Macrophage turnover and activation were evaluated in dermal BCG lesions produced in normal and tuberculin-positive rabbits. Turnover, i.e., the rate of entry of mononuclear cells (MN) into the lesions and their rate of dealth, was studied by labeling the MN with tritiated thymidine (3HT). Their activation was studied by staining the MN for the lysosomal enzyme β-galactosidase.

A single pulse of 3HT was given 1 day before, or 6, 14 or 27 days after the tuberculous lesions were begun. Five days after the injection, 19 to 33% of the MN in the lesions were labeled with 3HT and their fate could be followed by means of periodic biopsies, each on a different lesion.

3HT-labeled MN entered BCG lesions of reinfection more rapidly than primary lesions. Such MN also died more rapidly in the former. Thus the presence of preexisting tuberculin hypersensitivity markedly accelerated MN turnover.

This conclusion was confirmed in the experiments in which 3HT was given 6, 14 or 27 days after primary BCG lesions were begun. During the week following the 14-day 3HT injection (when tuberculin hypersensitivity was strong), the highest rate of MN entry and the highest rate of MN death were found.

Delayed hypersensitivity to the tuberculin-like products of the bacilli was also correlated with increased numbers of 3HT-labeled, β-galactosidase-positive macrophages. The level of this lysosomal enzyme is a measure of the macrophage's state of activation and reflects its microbicidal capacity, i.e., the degree of its nonspecific cellular immunity. The 3HT-labeling studies just outlined showed that the rate of development of 2- to 4-plus galactosidase activity was most rapid in MN that entered the lesions between 14 and 21 days. At this time the host was highly sensitive to the antigen, and this antigen had probably reached a relatively high concentration. A more rapid development of high β-galactosidase levels also occurred in the MN present in BCG lesions of reinfection.

This work has changed our concept of the pathogenesis of tuberculosis. Formerly, tuberculous lesions were thought to be rather static, and macrophages were thought to become activated and develop antimicrobial immunity gradually. Now such lesions are thought to be dynamic. Macrophages constantly enter and constantly die, and the speed with which they become activated and increase their microbicidal ability seems to be of crucial importance.

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