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Published online by Cambridge University Press: 15 May 2009
By means of the graphic records given on Plates II–VI and VIII the following facts have been illustrated.
Immunity to Erythrocytes.
Normal rabbit's serum is relatively innocuous for bullock's erythrocytes. The serum of an immunised rabbit acquires the power to dissolve bullock's erythrocytes.
Besides acquiring the power to dissolve bullock's erythrocytes, an immune serum may also acquire power to clump them, and it has been shown that the phenomena of haemolysis and of agglutination are independent.
The powers acquired by the immune serum can be artificially modified. The serum may be deprived of its powers by heat. Serum cautiously so deprived of its haemolytic power can have it restored by the addition of normal serum. The haemolytic power of the un-heated serum is augmented if normal serum be superadded.
It has been shown that an immune serum only differs from a normal serum by its containing antitoxic bodies which are endowed with powers of specific reaction with the bullock's erythrocytes.
The mechanism by which erythrocytes are laked by an immune serum has been analysed, and it has been shown that the solution of the erythrocytes is effected through the intervention of an anti-erythrocytic body called forth by immunisation. The erythrocytes which have been subjected to the action of this product of immunity give indication of their reaction with it if they are subsequently or concomitantly placed under the influence of normal serum. The erythrocytes and normal serum together, therefore, form a combined indicator of the presence of the anti-eiythrocytic body. The part played by normal serum has nothing to do with the acquisition of immunity.
The only conclusion drawn from the above observations is that in the production of immunity to erythrocytes the serum of the immunised animal acquires certain powers which are concomitant with, but are not necessarily the cause of the immunity. This special case of immunity to erythrocytes is therefore probably parallel to induced immunity to those bacterial toxines for which antitoxines are known to exist.
The course and progressive augmentation of artificial immunity to erythrocytes has also been illustrated, and it has been shown that erythrocytes saturated with anti-erythrocytic body retain the power to augment the immunity of an already immune animal.
The serum of an animal actively immunised has power to confer passive immunity upon other animals, and the course of this passive immunity differs in the two cases when it is induced in the same species and in a species alien to that providing the immune serum.
The experiments with bullock's erythrocytes have been repeated in parallel observations with ricin in order to permit of the observations on haemolysis being utilised in drawing conclusions on the behaviour of bacterial toxines.
By adjusting the conditions of experiment in such a way that the minimal lethal dose for an animal was also the minimal agglutinating dose in test-tube experiments, it has been possible to give graphic records showing the parallelism between the processes when erythrocytes or living animals are used as indicators of the presence of free ricin. In this way it has been possible to illustrate the determination of the minimal lethal and minimal agglutinating doses of ricin and that quantity of antitoxine (antiricin) which is necessary to abolish the corresponding actions in the animal and in the test-tube, and to show that the mixture of toxine and antitoxine which is physiologically neutral in vitro is also physiologically neutral in vivo within the limitations imposed by the preliminary determinations.
The consequences of conferring passive immunity upon the guinea-pig by means of active immune serum of the rabbit have also been illustrated, and it has been shown that the alien antiricin serum leads to the production of agencies directed against itself.
Ricin neutralised by antiricin retains its power to produce immunity when injected into the species of animal which has yielded the antiricin.
In connection with the conference of immunity to erythrocytes and to ricin, the nature of the difference between normal and immune sera has been studied. Attention has been directed to the possession by normal sera of properties which simulate those possessed in more marked degree by the immune sera. In the case of haemolysis, it has not been possible to clearly demonstrate that the actions manifested by the normal and immune sera are distinct, although the weight of evidence is in favour of this view. In the case of ricin, however, it has been possible to demonstrate that the immune serum possesses properties which are quite distinct from those possessed by normal serum, and that the latter does not interfere with the action of ricin because of the natural presence of a trace of antiricin. In the case of immunity to ricin, the antitoxine is certainly something which has been super-added to the serum in consequence of the process of immunisation.
The facts ascertained in regard to artificial immunity to erythrocytes and to ricin completely agree. Only in oue point is it impossible to be quite sure that the phenomena are identical, viz., in the simulation by normal serum of the powers characteristic of the immune serum; for the demonstration that the two are distinct has been possible for ricin, but open to doubt in the case of erythrocytes. My investigations have been extended to diphtheria and tetanus toxines and to cobra venom, kindly placed at my disposal by Sir Thomas R. Fraser. They have however been interrupted, but so far as they go they support fully the observations made on ricin and erythrocytes.
page 32 note 1 The following studies formed a portion of the preliminary stages in an extensive investigation into the mechanism of antitoxine production. New duties have interfered with the satisfactory completion of this work. The subject-matter of this paper formed part of an introduction to a progress report submitted to the Scientific Assessors of the Worshipful Company of Grocers, April, 1902. For a critical discussion of the theoretical explanations of some of the facts related in this paper I would refer to the recent papers of Professor R. Muir (Lancet, August 15th, 1903), and Dr Ritchie (Journal of Hygiene, 1902), and to the literature there quoted.
page 32 note 2 It is scarcely necessary to point out that immunity to blood implies immunity to all the different constituents of blood. Only some of the manifestations of immunity to the erythrocytes are considered in this paper.
page 35 note 1 See footnote No. 2 on p. 32.
page 45 note 1 In reality more than ten times the quantity determined in Experiment III, Plate IV, viz. 3.5 c.c. of 1:10 dilution.
page 47 note 1 Cf. also Robert Muir, loc. cit..
page 49 note 1 Immediately following the injection there is a transitory fall in haemolytic or antitoxic power (see Bullock, Trans. Path. Soc. London, 1902).
page 50 note 1 The toxic effects of multiples of the lethal dose are abolished, and it is perhaps loose reasoning to assume by analogy that all effects will be abolished, for obviously they are not.
page 50 note 2 Experiments in which such saturated erythrocytes were used for the primary injection yielded positive results in 6 out of 8 cases. The haemolytic power was, however, in three instances less than in the controls in which the same quantity of erythrocytes in their natural condition was injected. The reasons for this difference seem obvious. The anti-erythrocytic body produced is identical in both cases.
page 51 note 1 It is to be noted that throughout these experiments the normal serum used has been obtained from the same species as the immune serum, viz., the rabbit. It is customary to employ the normal serum of the guinea-pig. I used normal rabbit's serum to obviate introducing new factors in the conditions of experiment and consequently possible fallacies. The relations of the quantities of the immune and normal sera necessary to effect laking may be made to vary—a larger proportion of heated immune serum requires a smaller quantity of normal serum and vice versâ.
page 53 note 1 This is merely stating in other terms the experimental observations necessary for the study of the progressive augmentation of immunity to erythrocytes recorded on p. 49. A physiologically neutral mixture of toxine and antitoxine can only be determined with a large margin of error. I explained this matter fully in a paper on “The qualitative and quantitative relations of toxine and antitoxine” (Lancet, Oct. 17, 1903). For the purposes of immunisation by “neutralised” toxine or erythrocytes, I avoided an obvious fallacy by using more antitoxine than the erythrocytes indicated was necessary.
page 54 note 1 Exact figures are stated on Plate VII, and full details of similar experiments will be found in a paper in the Journal of Pathology and Bacteriology, Dec. 1903.
page 56 note 1 The control experiments are discussed fully in a paper appearing in the Journal of Pathology and Bacteriology.
page 60 note 1 Futher details are given in the Journal of Pathology and Bacteriology (March, 1902) and in the Archives de Pharmacodynamie (T. VIII. 1900).
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