EXPERIMENTAL IMMUNITY WITH REFERENCE TO THE BACILLUS OF LEPROSY : PART I. A STUDY OF THE FACTORS DETERMINING INFECTION IN ANIMALS.
Repeated experiments have proven that few, if any, of the ordinary laboratory and domestic animals are immune against infection by Bacillus leprae. As previously reported, the goat, horse, guinea pig, and many cold-blooded animals (Couret) have been found susceptible to invasion by this organism. Two factors are of great importance in effecting infection. In the first place, a sufficiently large number of organisms must be employed, and, what is still more important, second and subsequent inoculations are more liable to produce leprous lesions than are primary injections. Moderate doses used in the first inoculation of animals are comparatively harmless as regards their ability to induce lesions. Such preliminary doses, whether they consist of living or dead organisms, produce a condition of hypersensitiveness or allergy, which renders it possible by a second injection of viable bacilli to induce the development of a reactionary lesion. Lesions arising as the result of a second inoculation develop more rapidly, increase in size more quickly, and persist for a longer period than those taking place as the result of a single inoculation, even though very large doses are used. Moreover, the bacilli in these lesions are more liable to lead to metastasis and to a generalized infection. We regard the results of these experiments as having considerable bearing upon the development of the disease in human cases, since we find that it is chiefly among those living in prolonged intimate contact with leprous patients that leprosy develops. The proper interpretation of these findings is difficult and becomes, apparently, more complex the longer they are studied. We are accustomed to similar phenomena of anaphylaxis or allergy with protein materials and with certain bacteria, especially the tubercle bacillus. It is not surprising that a specific allergy or altered reaction should take place in animals previously injected with leprosy bacilli, either alive or dead; why, however, lesions should develop in which the bacilli continue to grow in animals which had recovered from previous injections, or the serum of which showed bactericidal properties and contained other specific antibodies, is not so easily understood. It is unnecessary in this paper to discuss the relative value of the different theories brought forward to explain the phenomenon of anaphylaxis. It must, nevertheless, be assumed that either as the result of the splitting of certain essentially non-toxic substances in the bacillus by specific ferment-like substances in the blood, which increase after a sensitizing dose, or by the joining of some body in the serum with certain substances in the bacilli, a toxic body is produced. Following the setting free or development of these injurious bodies, there results a cellular reaction, an area of local necrosis followed usually by the appearance of cells of the lymphoid and epithelioid type, and, especially if dead bacilli are used, by polymorphonuclear leucocytes. Such a reaction is usual in all allergic or anaphylactic conditions; but why the reaction should pre-dispose to the more or less permanent development of parasitic powers on the part of the bacilli is not so plain. The idea has been expressed by us, as the result of observations based chiefly upon the study of the changes in the tissues of human leprosy, that the presence of bacilli within the large multinucleated cells that are characteristic of the lesion is the result of active multiplication of the bacilli in these cells rather than of phagocytosis by the cells, although it is possible that their original entrance may be the result of phagocytic action. If this be the case, it is possible that, through the cellular reaction plus the necrosis of certain of the fixed tissue cells, a pabulum of split protein products results upon which the bacilli feed, and in which they find protection from the antibodies present in the blood serum. In our attempts to induce infection in various mammalian species with cultures of human leprosy, positive results have been obtained in almost every instance after the second injection of large numbers of the organism. In this manner, we have been successful in the production of lesions in the monkey, goat, horse, guinea pig, and mouse. The results of these experiments lead us to believe that the mechanism through which invasion and multiplication follows in these lower animals is similar to if not identical with that in man. A careful study of the progress of the disease in man together with the behavior of the organism in the monkey and the goat would suggest, at least, that the function of toxin production is, after all, of little use to the leprosy bacillus because it has seemingly acquired a highly parasitic existence; instead of which it is not only possible, but highly probable, that its defensive protection, whatever it may be, is enormously developed. After the inoculation of animals with either dead or living bacilli, the production of specific antibodies is induced; these do not develop in any considerable amount and apparently show no marked tendency to increase upon repeated injections. The tests of the sera in vitro indicate that the antisubstances are produced chiefly by the first few injections. Either the existence of some specific bacterial protective body, or what seems more probable, the protection afforded by the host cells in which the bacilli become ensconsed accounts, we believe, for the difficulty of producing in animals an antiserum of high potency. The idea, too, that the bacilli do not multiply to any great extent until they have entered certain cells of the host has, in a large measure, been verified by the artificial cultivation experiments. We know from our studies upon the biology of the organism that it will live for years in the most unfavorable conditions. This would suggest that during their sojourn in the tissue cells death as the result of autolysis rarely occurs, and as long as the cells can withstand the multiplication of the bacilli within and remain alive, so long are the bacilli protected from outside injurious influences, in consequence of which no disintegration of bacilli occurs to induce the production of immune bodies. On the other hand, death of the cells carrying the bacilli must occur from time to time, and this exposes large numbers of the organisms to the action of the body fluids, and, in consequence, to the condition of formation of specific antibodies.
Duval
C W
CW
Laboratories of Pathology, Tulane University, New Orleans, La.
Gurd
E B
EB