The Lymphocyte in Graft and Tumour Rejection (Murphy 1926)

Introduction

While the work of Paul Ehrlich (1854-1915) and many others had clearly established the existence of humoral (soluble antibody-based) immunity by the beginning of the twentieth century, and while the work of Elie Metchnikoff  (1845-1916) and many others had clearly established the phagocytic role (ingesting and degrading foreign organisms) of many of the cells of lymphoid tissues (lymph-nodes, spleen), the recognition of the role of the "round cell infiltrate" seen around grafts of foreign tissue, or tumours, in actively promoting the rejection of the grafts or tumours, was not established until the studies of James B. Murphy (1884-1950) at the Rockefeller Institute (1911-1926) were reported in the Journal of Experimental Medicine, and summarized in a monograph (1926).

    The reasons why Murphy's work failed to gain prominence have been explored by biohistorians (Lowy 1999; Silverstein 2001). Here the Table of Contents and Bibliography of the 1926 monograph are displayed to give the reader some feel for the wide range and thoroughness of Murphy's work. Also included here are the Summary and Conclusions presented at the end of the monograph.

Lowy, I. (1999) Brit. J. Hist. Med. 63, 356-391. Biomedical research and the constraints of medical practice: James Bumgardner Murphy and the early discovery of the role of lymphocytes in immune reactions.

Silverstein, A. M. (2001) Nature Immunology 2, 569-571. The lymphocyte in immunology: from James B. Murphy to James L. Gowans. 

Donald Forsdyke

MONOGRAPHS OF THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH, NO. 21,  September 20, 1926.

THE LYMPHOCYTE IN RESISTANCE TO TISSUE GRAFTING, MALIGNANT DISEASE, AND TUBERCULOUS INFECTION:

AN EXPERIMENTAL STUDY

BY JAMES B. MURPHY, M.D.

(From The Rockefeller Institute for Medical Research.) PLATES 1 to 20.

(Received for publication January 6 1926.)

[Figures, coloured emphasis and italics by DRF unless otherwise stated] 

CONTENTS

INTRODUCTION

I. HETEROPLASTIC TISSUE GRAFTING AND THE MECHANISM OF DEFENSE

Heteroplastic Tissue Grafts in the Chick Embryo 7

Heteroplastic Tissue Grafts in the Adult Brain 19

Heteroplastic Grafting in the Adult Animal Deprived of Lymphoid Tissue 24

II. HISTOLOGICAL MANIFESTATIONS ACCOMPANYING RESISTANCE TO THE INOCULATED TUMOR

Local Reactions about Cancer Grafts in Resistant Animals 31

Changes in the Blood Associated with Resistance to Transplanted Cancer 32

Histological Comparison of the Lymphoid Tissue of Naturally Resistant and Susceptible Mice 34

Lymphoid Tissue in Animals with Induced Resistance to Transplanted Cancer 36

III. EFFECT OF DESTRUCTION OR SUPPRESSION OF THE LYMPHOID TISSUE ACTIVITY ON RESISTANCE TO TRANSPLANTED CANCER

Destructive Action of X-Ray on the Lymphoid Tissue 47

Effect of X-Ray Destruction of the Lymphoid Tissue on Natural and Induced Resistance to Transplanted Tumors 52

Suppressive Effect of Olive Oil on the Lymphoid Tissue and on Induced Resistance to Inoculated Cancer (Nakahara) 57

Results of Olive Oil Injection on the Cellular Reactions Accompanying Resistance 59

IV. EFFECT OF STIMULATION OF LYMPHOID TISSUE ON RESISTANCE TO TRANSPLANTED CANCER

Stimulative Action of X-Ray on the Lymphoid Tissue 63

Effect of X-Ray Stimulation of the Lymphoid System on Resistance to Transplanted Cancer 73

Stimulation of the Lymphoid Tissue by Dry Heat 78

Effect of Dry Heat on Resistance to Transplanted Cancer 82

Stimulation of the Lymphoid Tissue by Olive Oil (Nakahara) 85

Effect of Olive Oil and Fatty Acids on Resistance to Transplanted Cancer 86

V. LOCAL CELLULAR REACTION AND RESISTANCE TO TRANSPLANTED CANCER

Local Reaction of Sensitized Mice to Foreign Blood, and Its Effect on Cancer Grafts 95

Effect of Local Cellular Reaction Induced by X-Ray on the Fate of Cancer Grafts 100

Absence of Local Cellular Reaction and the Growth of Cancer Grafts 110

VI. EFFECT OF GENERAL AND LOCAL LYMPHOID STIMULATION ON RESISTANCE TO SPONTANEOUS TUMORS

Effect of X-Ray on the Rate of Growth of Spontaneous Tumors in Mice 120

Effect of Dry Heat on Resistance to Spontaneous Tumors 122

Resistance to Spontaneous Mouse Tumors Induced by Injections of Oleic Acid 123

Local Resistance to Spontaneous Mouse Cancer Induced by X-Ray (Nakahara) 129

VII. LYMPHOCYTE IN RESISTANCE TO EXPERIMENTAL TUBERCULOSIS

Effect of Destruction of the Lymphocytes on Resistance to the Tubercle Bacillus 139

Resistance of Cancer-Immune Mice to Experimental Tuberculosis 141

Effect of Dry Heat on Resistance to Tuberculosis 144

General Leucocytic Response during the Reaction of Artificial Immunity in Experimental Tuberculous Infection 147

VIII. GENERAL SUMMARY AND DISCUSSION 155

BIBLIOGRAPHY 165

[All sections omitted here except VIII and Bibliography]

VIII. GENERAL SUMMARY AND DISCUSSION

Investigators in determining the function of an organ or a type of cell have as a rule resorted to indirect methods. Much information has been gained from the study of pathological conditions, where function has been interfered with, or by study of deficiencies after the removal of an organ. Rarely has it been possible to vary experimentally the size or activity of an organ or tissue, conditions which would yield more or less direct evidence of function.

Circulating blood cells, showing many small red erythrocytes, lymphocytes at the bottom, and various types of phagocytic cells at top.The lymphoid tissue considered as an organ has been particularly difficult to investigate. It not only composes largely the spleen and numerous lymph nodes but small deposits are scattered through most of the organs and tissues of the body and in addition large numbers of the cells are to be found in the circulation. If all this tissue could be brought together in a single mass it would represent an organ of considerable size. It is not surprising that removal of the spleen, the largest single deposit, representing however only a fraction of the total, is so quickly compensated for that no definite deficiencies are detectable.

The development of methods by which the total lymphoid tissue may be varied at will, practically depleted on the one hand with repeated small doses of x-ray or stimulated by single small doses of x-ray, dry heat, and unsaturated fatty acids, has opened up possibilities for the study of the function of this tissue. The methods were developed primarily to determine the importance of the lymphoid reaction in tissue grafting and in resistance to cancer, and the study has been confined, with two exceptions, to these subjects. The two exceptions are the part played by these cells in antibody formation and their role in resistance to certain infections where humoral antibodies are of little moment. One of these studies, namely that dealing with resistance to the tubercle bacillus, has been reviewed here as an example of the application of the methods.

Heteroplastic Tissue Grafting. - The association of the lymphoid type of cell with the mechanism by which an animal prevents the growth of an implanted tissue from another species and which eventually brings about the death of foreign cells is a subject which has long attracted the attention of pathologists. The possibility of utilizing the tissues of related species in human repair surgery and in organ deficiencies has been attempted even on a large scale. In spite of certain reported successful clinical results, the consensus of opinion is that it is impossible to graft tissues from one species to another in the higher animals and that rarely does such grafting succeed from one individual to another even of the same species. The very sensitive mechanism through which an organism rejects the cells of another species even though those cells be capable of supplying a real deficiency in some vital function is as yet little understood.

In Section I we have reviewed several theories which have been brought forward to explain tissue specificity but none of these have stood the test of adequate investigation. While the new evidence presented here is not intended to furnish a basis for a new theory, it does suffice to indicate that the round cell infiltration so characteristic of the reaction to foreign tissue grafts is a purposeful reaction and that these cells are the agent through which the mechanism exerts its force. The evidence on which this conclusion is based is as follows: 

The avian embryo and the adult brain have proved to be without defense against heteroplastic grafts and in both there is a notable absence of the round cell reaction. From this it might be supposed, as suggested by a number of investigators, that the round cell reaction only appeared about cells injured by some other agent, but this conception is eliminated by the finding that

  • the avian embryo and the adult brain are rendered completely resistant when supplied with lymphoid tissue. 

  • Furthermore the adult organism may be rendered non-resistant to heteroplastic tissue by destruction of the major portion of the lymphoid system and 

  • the power to rid itself of the foreign tissue is regained only when the lymphoid tissue has regenerated approximately to the normal amount.

What other interpretation therefore are we to assume, than that these round cells are a necessary factor in this phenomenon and are to be considered at least as the guardians of the species' individuality?

Resistance to Transplantable Neoplasms in Mice. - The extensive experimental study of the relationship of the lymphocyte to resistance against the transplanted malignant tumor has yielded strong evidence that in the 1ymphoid elements we have an important link in the process of so called cancer immunity

  • First we have the facts brought out by the study of the natural progress of the inoculated tumor. When the host is resistant this is evidenced by a local round cell reaction about the graft, a condition entirely absent in the susceptible animal. This local reaction of resistance is accompanied by a great increase in the circulating mononuclears and, back of this, in turn, is an increased proliferation in the lymphogenic centers.


  • On the other hand the lymphoid tissue of a susceptible animal supporting a growing tumor shows marked degenerative changes which progress with the enlargement of the tumor. In other words the response to cancer inoculation is a general one, and the degree of resistance seems to depend on the reactibility of the lymphoid tissue.

So closely is resistance associated with the lymphocyte, that experimentally-produced variation in the amount and activity of the lymphoid tissue is accompanied by a variation in the resistance of the animal to cancer; increased activity resulting in increased resistance, depletion in decreased resistance. This statement is based on the following facts. 

  • Mice rendered potentially immune by the injection of homologous defibrinated blood may be reduced to a susceptible state by destruction of the lymphoid tissue (x-ray) or by the suppression of its activity (olive oil).

  • On the other hand stimulation of the lymphoid tissue by three types of agents, biological, physical, and chemical, results in enhanced resistance to the transplanted tumor. As far as can be determined by minute study the only biological activity shared in common by these various agents is the stimulative effect on the lymphoid tissue.

 

    A point probably not without significance is the apparent quantitative relationship between the amount of stimulation and the degree of resistance to tumors. This has been brought out not only by comparing the effectiveness of the resistance induced by the various agents but by the results of inoculation at various phases of the stimulation. 

    The fact that the result of cancer inoculation made soon after the administration of the stimulus, particularly x-ray, indicates no increased resistance on the part of the animal, but results in a neutralization of the stimulative effect of the agent on the lymphoid tissue, suggests an antagonistic action between the cancer and the stimulative agent acting on the lymphoid tissue. Other minor observations of this nature might be mentioned, all of which point in the same direction and strengthen the evidence for our final deductions in regard to the activity of the lymphoid cells.

    It is probable that the majority of intact normal animals possess sufficient lymphoid tissue to combat a cancer graft, but in the susceptible animal the mechanism by which these cells are attracted to the locality of the graft is for some reason imperfect. Some of the experiments quoted in Section V show that even in susceptible animals where a sufficient local lymphoid reaction is induced, by processes unrelated to general resistance, a high degree of local resistance results. Precisely what the mechanism is which determines whether or not a local reaction is to take place about a cancer graft and how the lymphocyte exerts its influence on the cancer cell are points on which we have been able to gain no light.

Resistance to Spontanous Neoplasms in Mice.-The general opinion that one is not justified in drawing conclusions in regard to cancer as a disease from the results of the study of the transplanted cancer has some foundation. The host of a transplanted cancer acts only as a supporter of the actively growing cells from another individual and there is no evidence that the cells of the host ever become malignant by contact. It is probable that an animal may react to and destroy the inoculated cancer more readily than it would to one arising in its own body. 

    Nevertheless the mechanism by which the destruction of cancer cells is brought about seems to be the same regardless of whether the tumor be a transplanted one or has developed spontaneously. The principal methods by which resistance to the transplanted cancer may be enhanced (x-ray, heat, and fatty acids) are shown in Section VI to be equally effective in augmenting the defense of the cancerous animal to its own spontaneous tumor. These observations leave no doubt that the principles and the deductions drawn are not confined to the experimentally transplanted tumors only but apply equally to cancer as a natural disease.

Resistance to Neoplasms in Other Species. - Although the main facts of our investigation have been arrived at through the study of mice, selected because of their great susceptibility, there is considerable evidence from other sources that the relationship between lymphoid reaction and cancer resistance is not confined to this species. Ribbert (1) called attention to the association between the round cell reaction and retrogressing areas in human cancer, and more recently MacCarty (2) has demonstrated the prognostic importance of the amount of lymphoid infiltration, particularly in breast cancer.

The histological study of the fate of grafts of transplantable tumors of rats (3), chickens (4), and rabbits has shown that the local lymphoid reaction is just as constant an accompaniment of resistance as it is in mice. Varying the lymphoid content by means of x-ray has been shown to exert the same influence on the fate of rat tumors as it does with mouse cancer. The recent studies of Ewing (6) and of Alter (7) indicate that the cell reaction induced by x-ray and radium is probably the intermediate agent in bringing about the favorable therapeutic result in human cancer, a conclusion analogous to the one we arrived at from the study of mouse cancer. In view of all these observations it would seem that the association of the cellular reaction with resistance to neoplastic growths is not a peculiarity of the mouse and also that the results could be duplicated in other species than those studied.

    The question as to why cancer metastases grow so regularly in the lymph nodes, particularly in man, is a point which has not yet been adequately investigated. The dissemination to the lymph node is probably a mechanical affair. One possible explanation of the growth of the cancer in the presence of antagonistic cells, is that the lymphocyte as it exists in the node is inactive and is capable of functioning only when it migrates into the tissues. There is a somewhat analogous phenomenon in the polymorphonuclear leucocyte, which is unable to perform one of its important functions, i.e. phagocyting, inside the vessels. 

    Another explanation, more plausible and with some supporting evidence, is that the lymph node only becomes the seat of an active metastasis when it has become exhausted. In addition to this consideration there seems little doubt that the lymphogenic function of an involved node is largely obliterated and the number of lymphoid cells is markedly decreased as the growth progresses. There is at present not sufficient evidence at hand to answer the question inasmuch as it has not been studied from this point of view.

    The mechanism by which the various agents bring about stimulation of the lymphoid system and induce resistance to cancer is a point on which we have no direct knowledge. One suggestive fact only is available to indicate a possible explanation, namely that the serum collected from an animal after an exposure to x-ray or dry heat has a definite stimulating action on lymphoid cells in vitro. From this fact it may be assumed that some chemical change has been produced in the body fluids which in turn is capable of acting on the lymphoid cell. The presence of a stimulative substance in the blood of oil-injected animals or those treated with homologous tissue has not been tested, so that there is wanting evidence for a more general conclusion on this point.

    In this connection it is of interest to note, a propos of the recent discussion of whether or not x-ray exerts stimulative properties, that our studies have demonstrated beyond doubt that this physical agent under proper conditions may induce a real stimulation of an animal tissue.

    Other questions similar to the above which have not been subjected to experimental verification because of their comparative unimportance may be mentioned. One finds occasionally among the mice with spontaneous tumors a disease similar to lymphatic leucemia and a like condition has been described in man. Under these circumstances there seems no more reason to expect the abnormal lymphocyte to perform its normal function than for a cancer cell to produce a normal secretion. 

    We have also noticed that an animal with an initial high lymphocyte count is no more apt to be resistant than one with a low count. Presumably the normal number of these cells in the circulation is maintained to meet the requirements of the animal. When called on to meet an additional burden, such as an inoculation with cancer, the degree of success seems to depend on the ability of the animal to produce more cells and the animal with a low initial count is just as apt to react as one with a high count. The production of a blood lymphocytosis without stimulation of the lymphogenic tissue, particularly the transitory lymphocytosis following the administration of certain drugs, is without effect on the resistance to cancer. This is not surprising when it is considered that the increase in numbers of the cells is caused by contraction of the spleen with a forcing out of the lymphocytes m the pulp spaces and that these quickly disappear from the circulation.

Bearing of These Studies on the X-Ray Therapy of Cancer.- In the course of our study of the function of the lymphoid tissue, certain points have been developed, incidentally, which seem to have a bearing on x-ray therapy of cancer and may at least offer an explanation of some of the clinical results from this form of treatment.

    An occasional observation has been noted of instances where malignant tumors have apparently grown more rapidly and disseminated more freely after x-ray treatment. This fact has led to a controversy as to whether under certain conditions x-ray may not actually stimulate tumor cells rather than destroy them. So far there has been no experimental evidence to support this idea, but in Section III we have shown that doses of x-ray sufficient to deplete the lymphoid system, definitely lower an animal's resistance to implanted tumor. This is true more or less regardless of the type of resistance, whether it be natural, induced, or acquired. 

    May not some such interference with the defensive mechanism result from the intense x-ray dosage used in man? There is no doubt that the amount of irradiation used in some cases is sufficient to reduce the circulating lymphocytes to a point indicating a very widespread destruction of this tissue and at least comparable to the condition in mice representing a state of reduced resistance to cancer.

    If it be true that the human cancer cell is no more susceptible to an x-ray than the mouse cancer cell (8), and there is very good reason to believe that this is true, how is one to account for the high percentage of cures in certain types of skin cancer? If this result depended on an unusual degree of sensitiveness of this group of cancer to the direct action of x-ray, it would be expected that the metastatic cells in a superficial lymph node would be almost as easily influenced by the ray as the cells in their original location, but this is not true. The dose of x-ray utilized in the treatment of skin cancer is given over too small an area to induce any general effect on resistance of the type described in mice.

    The experiments described in Sections V and VI offer an explanation which at least has some experimental basis. The x-ray treatment, as shown by these tests, confers a local immunity on the exposed skin and renders it an unsuitable soil for the support of tumor growth. This resultant refractory state was found to be confined to the skin layers and did not extend even to the underlying connective tissue (see Text-fig. 23). The cellular reaction resulting from the treatment was also confined to the skin layers. This result led us to suggest that the therapeutic action of x-ray in cancer depended on the cellular reaction induced in the normal tissues surrounding the growth.

    This idea was more exhaustively tested with spontaneous cancers of mice. Cancers growing in the skin disappeared promptly after a mild erythema dose of x-ray, but if after exposure in situ the tumor was removed and replanted in an unexposed area of skin in the same animal, growth progressed as uninterruptedly as if no x-ray had been given. A histological study of the fate of a cancer graft inoculated into an area previously exposed to x-ray, shows a series of degenerative changes identical with those which have been repeatedly described as the result of the direct action of x-ray on the cancer cells. Yet these particular cells had received no x-ray.

    While there is not conclusive evidence that the above observations would hold true for man, practically the only study on human material carried out from this point of view supports the idea of the importance of the induced cellular reaction. Ewing based his investigation on a large number of cases treated with both x-ray and radium and concludes that there is little or no evidence of direct destruction of cancer cells, but that the subsequent cellular exudate appears to exert a damaging effect on the neoplasm. He considers the latter as an essential factor in the curative process.

To summarize: there is no evidence that cancer cells are more easily destroyed by x-ray than normal cells; x-ray in a mild erythema dose renders the exposed area highly resistant to a subsequent cancer implant; this resistance seems to depend on the amount of cellular reaction induced; x-ray in large generalized doses definitely lowers an animal's resistance to implanted cancer.

GENERAL CONCLUSION

    In drawing any general conclusion from the experimental results recorded here, the possibility cannot be absolutely excluded that other organs, physiological processes, or chemical reactions are influenced by the treatments but with present methods common changes other than that induced in the lymphoid tissue have been undetectable. With this possible limitation we have been led to conclude that in resistance to malignant tumors, whether transplanted or spontaneous is closely associated with the lymphoid tissue and there are indications that the same is true of other species including man. The nature and the extent of the evidence is such that we are forced to conclude that this association is not without purpose and that we have in the lymphoid elements an important link in the chain of the process which determines resistance to cancer.

 

BIBLIOGRAPHY

1. Ribbert, H., Das Karzinom des Menschen, Bonn, 1911, 195.

2: MacCarty, W. C., Surg., Gynec. and Obst., 1914, xviii, 284.

3. Mottram, J. C., and Russ, S., Proc. .Roy. Soc. London, Series B, 1917-19, xc, 1; Woglom, W. H., J. Cancer Research, 1925, ix, 171.

4. Rous, P., and Murphy, Jas. B., J. Exp. Med., 1912, xv, 270.

5. Mottram, J. C., and Russ, S., Proc. Roy. Soc. London, Series B, 1917-19, xe,

1; Russ, S., Chambers, H., Scott, G. M., and Mottram, J. C., Lancet, 1919, cxcvi, 692.

6. Ewing, J., J. Am. bred. Assn., 1917, lxviii, 1238; Am. J. Roentgen., 1922, ix, 331.

7. Alter, N. M., J. Med. Research, 1919, xl, 241.

8. Hill, B., Morton, J. J., and Witherbee, W. D., J. Exp. Med., 1919, xxix, 89.

GENERAL BIBLIOGRAPHY

I. Heteroplastic Tissue Grafting

Murphy Jas. B., Transplantability of malignant tumors to the embryos of a foreign species, J. Am. Med. Assn., 1912, lix, 874.

Murphy, Jas. B., Transplantability of tissues to the embryo of foreign species. Its bearing on questions of tissue specificity and tumor immunit J. Exp. Med 1913, xvii, 482.

Murphy, Jas. B. A source of defense to heteroplastic tissue e grafting, J. Am. Med. Assn., 1914, lxii,199.

Murphy, Jas. B., Studies in tissue specificity. II. The ultimate fate of mammalian tissue implanted in the chick embryo, J. Exp. Med.,1914, xix,181.

Murphy, Jas. B., The bearing of the growth of foreign tissue in the embryo on the question of heteroplastic grafting, Proc. 17th Internat. Congr. Med., London, 1913, 256.

Murphy, Jas. B., Factors of resistance to heteroplastic tissue-grafting. Studies in tissue specificity. III, J. Exp. Med.,1914, xix, 513.

Murphy, Jas. B., Heteroplastic tissue grafting effected through Roentgen-ray lymphoid destruction, J. Am. Med. Assn., 1914, lxii,1459.

Murphy, Jas. B. The effect of adult chicken organ grafts on the chick embryo, J. Exp. Med., 1916, xxiv,1.

Murphy, Jas. B., and Sturm, E., Homoplastic and heteroplastic tumor grafts in the brain, J. Am. Med. Assn., 1922, lxxix, 2159.

Murphy, Jas. B., and Sturm, E., Conditions determining the transplantability of tissues in the brain, J. Exp. Med.,1923, xxxviii,183.

Maisin, J., and Sturm, E., Contribution a la connaissance de la nature de 1'immunite cancereuse heterologue, Compt. rend. Soc. Mol.,1923, lxxxviii,1216.

II. Manifestations of Resistance to Inoculated Tumor

Murphy, Jas. B., and Morton, J. J., The lymphocyte in natural and induced resistance to transplanted cancer. II. Studies in lymphoid activity, J. Exp. Med.,1915, xvii, 204,

Murphy, Jas. B., and Morton, J. J., The lymphocyte as a factor in natural and induced resistance to transplanted cancer, Proc. Nat. Acad. Sci.,1915, i, 435.

Murphy, Jas. B., and Nakahara, W., The lymphocyte in natural and induced resistance to transplanted cancer. V. Histological study of the lymphoid tissue of mice with induced immunity to transplanted cancer, J. Exp. Med., 1920, xxxi,1.

Nakahara, W., and Murphy, Jas. B., The lymphocyte in natural and induced resistance to transplanted cancer. VI. Histological comparison of the lymphoid tissue of naturally immune and susceptible mice., J. Exp. Med., 1921, xxxiii 327.

III. Effect of Destruction or Suppression of the Lymphoid Tissue Activity on Resistance to Transplanted Cancer

Murphy, Jas. B., and Morton, J. J., The lymphocyte in natural and induced resistance to transplanted cancer. II. Studies in lymphoid activity, J. Exp. Med 1915, xxii, 204.

Murphy, Jas. B., and Taylor, H. D., The lymphocyte in natural and induced resistance to transplanted cancer. III. The effect of x-rays on artificially induced immunity, J. Exp. Med., 1918, xxviii, 1.

Taylor, H. D., Witherbee, W. D., and Murphy, Jas. B., Studies on x-ray effects. I. Destructive action on blood cells, J. Exp. Med., 1919, xxix, 53.

Hussey, R. G. A modified anaphylactic reaction induced by x-rays, Proc. Soc. Exp. Biol. and Med.,1921-22, xix, 22.

Nakahara W. Studies on lymphoid activity. VII. Suppression of induced immunity to transplanted cancer by large doses of olive oil, J. Exp. Med.,1923, xxxviii, 315.

Murphy, Jas. B., and Sturm, E., A comparison of the effects of x-ray and dry heat on antibody formation, J. Exp. Med.,1925, xli, 245.

IV. Lymphoid Stimulation and Cancer Resistance

Murphy, Jas. B., and Morton, J. J., The effect of x-ray on the resistance to cancer in mice, Science, 1915, xlii, 842.

Murphy, Jas. B., and Sturm, E., Effect of dry heat on the blood count in animals. III. Studies on lymphoid activity, J. Exp. Med.,1919, xxix,1.

Nakahara W. The source of the 1ymphocytosis induced by means of heat J. Ex p. Med., 1919, xxix, 17.

Murphy, Jas. B., and Sturm, E., The lymphocytes in natural and induced resistance to transplanted cancer. IV. Effect of dry heat on resistance to transplanted cancer in mice, J. Exp. Med.,1919, xxix, 25.

Taylor, H. D., Effect of exposure to the sun on the circulating lymphocytes in man, J. Exp. Med.,1919, xxix, 41.

Thomas, M. M., Taylor, H. D. and Witherbee, W. D., Studies on x-ray effects. II. Stimulative action on the lymphocytes, J. Exp. Med., 1919, xxix, 75.

Nakahara, W., Studies on x-ray effects. III. Changes in the lymphoid organs after small doses of x-rays [rabbits], J. Exp. Med.,1919, xxix, 83.

Nakahara, W., and Murphy, Jas. B., Studies on x-ray effects. V. Effect of small doses of x-rays of low penetration on the lymphoid tissue of mice, J. Exp. Med., 1920, xxxi, 13.

Murphy, Jas. B., The effect of physical agents on the resistance of mice to cancer. Proc. Nat. Acad. Sci.,1920, vi, 35.

Murphy, Jas. B., Nakahara, W., and Sturm, E., Studies on lymphoid activity. V. Relation between the time and extent of lymphoid stimulation induced by physical agents and the degree of resistance to cancer in mice, J. Exp. Med., 1921 xxxiii, 423 .

Nakahara, W., and Murphy, Jas. B., Studies on x-ray effects. VII. Effect of small doses of x-rays of low penetration on the resistance of mice to transplanted cancer, J. Exp. Med.,1921, xxxiii, 429.

Nakahara, W., and Murphy, Jas. B., Studies on x-ray effects. VIII. Influence of cancer inoculation on the lymphoid stimulation induced by small doses of x-rays, J. Exp. Med., 1921, xxxiii, 433. .

Nakahara, W., and Murphy, Jas. B. On the nature of the so-called germ center in lymphoid tissue, Anat. Rec., 1921, xxii, 107.

Murphy, Jas. B., Liu, J. H., and Sturm, E., Studies on x-ray effects. LX. The action of serum from x-rayed animals on lymphoid cells in vitro, J. Exp. Med, 1922, xxxv, 373.

Nakahara, W., and Murphy, Jas. B., Studies on x-ray effects. X. The biological action of small doses of low frequency x-rays, J. Exp. Med.,1922, xxxv, 475.

Nakahara, W., Studies on lymphoid activity. VI. Immunity to transplanted cancer induced by injection of olive oil, J. Exp. Med., 1922, xxxv, 493.

Hussey, R. G., The influence of x-rays on the properties of blood, J. Gen. Physiol., 1921-22, iv, 511.

Murphy, Jas B., A propos des reactions locales et generales de l’organisme a 1'egard du cancer, Bull. Assn. franc. etude cancer, Congres du cancer, July, 1923.

Nakahara, W., Effect of fatty acids on the resistance of mice to transplanted cancer, J. Exp. Med.,1924, xl, 363.

V. Local Cellular Reaction and Resistance to Transplanted Cancer.

Hill, E., Morton, J. J., and Witherbee, W. D., Studies on x-ray effects. IV. Direct action of x-rays on transplantable cancers of mice, J. Exp. Med., 1919, xxix, 89.

Murphy, Jas. B., Hussey, R. G., Nakahara, W., and Sturm, E., Studies on x-ray effects. VI. Effect of the cellular reaction induced by x-rays on cancer grafts, J. Exp. Med.,1921, xxxiii, 299.

Murphy, Jas. B., Hussey, R. G., Sturm, E., and Nakahara, W., Effect of induced cellular reaction on the fate of cancer grafts. IV. Studies on lymphoid activity, J. Exp. Med.,1921, xxxiii, 315.

Liu, J. H., Sturm, E., and Murphy, Jas. B., Studies on x-ray effects. XI. The fate of cancer grafts implanted in subcutaneous tissue previously exposed to x-rays, J. Exp. Med., 1922, xxxv, 487.

Murphy, Jas. B., and Sturm, E., Conditions determining the transplantability of tissues in the brain, J. Exp. Med., 1923, xxxviii,183.

Nakahara, W., Studies on x-ray effects. XIIL Histological study of the fate of cancer grafts inoculated into an x-rayed area, J. Exp. Med., 1923, xxxviii, 309.

Murphy, Jas. B., A propos des reactions locales et generales de 1'organisme a 1'egard cancer, Bull. Assn. Franc. etude cancer, Congres du cancer, July, 1923.

VI. Effect of General and Local Lymphoid Stimulation on Resistance to Spontaneous Cancer

Murphy, Jas. B., and Morton, J. J., The effect of Roentgen rays on the rate of growth of spontaneous tumors in mice, J. Exp. Med., 1915, xxii, 800.

Murphy, Jas. B., and Morton, J. J., The effect of x-rays on the resistance to cancer in mice, Science, 1915, xlii, 842.

Murphy, Jas. B., and Sturm, E., Effect of stimulation [heat] of the lymphocytes on the rate of growth of spontaneous tumors in mice, J. Exp. Med., 1919, xxix 31.

Murphy, Jas. B., Maisin, J., and Sturm, E., Local resistance to spontaneous mouse cancer induced by x-rays, J. Exp. Med.,1923, xxxviii, 645.

Murphy, Jas. B., Maisin, J., and Sturm, E., Contribution a la connaissance du mecanisme d'action des rayons X sur le developpement des tumeurs spontanees ches la souris, Compt. rend. Soc. biol., 1924, xc, 972; Bull. Assn. franc. etude cancer, 1924, xiii,120.

Nakahara, W., Resistance to spontaneous mouse cancer induced by injections of oleic acid, J. Exp. Med.,1925, x1i, 347.

VII. Lymphocyte in Resistance to Experimental Tuberculosis

Murphy, Jas. B., and Ellis, A. W. M., Experiments on the role of lymphoid tissue in the resistance to experimental tuberculosis in mice, J. Exp. Med., 1914, xx, 397.

Morton, J. J., A rapid method for the diagnosis of renal tuberculosis by the use of the x-rayed guinea pig, J. Exp. Med.,1916, xxiv, 419.

Taylor, H. D., and Murphy, Jas. B., Experiments on the ro1e of lymphoid tissue in the resistance to experimental tuberculosis in mice. II. Effect of cancer immunity on resistance to tuberculosis, J. Exp. Med., 1917, xrv, 609.

Murphy, Jas. B., and Sturm, E., Experiments on the role of lymphoid tissue in the resistance to experimental tuberculosis in mice. III. Effect of heat on resistance to tuberculosis, J. Exp. Med., 1919, xxix, 35.

Taylor, H. D., Blood counts in experimental poliomyelitis in the monkey, J. Exp. Med., 1919, xxix, 97.

Amoss, H. L., Taylor, H. D., and Witherbee, W. D., Effects of large doses of x-rays on the susceptibility of the monkey to experimental poliomyelitis. J. Exp. Med., 1919, xxix,115.

Hussey, R. G., General leucocytic response of the guinea pig during the reaction of artificial immunity in experimental tuberculous infection, J. Exp. Med.,1921 xxxiii, 337.

Note that many of Murphy's papers are available online; for example, all copies of the Journal of Experimental Medicine from the 19th century onwards became available online in 2004.

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This page was established circa 2001, and was last edited on 20 July 2004 by Donald Forsdyke