Benjamin Abraham Thomas.

Applied immunology; the practical application of sera and bacterins prophylactically, diagnostically and therapeutically; online

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Online LibraryBenjamin Abraham ThomasApplied immunology; the practical application of sera and bacterins prophylactically, diagnostically and therapeutically; → online text (page 1 of 23)
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Demonstrating phagocytosis of various bacteria as observed in the determina-
tion of the opsonic index. 1, Staphylococcus; 2, Micrococcus candicans; 3, Strepto-
coccus pyogenes; 4, Colon bacillus; 5, Gonococcus; 6, Tubercle bacillus. {See p. 234.)



APPLIED

IMMUNOLOGY

THE PRACTICAL APPLICATION OF SERA
AND BACTERINS PROPHYLACTICALLY,
DLVGNOSTICALLY AND THERAPEUTICALLY



WITH AN APPENDIX ON

SERUM TREATMENT OF HEMORRHAGE, ORGANOTHERAPY
AND CHEMOTHERAPY



BY

B. A. THOMAS, A.M., M.D.

PROFESSOR OF GENITO-URINART SURGERY IN THE POLYCLINIC HOSPITAL AND COLLEGE

FOR GRADUATES IN MEDICINE ; INSTRUCTOR IN SURGERY IN THE UNIVEK81TT

OF PENNSYLVANIA ; ASSOCIATE IN THE WILLIAM PEPPER

LABORATORY OF CLINICAL MEDICINE

AND

R. H. IVY, M.D., D.D.S.

ASSISTANT INSTRUCTOR IN SURGERY IN THE UNIVERSITY OP PENNSYLVANIA ; INSTRUC-
TOR IN GENITO-URINARY SURGERY IN THE POLYCLINIC HOSPITAL AND
COLLEGE FOR GRADUATES IN MEDICINE
PHILADELPHIA



5 COLORED INSERTS AND 68 ILLUSTRATIONS IN TEXT



PHILADELPHIA AND LONDON

B. LIPPINCOTT COMPANY



T5



BiOtOGX



Copyright, 1915
By J. B. LiPPiNcoTT Company



Printed by J. B. Lippincott Company
The Washington Square Press, Philadelphia, U, S. A.






To

ALFRED STENGEL. M.D.

PROFESSOR OF MEDICINE IN THE UNIVERSITY OF PENNSTLVANIA

IN GRATEFUL RECOGNITION OF HIS WISE COUN-
SEL AND KINDLY ADVICE THIS VOLUME IS
BESPECTFULLY DEDICATED BY THE AUTHOBS



Sf)Kf^.^i



PREFACE

Despite the enormous strides, experimentally and
clinically, that have marked the progress in serological
and bacteriological research in medicine for the past
quarter of a century, leading to results of the highest
clinical value diagnostically and therapeutically, three
facts stand out in bold relief: First, that the average
practitioner's knowledge of biological therapeusis is a
" dangerous thing " because he does not " drink deep
of the Pierian spring " ; second, insufficient practical
instruction is given to students in our medical schools
in view of the prevalent practice of this mode of diag-
nosis and treatment; third, authors have sadly neg-
lected to give a concise presentation of immunology in
its entirety for the practical grasp and comprehension
of students and practitioners. The vast majority of
standard works on the subject of " immunity " are
exhaustive treatises on the experimental and theoreti-
cal phases of the subject and are often unintelligible
and of little value to the average practicing physician.

The result of the above has been that pharmaceuti-
cal firms have assumed the function of the Department
of Therapeutics in our medical colleges, not always
impartially and to the best interests of medical science.



vi PREFACE

Obviously, licentiates to practice medicine should re-
ceive instruction of a definite and practical nature in
this important branch of modern medicine, or immu-
nology should receive a place in the classification of
specialties, a fact which the importance of the subject
may command.

In this book it has been the aim of the authors
purposely to omit most of the experimental research
and to present theories only in so far as they may
assist in a more thorough comprehension of biological
prophylaxis, diagnosis and therapeusis.

The primary object has been to crystallize and de-
tail the practical phases of serum and bacterin applica-
tions in medicine, thereby enabling the student and
general practitioner, with even a slight laboratory ex-
perience, to appreciate the significance of, and more
competently apply the principles underlying, immu-
nology. In order to render the treatise more complete
allusion has been made in places to certain allied sub-
stances that have been utilized from time to time in
attempts at immunization, with a consideration of
their merits and demerits.

The interest and close association of blood trans-
fusion, organotherapy and administration of salvarsan
and neosalvarsan to the main subject have prompted
the authors to devote an appendix to their discussion.

The reader who may have his enthusiasm aroused



PREFACE vii

and is ambitious to enter more deeply into the realms
of immunity is referred to the systems of Kolle and
Wassermann, and Kraus and Levaditi, or the works
of Ehrlich and Bolduan, and Bordet and Gay on
" Studies in Immunity "; Emery on " Immunity and
Specific Therapy "; Wright on " Studies on Immuni-
zation "; Simon on " Infection and Immunity "; Cit-
ron on " Immunity," and Vaughan on " The Relation
of Anaphylaxis to Immunity and Disease."

B. A. Thomas
R. H. Ivy

William I*epper Laboratory of
Clinical, Medicine,
Philadelphia, 1915



CONTENTS



CHAPTER I PAOB

Introduction 1

Immunity and Immunization — Natural and Acquired Immunity —
Active and Passive Immunization — Mechanism of the Production of
Immunity — History and Development of Immunology.

CHAPTER II

Antigens and Antibodies 19

Toxins and Antitoxins — Agglutinins — Precipitins — Lysins — Isocytoly-
sins — Opsonins — Antiferments — Auto-antibodies — Allergy and Ana-
phylaxis.

CHAPTER III
Ehrlich's Side-chain Theory 24

CHAPTER IV
Anaphylaxis or Hypersusceptibility 27

CHAPTER V

Antisera 34

Preparation of Antisera — Indications for Therapeutic Use of Antisera.

CHAPTER VI

Antitoxic Sera 42

Antidiphtheritic Serum — Antitetanic Serum — Antigonococcic Serum —
Antituberculosis Serum — Antidysenteric Serum — Antibotulism Serum
— Antiphytotoxic Serum — Antivenin.

CHAPTER VII

Antibacterial Sera 55

Antistaphylococcic Serum — Antistreptococcic Serum — Antipneumo-
coccic Serum — Antigonococcic Serum — Antimeningococcic Serum —
Antityphoid Serum — Anticolonic ' Serum — Antidysenteric Serum —
Anticholera Serum — Antiplague Serum — Anti-anthrax Serum — Anti-
melitensic Serum.

CHAPTER VIII

Miscellaneous Sera and Extracts 64

Antirabic Serum — Antileprosy Serum — Antityphoid Extract of Jez —
Leucocytic Extract — Antiferment — Anticarcinomatous Extracts —
Pyocyanase — Antithyroid Serum and Extracts — Spangler's Crotalin
— Phylacogens.

CHAPTER IX

Agglutinins 72

The Widal Phenomenon and Other Agglutination Reactions.

ix



X CONTENTS

CHAPTER X

Precipitins 82

Significance and Application of Precipitins — Technic of Reaction —
Specific Identification of Blood and Other Proteins.

CHAPTER XI

Ltsins 86

Bacteriolysins and Cytolysins (Hsemolysins).

CHAPTER XII

Fixation of Complement 90

Principles of the Reaction — Bordet-Gengou Phenomenon — Wasser-
mann-Neisser-Bruck Modification — Technic of the Wassermann Re-
action in the Diagnosis of Syphilis — Modifications of the Wassermann
Reaction — Hecht-Weinberg Modification — Clinical Application of the
Wassermann Reaction — Effects of Treatment on the Wassermann
Reaction.

CHAPTER XIII

Fixation of Complement (Continued) 141

Gonococcus Complement-fixation Test — Serum Diagnosis of Echino-
coccus Disease — Complement-fixation Reaction in Typhoid Fever —
Complement-fixation Reaction in Tuberculosis — The Complement-
fixation Reaction as Applied in Protein Differentiation (Neisser-Sachs
Reaction).

CHAPTER XIV

Miscellaneous Biochemical Reactions 157

Abderhalden's Biological Test for Pregnancy — Sero-enzyme Test for
Syphilis — Abderhalden-Fauser Reaction in Mental Diseases — Meio-
stagmin Reaction — Epiphanin Reaction.

CHAPTER XV

SPEaFic Bacterial Cutaneous Reactions 167

Allergic Phenomena — Tuberculin Tests — Luetin, Gonorrhoea! and
Typhoid Tests — Schick's Diphtheria Toxin Skin Reaction.

CHAPTER XVI

Tuberculin Therapy 193

Prophylaxis — Therapeutic Administration of Tuberculin — Available
Preparations — Modes of Administration and Dosage — Control of
Tuberculin Treatment — Limitations and Contra-indications — Indica-
tions and Results.

CHAPTER XVII
Phagocytosis 211

CHAPTER XVIII
Recovery from Bacterial Infections 21S



CONTENTS xi

CHAPTER XIX

Bacterial Inoculation 216

Principles Underlying Inoculation Therapy — Preparation of Bacterins
— Autogenous versus Heterogeneous Preparations — Clinical Symptoms
versus Opsonic Index in Control of Treatment.

CHAPTER XX

The Opsonic Index 228

Definition of Opsonins and the Opsonic Index — Technic of Determina-
tion of the Opsonic Index — Interpretation, Value and Limitations of
the Opsonic Index.

CHAPTER XXI

Practical Application of Bacterial Inoculation in Medicine,

Prophylactically and Therapeutically 242

General Considerations — Induced Auto-inoculation — Duration of Ac-
tive Immunity — Modes and Technic of Administration of Bacterins —
Dosage — Contra-indications, Limitations and Causes of Failure in
Bacterin Therapy — Application and Results of Bacterial Inoculations
in Special Diseases — Diseases of the Skin and Soft Parts — Diseases of
the Genito-urinary System — Diseases of Bones and Joints — Diseases
of the Eye, Ear, Nose and Throat — Diseases of the Lungs — Diseases
of the Alimentary System — Diseases of the Cardiovascular, Lymphatic
and Nervous Systems, also Other Acute Specific Fevers — Malignant
Neoplasmata — Yeast and Sour Milk.

APPENDIX

Part A. Serum Treatment of Hemorrhage 306

Normal Fresh Serum — Precipitated Horse Serum — Transfusion of
Blood.

Part B. Organotherapy 312

Thyroid Gland — Adrenal Gland — Pituitary Body — Ovary — Corpus
Luteum — Thymus Gland.

Part C. Chemotherapy 318

Administration of Salvarsan and Neosalvarsan, Intravenously, Intra-
muscularly and Intraspinally — Autosalvarsanized and Artificially Sal-
varsanized Serum.



ILLUSTRATIONS

PLATES

PAGE

I. Demonstrating Phagocytosis of Various Bacteria as Observed in

the Determination of the Opsonic Index Frontispiece

II Graphic Portrayal of the "Wassermann Reaction/' Demonstrating
the Results in the Case to be Tested, the Positive Control, and
the Negative Control 125

III. Von Pirquet's Cutaneous Tuberculin Test (Positive Reaction) . . 182

IV. Luetin Cutaneous Reaction, Demonstrating the Papular Charac-

ter of the Reaction on an Erythematous, Indurated Base 187

V. Gonorrhoeal Allergic Reaction, Demonstrating the Papulo-erythe-
matous Cutaneous Response on the Third Day after the Intra-
dermic Injection of One Cubic Millimetre of a Killed Polyvalent
Suspension of Gonococci 189

FIGURES

FIG.

1. Diagrammatic Representation of Structure of Different Antibodies 25

2. Illustrative of Opsonic Curve, Showing Immunity of Rabbit 39

3. Illustrative of Inoculations and Curve of Opsonic Indices Demon-

strating Immunity of Ram 40

4. Capillary Teat Pipette for Removal of Senun from Clotted Speci-

men of Blood 74

5. Widal's Test, Positive 78

6. Widal's Test, Negative 78

7. Method of Obtaining Blood from Sheep's Ear 105

8. Showing Method of Intravenous Injection or Immunization of

Rabbit 107

9. Demonstrating Method of Obtaining Complement by Bleeding

to Death an Anaesthetized Guinea-pig 109

10. Titration of Antigen 113

11. Showing Method of Collecting Blood from Vein of Arm with

Keidel's Vacuum Ampoule 114

12. Showing Authors' Method of Obtaining Blood for Complement-

fixation Reactions 115

13. Titration of Complement 119

14. Showing Arrangement of Tubes in Performance of Wassermann

Reaction on One Unknown Case, with Positive and Negative

Controls 126

ziii



xiv ILLUSTRATIONS

15. Tuberculous Mastoiditis 177

16. Bilateral Tuberculous Epididymitis 178

17. All-glass Tuberculin Syringe, Graduated into Hundredths of a

Cubic Centimetre 179

18. Chronic Pulmonary Tuberculosis 207

19. Tuberculous Coxitis 208

20. Electrical Mechanical Shaker 219

21. Various Forms of Containers for Storage of Bacterins 223

22. Capillary Glass Capsules for Collection of Specimens of Blood. . . 231

23. Showing the Collection of Blood in Sodium Citrate Saline Solution 231

24. Blood after Centrifugation in Decalcifying Medium 231

25. Electric Centrifuge 231

26. Various Ingredients Necessary for the Determination of the

Opsonic Index 231

27. Washing the Culture of the Given Bacterium from the Culture

Medium 232

28. Opsonizing Capillary Pipettes 233

29. Opsonizer or Thermostat 233

30. Illustrating the Construction of Kuhnhardt's Spreader 233

31. Kuhnhardt's Spreader Property Held for Preparation of a Satis-

factory Smear 234

32. Analysis of Curve of Opsonic Indices 236

33. Case of Gonorrhoea! Arthritis of Knee 238

34. Pneumonia 239

35. Sho^dng Effect of Variable Concentrations of Bacterial Suspension

on Determinations of Opsonic Index 240

36. Case of Gonococcal Arthritis 245

37. Case of Tuberculous Cervical Lymphadenitis 246

38. All-glass Hypodermic Syringe 249

39. Case of Long-standing and Obstinate Pustular Acne Vulgaris 260

40. Furunculosis of Nostril 261

41. Carbuncle of Neck 262

42. Case of Typhoid Fever 263

43. Burns One-third to One-half Body Surface; Multiple Subcutaneous

Abscesses 263

44. Recurrent Erysipelas 264

45. Tonsiintis, Peritonsillitis and Toxic Arthritis 265

46. Temperature. Subdiaphragmatic Abscess Drained per Laparotomy 266

47. Pelvic Abscess with Recto-urethro-vaginal Fistulse 267

48. Pyonephrosis 272

49. Reno-lumbar Fistula Following Nephrohthotomy Complicated by

Pyonephrosis 273

50. Pyelitis and Cystitis 274



ILLUSTRATIONS xv

51. Cystitis and Toxic Neuritis 275

52. Chronic Prostatitis 277

53. Typhoid Fever Complicated by Epididymitis 278

54. Acute Osteomyelitis of Tibia Followed by Septicaemia 281

55. Corneal Ulcer with Hypopyon 285

56. Cultures both from Ethmoidal Sinuses and Bronchial Expectoration 287

57. Illustrating Typhoid Fever Rates in United States Army 296

58. Antityphoid Inoculation or Immunization 297

59. Site for Deep Intramuscular Injection 330

60. Position of Patient for Intravenous Injection of Salvarsan 332

61. Apparatus Ready for Preparation of Salvarsan or Neosalvarsan . . 333

62. Thomas' Salvarsan and Neosalvarsan Outfit 333

63. Water Still as Used in Authors' Offices 333

64. Illustrating Method of Eliminating Air from Tubing 335

65. Thomas' Salvarsan and Neosalvarsan Burette 335

66. Showing Position of Patient for Spinal Puncture 341

67. Lumbar Puncture with Strauss Needle 341

68. Intraspinal Administration of Serum, Using Syringe 341



APPLIED IMMUNOLOGY



INTRODUCTION

IMMUNITY AND IMMUNIZATION— NATURAL AND AC-
QUIRED IMMUNITY— ACTIVE AND PASSIVE IMMUNIZA-
TION—MECHANISM OF THE PRODUCTION OF IMMU-
NITY—HISTORY AND DEVELOPMENT OF IMMUNOLOGY

Definition of Immunity, — Immunity is the resis-
tance manifested by man and various animal species to
infectious microorganisms or other foreign proteins.
It is influenced by numerous factors, as changed en-
vironment, physical condition of the animal, species,
idiosyncrasies, virulence of the prevalent microbe, etc.
Conversely, the absence of this resistance implies
susceptibility. Occasionally, hypersusceptibility to
certain proteins is observed and to this state of
supersensitiveness Richet has applied the term " ana-
phylaxis " (see Chapter IV).

Two kinds of immunity are recognized, natural
and acquired.

Natural Immunity. — The natural or spontaneous
resistance of the animal organism to disease is only

relative, never absolute. The ability of animals to

1



2- •:*•'•'• '• APPLIED IMMUNOLOGY

ward off disease varies with different species and
among individuals of the same family. Under nor-
mal conditions, an animal may be protected indefi-
nitely from infection. Nevertheless, if his vital resis-
tance be permitted to fall or he be exposed to a viru-
lent infection, his defences may crumble instantly and
disease be contracted. On the other hand, the natural
immunity of certain species to infection is remarkable ;
the negro to yellow fever and most of the lower ani-
mals to the venereal diseases.

In this connection allusion should be made to local
immunity. By this we mean a natural state of certain
organs or tissues, prevalent from birth, due to " in-
fective tolerance." For example, the mouth and an-
terior urethra normally harbor many different patho-
genic bacteria without ill effect, owing to life-long
local tolerance with resultant immunity. Introduce
some of these germs into the synovial membrane of a
joint or into the peritoneal cavity and a virulent in-
fection results. Again, the intestinal tract tolerates
colon bacilli normally in numbers, which, if access be
gained to the urinary tract, may precipitate a grave
pathological process.

Infections common in warm-blooded are rare
among cold-blooded animals and vice versa. Verte-
brates and invertebrates are not subject to similar in-
fections. Field mice are susceptible to glanders.



INTRODUCTION 3

while house mice are immune. Tuberculosis is more
prevalent among Jersey than Holstein cattle. Birds
and reptiles are not necessarily subject to the same
diseases that victimize man. Thus the problem of
natural immunity presents many interesting phases,
but still lacks an absolutely satisfactory solution.

Explanations for the existence of natural immu-
nity are founded on the protection afforded: first, by
the external and internal surfaces of the body ; second,
by inflammatory processes ; third, by natural antibac-
terial and antitoxic substances, and fourth, by the
natural metabolic activity or vital resistance of the
organism.

Bacteria are unable to penetrate the unbroken cu-
taneous epithelium, but may reach the subcutaneous tis-
sues through abrasions although microscopical in size,
through sudoriferous and sebaceous ducts and glands
although their secretions are mildly antibacterial, and
through the hair follicles. In the subcutaneous tissues,
bacterial encroachment is further combated by cellular
proliferation and extravasated plasma containing
serum, fibrinogen, and leucocytes. Bacteria entering
the nasal and oral passages encounter in the mucus
and saliva both physical and chemical barriers. The
gastric, biliary and pancreatic juices exert antibac-
terial and neutralizing functions.

Inflammation, a manifestation of tissue injury, is



4 APPLIED IMMUNOLOGY

a process designed to resist infection, if that be its
cause, and proves successful for mechanical and im-
munological reasons, if the reactive forces of the in-
dividual be capable. The invading bacteria develop a
condition of positive chemotaxis and leucocytes
swarm to the battle-field. Already the bacteria have
stimulated the tissue cells to the production of specific
substances or antibodies and many bacteria are killed
by lysis (see Chapter XI) ; the remainder, by virtue
of sensitization with their specific antibodies (opsonins
of Chapter XX), are ingested and destroyed by the
phagocytes (see Chapter XVII). While the mortal
conflict between bacteria and bacteriolysins and phag-
ocytes is being waged, inflammatory exudate and
proliferation of fi:xed tissue cells occur and raise bar-
riers to the further extension of the morbid process.
Coincidently, the antibodies are formed in excess and
impregnate the blood-serum, establishing the phenom-
enon of immunity.

There is little evidence pointing to the presence of
natural antitoxic substances in animals, although they
have been claimed to occur to a limited extent in horses
and more abundantly in children and adults. Natu-
ral antibacterial substances are more extensively de-
monstrable in the tissue fluids and blood-serum.
Buchner has given the name " alexins " to these nor-
mal bacteriolytic substances. They appear to be



INTRODUCTION 5

identical with opsonins and may be increased by active
immunization.

Acquired Immunity, — Acquired immunity is that
condition of protection against disease, resulting from
recovery from infection or arising by virtue of arti-
ficial inoculation. It may be produced in two ways,
namely, by active or passive immunization.

Active immunization signifies the process by which
the bodily cells of an animal are sti7nulated by a toocin
or foreign body {antigen) to the production of cer-
tain other bodies {antibodies) specific against the
given foreign substance (see Chapter II). Thus the
animal is actively concerned in the elaboration of its
own antibodies, hence the process is termed active.
Untreated disease terminates in either one of three
ways — death, recovery, or chronicity. If the viru-
lence of the infection is great and the dose large or
overwhelming, the animal succumbs, especially if his
vital resistance be slight. If the infection is relatively
avirulent, even though the dose be large, recovery al-
though protracted may take place provided the ani-
mal's resistance is great. If the degree of virulence of
the infection be merely the average, but the vital resis-
tance of the animal be only mediocre, its cellular ac-
tivity or infective dose may prove inadequate for the
normal generation of sufficient specific antibodies to
insure immunity, and chronic invalidism results. Thus



6 APPLIED IMMUNOLOGY

in patients suffering from chronic infections, particu-
larly, and also in certain acute conditions, the number
of specific antibodies may be materially increased and
convalescence shortened or recovery insured by artifi-
cial inoculation employing homologous bacteria. This
result may be achieved by injecting the bacteria with a
hypodermic syringe directly into the tissues, or by
carefully regulated and graduated auto-inoculation,
by manipulations, as massage, hyperemia, etc., of the
infected area. The discovery of the feasibility of pro-
ducing auto-inoculation in patients afflicted with a
localized infection was one of great magnitude and
vital consideration in the study and correct interpreta-
tion of infection and immunity, particularly in connec-
tion with bacterin therapy. By its utilization difficult
diagnoses have been established, successful treatment
conducted in selected cases and in constitutional dis-
eases, clinical interpretations correctly deduced, and
proper treatment applied (see Chapter XXI) . It is
evident, therefore, that when an individual recovers
from an infectious disease he enjoys for an indefinite
time immunity against repeated attacks due to the
same infective organism. It can also be readily under-
stood that immunity against particular diseases can be
conferred by artificial inoculation, using the specific
bacteria, viruses, etc. (prophylactic inoculation or
vaccination).



INTRODUCTION 7

The methods by which immunity may be acquired
through active immunization are as follows, enu-
merated in their order of efficiency:

1. Inoculation with virulent living bacteria, typi-
fied by the subcutaneous injection of spirilla of Asiatic
cholera.

2. Inoculation with attenuated or relatively aviru-
lent microorganisms. This method is exemplified by
vaccination against smallpox and antirabic inocula-
tion.

3. Inoculation with dead bacteria. This embraces
the prevalent practice of bacterin as prophylactic
(vaccine) therapy, notable examples of which include
bacterial inoculations against typhoid fever, plague,
tuberculosis, furunculosis, carbunculosis, etc. A
higher immunity may be produced by supplementing
the dead bacterins with inoculations of attenuated and
finally living virulent bacteria.

4. Inoculation with the excreted bacterial prod-
ucts. The injection of the horse with the tetanus
toxin for the production of antitoxin is the familiar
example of this method.

5. Inoculation with the disintegrated products of
dead bacteria (autolysates). Little of value has at-
tended this procedure and for practical purposes it
may be disregarded.



8 APPLIED IMMUNOLOGY

Passive immunization signifies the process by
which immunity is acquired when artificial antisera are
injected into the animal body (see Chapter V) . Thus
the inoculated animal plays no part in the production
of the antibodies or antitoxin which he receives, and
the process is termed passive. Hence the animal is in-
jected with the specific cellular products (antitoxin)
of another animal previously actively immunized, and
by a process of simple neutralization the toxins in the
diseased animal are destroyed and immunity con-
ferred. In passive immunization the antibodies bear a
close chemical combination to the cells. The acquired
immunity of passive immunization is of vastly shorter
duration than that resulting from active immunization.

Mechanism of the Production of Immunity

There is a group of foreign chemical substances,
conveniently styled antigens, to which the animal body
reacts in a definite manner. This group must be dif-


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Online LibraryBenjamin Abraham ThomasApplied immunology; the practical application of sera and bacterins prophylactically, diagnostically and therapeutically; → online text (page 1 of 23)