic activity similar to that of monocytes or exudate macrophages (positive granules; negative Golgi apparatus, RER, and nuclear envelope); we call these cells early macrophages. In addition, transitional macrophages with both positive granules and positive RER, nuclear envelope, negative Golgi apparatus (as in exudate- resident macrophages in vivo), and mature macrophages with peroxidatic activity only in the RER and nuclear envelope (as in resident macrophages in vivo) were found. A considerable number of cells without detectable peroxidatic activity were also encountered. Our finding that macrophages with the peroxidatic pattern of monocytes (early macrophages), exudate-resident macrophages (transitional macrophages), and resident macrophages (mature macrophages), develop in vitro from proliferating precursor cells deriving from the bone marrow, demonstrates once again that resident macrophages in tissues originate from precursor cells in the bone marrow. Therefore, this conclusion can no longer be challenged on the basis of a cytochemical difference between monocytes and exudate macrophages on the one hand and resident macrophages on the other.
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The activity of cefazolin (CEZ) and cephradine (CED) was studied in experimentally infected neutropenic mice. Neutropenia was induced by 600 rad whole-body irradiation; an infection was induced by the injection of 5 X 10(6) Escherichia coli into the thigh on Day 5 after irradiation. Antibiotics were administered 1 h later, and antibacterial activity was estimated from bacteria counts made in the homogenized individual thighs 3 h after infection. The effect of a low dose of each of the cephalosporins on the infection was significantly lower in the absence of granulocytes than in animals with intact host defence; at higher dosages the effect of both antibiotics on the infection was the same in neutropenic and unirradiated mice. In the neutropenic mice, CEZ was 2.95 times more active than CED against E. coli in vivo, this difference in activity being similar to that found earlier in normal mice.