SENSITIZATION AND ANTIBODY FORMATION WITH INCREASED RESISTANCE TO TUBERCULOUS INFECTION INDUCED BY HEAT KILLED TUBERCLE BACILLI
Authors: Jules Freund, Eugene L. Opie
Journal: The Journal of Experimental Medicine (1938)

Rabbits (and human beings) differ widely in the rapidity with which they undergo sensitization with heat killed tubercle bacilli, but after repeated injections all animals become sensitized. Intracutaneous injection of a small quantity of heat killed tubercle bacilli into a previously normal animal produces a nodule which persists from 8 to 12 weeks; the same injection into well sensitized animals produces a lesion which ulcerates within from 1 to 3 weeks and is completely healed after about 5 weeks. Complete healing is functional evidence of the disappearance of the antigen. Intracutaneous injection of heat killed tubercle bacilli induces more rapid sensitization than subcutaneous or intravenous injection, but after repeated injections the difference disappears. Increasing quantities of heat killed tubercle bacilli or the same quantity divided into several simultaneous injections accelerates sensitization. The rapidity of antibody formation measured by complement fixation varies in different rabbits under the same conditions but complement fixation is always demonstrable after repeated injections of heat killed tubercle bacilli. Antibody formation is more rapid and reaches higher titers with intravenous than with intracutaneous or with subcutaneous injections. It is accelerated by division of the injected antigen into multiple simultaneous injections. Small quantities of BCG induce rapid sensitization and more abundant antibody formation measured by complement fixation than heat killed tubercle bacilli but with repeated injections the difference disappears. Animals that are sensitized and immunized (allergic) before infection are in most instances more resistant to infection than previously normal animals, but there is no correlation between the intensity of sensitization or the titer of antibodies, on the one hand, and resistance to infection on the other. A previously normal animal subjected to infection differs essentially from a sensitized and immunized animal during the first few weeks of infection when sensitization and immunity are developing as the result of infection, but subsequently the progress of sensitization and antibody formation measured by the means at our disposal follows for a time the same course in both. Sensitization diminishes and in most instances disappears, whereas the titer of complement fixation remains elevated. When infection pursues a fatal course sensitization permanently disappears, but in animals that proceed toward recovery sensitization measured by injection of tuberculin into the skin repeatedly diminishes, usually to complete disappearance, and then increases in successive waves which tend to diminish in height with recovery from infection. The titer of complement fixation gradually diminishes with recovery from infection. It is probable that the skin test for sensitization and complement fixation applied to the blood serum measure antibodies or other factors determining sensitization and immunity that are in excess of those actively concerned in the maintenance of resistance.