FLUCTUATIONS IN CONCOMITANT IMMUNITY

Transcription

1 FLUCTUATIONS IN CONCOMITANT IMMUNITY F. D. BULLOCK AND G. L. ROHDENBURG From Columbia University, George Crocker Special Research Fund, F. C. Wood, Director Reaeived for publioation, July 2, 1919 The variations in the percentage of induced immunity which we obtained by the methods commonly used in immudaing animals against transplanted tumors have been discussed in another publication (1). In the present paper it will be shown that fluctuations of a similar character occur in concomitant immunity, following a previous inoculation with either a receding or a progressively growing tumor. In investigations which have been recorded elsewhere (2) the action of degenerative tumor products upon immunity was studied, it being our original intention in planning these experiments to see if tumors which do not produce concomitant immunity could be made to do so by an increase in the products of tumor degeneration. In this connection it will be remembered that Russell (3) has divided tumors into two classes, those which immunize against subsequent grafts of a tumor of the same strain (concomitant immunity) and those which do not. He presented the mouse carcinomata Twort and 631 as typical of those which do not produce concomitant immunity. The results of our experiments referred to above are of interest in this connection because of the fact that in our hands these two tumor strains did produce concomitant immunity. Chart 1 copied from Russell s article shows his results with the Twort tumor, while Chart 2 depicts our results with the same strain. Chart 3 is a reproduction of Russell s results with tumor 63, while charts 4a, 4 b and 4 c represent our results with the same strain. It will Research Fund of London, England, for the tumor strains Twort, 63, and This laboratory is indebted to Dr. Murray, Director of the Imperial Canaer 129

2 130 F. D. BULLOCK AND G. L. ROHDENBURG 4/12 lfi2 RLn - t' -i - 4 -i CHART 1. TWORTUMOR IN NON-IMMUNIZINQ PEASE (AFTER RUSSELL) Mice inoculated in right axilla 20/10. Tumors excised 22/11 and the animal reinoculated in left axilla 24/11.

3 FLUCTUATIONS IN CONCOMITANT IMMUNITY be noted that our results do not agree with those obtained by Russell. Prime, of this laboratory, unaware of our experiments and while working on another problem, also obtained results at variance with those of Russell while using the British mouse carcinoma 206 as an immunizing agent. According to Russell (4) n,rr 011f1 * SLCOYD C U I l DIVI I0 I> I, no I I.. -,. **-,. * - I.._ I.. 0,..--.,..,..-- a,.. 9,..,. * I,. - - * I l * l a DCM l a ( I... J 3.. I?....,I).., I * I.. -. s...in I : I.. -,.. --,... l a..-,..-- I... t, ,..-. s , _--.-., I.. -- D I.. - * O... I Y. - -,I.., I. --, 0. I..... this tumor strain immunizes against a subsequent inoculation of the British mouse carcinoma 63 and the records of his experiment show an immunity of 100 per cent. Prime, on the contrary, in an experiment heretofore unrecorded (chart 5), obtained but 23 per cent immunity in one generation and 30 per cent in the next, a variation of approximately 70 from Russell's figures. ' I

4 132 F. D. BULLOCK AND Gt. L. ROHDENBURQ CHART 3. TUMOR 63 IN NON-IMMWNIZINO PHASE^ ( A ~ RUSS~LL) R Mioe 1 to 8 inooulsted in right axilla 31 /8. Tumors exoieed 19 /9 and the mioe reinooulated in left sxilla 21 D. Mioe 9 to 18 oontrols for seoond inooulstion.

5 FLUCTUATIONS IN CONCOMITANT IMMUNITY 133 The objection may be raised that these are isolated occurrences readily explained by the fact that English tumors have been transplanted into animals of American stock. In answer to this objection, we present similar results which were obtained with the Buffalo rat sarcoma. Chart 6 shows this tumor in a lyyullzlro EFFECT OF TUMOR sa- - - CHART 4 A. AN EXPXRIMENT IN WHICH TUMOR 63 GAVE RISB TO A HIQH DEQREE OF CONCOMITANT IMMUNITY phase when it did induce concomitant immunity, while chart 7 shows it at a time when that power was lost. The above examples have been cited to show that fluctuations in concomitant immunity do occur. The experiments recorded in this paper were planned to determine the frequency of this occurrence and to discover, if possible, the factor or factors which are responsible for these variations. As in our experi-

6 134 F. D. BULLOCK AND G. L. ROHDENBURG ments in induced immunity, three tumor strains were used, the Buffalo rat sarcoma, the Flexner Jobling rat carcinoma, and the English mouse carcinoma : :.. I ) CHART 4 B. ANOTHER EXPERIMENT IN WHICH TUMOR 63 GAVE RIaB TO A HIQH DEQREE OF CONCOMITANT IMMUNITY To eliminate variations due to differences in technic, a standard was decided upon and all inoculations were performed by the same operator. Animals were inoculated with gram2 of 2 In previous publications from the Imperial Cancer Research Fund and from this laboratory, the inoculation dose, when the needle method is used, has been estimated aa 0.01 or 0.02 gram; but such grafts have recently been found, as a matter of fact, to weigh about and gram, respectively.

7 FLUCTUATIONS IN CONCOMITANT IMMUNITY 135 CONCOMITAHT IWMUIITl TUMOR 63 * ' 0 a. ' J.. 10,. I s - - no '-- a - a I- I '- I0-0 1) s 4 3 a ' * b e 0II-I I * I1 - - CHART 4 c. AN EXPERIMENT IN WHICH TUMOR 63 CLOSELY FOLLOWED RUSSELL'S EXPE~RIENCE

8 136 F. D. BULLOCK AND 0. L. ROHDENBURQ the given tumor strain, the tumors for inoculation being derived, whenever possible, from the preceding generation, and being 18 days old. Eighteen days after inoculation, the animals were reinoculated in the tissues of the opposite side of the body with a similar dose of tumor of the same strain. The tumor used CHART 5. A COMPARISON OF THE PERCENTAOES OF TAKES OBTAINED BY RUSSELL THE^ TUMOR 206 AND 63 AND BY PRIMP: USINO for the second inoculation was selected from the tumors resulting from the first inoculation. Twenty-four animals were used for each generation, and each set of inoculations was controlled by a normal group of 24 animals. In the entire experiment animals of about the same age, development, and state of health were chosen. The tumors were charted for the first time ten

9 FLUCTUATIONS IN CONCOMITANT IMMUNITY 137 days after inoculation and weekly thereafter, and our figures are based on the condition present on the twenty-fourth day of growth of the second graft. Concomitant immunity, as observed through six generationa of the Buffalo rat sarcoma (chart S), ranges between 100 per (.. I#. (.. ( I)..I I#- - 0.I - a...i l o e. - II,. - - n r * - I). n l. 0 n.. - a, n r n r.i- 18,.. r cent and 65 per cent, a variation of 35 per cent. No relationship is apparent between the curves of concomitant and those of induced or natural immunity in the same generations (chart 9). Although the power to produce concomitant immunity is not THID JOURNAL OF CANCER RIDBEARCE, VOL. V, NO. 2

10 138 F. D. BULLOCK AND a. L. ROHDENBURG 0

11 FLUCTUATIONB IN CONCOMITANT IMMUNITY 139 CHART 8. A COMPARISON OF THE PERC~NTAQES OF CONCOMITANT IMMUNITX AND MORTALITY WITH THE BUFFALO RAT SARCOMA

12 140 F. D. BULLOCK AND Q. L. ROHDENBURG so great, the variations observed through seven generations of the Flexner tumor (chart 10) are similar to those noted in the Buffalo tumor, the high point of immunity being 70 per cent, UHART 9. A COMPARISON OF THB~ VARIATIONS IN P~URCENTAGES OB CONCOMITANT, INDUCED, AND NATURAL IMMUNITY IN THID SAMW GIDN~RATION or mlp BUFFALO RAT SARCOMA while the low point was 32. With this tumor, also, the concomitant immunity is apparently independent of the induced and the natural immunity (chart 11).

13 FLUCTUATIONS IN CONCOMITANT IMMUNITY 141 To obviate the factor of familial or racial tendencies, a factor which is known to influence not only the percentage of takes in transplanted tumors, but also, as we have shown, the percentage of induced immunity, a pure strain of mice was used for the CHART 10. A COMPARISON OF THB PERCENTAQES OF CONCOMITANT IMMVNITY AND MORTALITY WITH TIIB FLEXNER JOBLINQ RAT CARCINOMA mou~e omcinoma 63, both tumor strain and animals being of &P;lish stock. Through eight generations of this tumor (charf 12) even more mmked and more frequent fluctuations occurred than with the previmb two atdm, the low being 21 and the

14 142 F. D. BULLOCK AND a. L. ROHDENBURG high being 60 per cent. As with the other strains, no relationship can be established between the variation in induced, concomitant, and natural immunity (chart 13). CHART 11. A COMPARISON OF THE VARIATIONS IN PERCENTAQES OF CONCOMITANT, INDUCED, AND NATURAL IMMUNITY IN TEE SAME GENERATION OF THE FLEXNER JOBLINQ RAT CARCINOMA In charts 8, 10, and 12, the mortality curves and the concomitant immunity curve8 for each of the three tumor strains are presented. It is evident that there is no relation between the health of the animals, as indicated by the mortality curve, and the percentage of concomitant immunity.

15 . FLUCTUATIONS IN CONCOMITANT IMMUNITY 143 From the experiments which have been described in the previous paragraphs, it is evident that fluctuations in concomitant immunity frequently occur with both epithelial and connective tissue neoplasms in mice and rats. It will be recalled that analagous variations in induced immunity were found to be due to differences in the host strain. This, however, is not true of con- CHART 12. A COMPARISON OF THE PBRCENTAQE~S OF CONCOMITANT IMMUNITY AND MORTALITY WITH TUMOR 83 comitant immunity. Neither can the variations be connected with similar fluctuations in either induced or natural immunity, apparently somewhat different forces being operative in each instance. Variations in technic have been eliminated by following the standard laid down in an earlier paragraph. By exclusion, therefore, the vacillations must be due to differences in the tumor itself. If, as Bashford has suggested in explaining

16 144 F. D. BULLOCK AND 0. L. ROHDENBURC) another phase of tumor biology, these variations are due to fluctuations in the growth energy of the tumor, then growth energy must be measured not by the infectivity of a tumor, as indicated by the number of takes, but by the rapidity of growth of a CHART 13. A COMPARISON OF THE VARIATIONS IN PERCENTAQES OF CONCOMITANT, INDUCED, AND NATURAL IMMUNITY IN THE SAME GENERATION OF TUMOR 83 single given tumor. Though it is probably impossible to establish a standard for size or weight of a given tumor strain after a fixed period of growth, it appears from our experiments that concomitant immunity occurred most often when the individual

17 FLUCTUATIONS IN CONCOMITANT IMMUNITY 145 tumor grew slowly but steadily, and least often when the tumor grew rapidly. Whatever the cause of the variations noted, their presence is proof of the inconstancy of tumors as immunizing agents. REFERENCES (1) BULLOCK AND ROHDENBURQ: Jour. Cancer Research, 1920, v, 119. (2) BULLOCK AND ROHDENBURQ: Jour. Cancer Research, 1917, ii, 455. (3) RUSSELL: Fifth Sci. Report, Imperial Cancer Research Fund, London, 1912, pp. 3 and 4. (4) RUSSELL: Fifth Sci. Report, Imperial Cancer Research Fund, London, 1912, p. 14. THE JOURNAL OF CANCER RESEABCB, VOL. V, NO. 2