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Experimental nephritis in rats induced by injection of anti-kidney serum. I. Preparation and immunological studies of nephrotoxin

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Abstract

Nephritis can be induced in rats by the injection of anti-kidney sera obtained from rabbits immunized with suspensions of perfused rat kidney. Anti-kidney sera, thus prepared, contain a number of antibodies capable, on injection into rats, of inducing a severe anaphylactoid reaction with general vascular manifestations that involve the kidney as well as other organs. These sera also contain a nephrotoxic agent that affects the kidney primarily. The nephrotoxic effect is characterized clinically by severe persistent albuminuria with casts, and transient anasarca during the acute disease, but no significant hematuria occurs. When a severe anaphylactoid reaction is superimposed on the nephrotoxic injury, hematuria is an outstanding feature. Nephrotoxin is demonstrable in vivo and is not related quantitatively to the precipitins in the anti-kidney serum against kidney extract. It is most readily obtained by immunization with kidney suspensions, but may occasionally appear after injections of other organ preparations; it does not result from immunization with erythrocytes or serum. Nephrotoxin is present in the globulin fraction of anti-kidney serum. The nephrotoxic action of anti-kidney serum is easily removed by absorption with kidney cells or fat-free kidney tissue. Similar preparations of liver likewise remove it, but less readily. Neither kidney, liver, or brain lipids affect it, nor does absorption with red blood cells or serum. Nephrotoxin appears to be an antibody that is relatively organ specific in its affinities. It differs from the more common antibodies involved in reverse anaphylaxis in one respect, at least: The animal rapidly becomes desensitized against the latter and fails to react, whereas desensitization to nephrotoxin is difficult to secure.

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Article
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Article
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Article
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Article
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Article
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Article
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Chapter
Pathogenetische Probleme hatten von jeher für die Nierenerkrankungen eine praktisch wichtige Bedeutung. Der beste Beweis ist die schnelle Anerkennung, die das „Pathogenetische System der Brightschen Nierenkrankheiten“ von Volhard und Fahr (1913) schon bald nach seiner Aufstellung gefunden hat. Erst nach dieser Klassifizierung der Nierenkrankheiten in degenerative, entzündliche und arteriosklerotische Leiden war es möglich, feste morphologische Begriffe mit den funktionellen Symptomen der Klinik zu verbinden. Prognostische Aussagen wurden möglich.
Article
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Article
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Article
In order to see whether or not the liver of different species of animals possesses antigenicity and also to study the significance of senstization with visceral antigens, the visceral specificity of liver antiserum, and the possible visceral disturbances the author carried out serological study on different species of animals (dogs and rabbits) and obtained the following results. 1. The liver of different species of animals possesses antigenicity, aud the serum of the rabbit sensitized with dog liver extract shows a relative visceral specificity in the reaction in vitro between this serum and the extracts of various organs, blood, and serum of the dog. 2. In the blood as well as in various organ tissues of the rabbit sensitized by the extract of dog liver can be detected antibody (liver antibody) as to react with such sentitizing agents. 3. When the serum of the rabbit sensitized with dog liver extract is inoculated into a normal dog, it disturbs the function of the liver and neighboring abdominal organs. Moreover, such a serum accelerates the production of antibody to react especially with the antigen extracted from the dog liver and also it reveals a relative visceral specificity.
Article
1. From the standpoints of the complement fixation reaction and the tissue reaction it has been proven that the liver homologous immunicity can be accomplished in rabbit liver by injecting homologous liver emulsion into the animals without resorting to Freund's adjuvant method. 2. When the liver tissue is rapidly destroyed by injecting an hypertonic physiological saline solution into the liver, the production of liver auto-antibody can clearly be recognized, and the sensitized state with tissue reaction can also be observed. 3. In comparing the tissue reaction in the case sensitized with microsome fraction of homologous liver or homologous liver phosphatid antigen with the reaction observable in the liver injected with homologous liver emulsion, hardly any difference can be seen in the former, while the tissue reactions such as necrosis of liver cells etc. are far more marked in the latter. 4. Although there are few differences in the tissue reaction according to the dosis and the titer of the injected homologous liver antiserum, a cytotoxin-like action and a relative organ specificity were recognized. 5. The mice sensitized with the homologous liver emulsion previously are secondary infected with ectromelia virus, so that serous inflammation of the liver tissue are used to be found additionally, moreover by the sensitization above mentioned the histological changes in the liver tissue of the mice become more stronger.
Chapter
Renal symptoms can accompany infectious diseases in two periods: (i) at the time of the onset of the infection, or (ii) after a latent period corresponding to the time needed for the production of human antibodies. In the first case we talk about early, intrainfectious or para-infectious nephritis, and in the latter, about postinfectious glomerulonephritis. Early nephritis is caused with all certainty by primary toxic effects, while in the development of postinfectious glomerulonephritis the antigen-antibody reaction plays the decisive role. It was realized as early as the beginning of this century that scarlatinal nephritis is an allergic disease [265]. Since then a number of explanations have been put forward for the aetiology and pathomechanism of post-streptococcal glomerulonephritis including the theory of autoimmunization. Nevertheless, no final solution of the problem has been reached. Some authors are of the opinion that autoimmunization is not the cause but the consequence of renal disease.
Article
It is well known that a few endothelial cells of the glomeruli accumulate a large quantity of fine particles or colloidal substances, such as carbon black, cholesterol, methyl cellulose, alcian blue, and trypan blue, when they were introduced in blood. This investigation was attempted first to compare the phagocytic activity of these cells with that of the members of reticuloendothelial system, and second to examine the role of them in normal and pathological conditions of the glomeruli. The materials were 7 normal and 23 unilateral Masugi nephritis rabbits. Vital staining was performed by the intravenous injection of carbon black suspension (25% dilution of Pilot black ink). The normal rabbits received 1 or 3 injections of 5 or 10 ml/kg of the suspension. They were killed 1, 2, 3, and 24 hours after the last injection. Unilateral Masugi nephritis was produced by a single injection of 1.25 ml/kg of duck anti-rabbit kidney serum during the transient ligation of the left renal artery. Clinical course of the disease was divided into five stages ; latent (within 5 days after the injection), initial (6-7th day), severest (8th day), lasting (10-2lth day), and healed stage (21-66th day). At each stage, some of the animals were sacrificed, receiving intravenous injection of carbon black suspension (10 ml/kg) 24 hours before the sacrifice. Further 3 nephritic animals were injected with daily dosis of 30 mg of predonisolone for 1, 2 or 3 days before the sacrifice at the 8th, 9 th or 10 th day after the injection of nephrotoxin, respec-tively. They also were vitally stained 24 hours before the sacrifice. Light-microscopic studies were performed on the kidney, liver, spleen, bone marrow, adrenal glands and hypophysis. The results obtained were as follows ; 1) In vital staining of the norma rabbits, four kinds of cells were differentiated in glomerular tufts : (i) glomerular epithelial cells negative to vital stain, (ii) common capillary endothelial cells, nearly or perfectly negative, (iii) mesangial cells, weakly positive, (iv) phagocytic endothelial cells, markedly positive. The ratio of the number of the latter three kinds of cells was as follows, mesangial cells 53.3%, common endothelial cells 46. 2%, and phagocytic endothelial cells 0.60. 2) When the phagocytic activity of the glomerular phagocytic endothelial cells and of the members of the reticulo-endothelial system was compared, the former seemed to take the carbon black after the blockade of the latter. 3) In the glomerular tufts of the Masugi-nephritis, there were found the phagocytic endothelial cells, common endothelial cells, mesangial cells, and endothelium-like cells. The phagocytic endothelial cells appeared in all stages, except for the severest stage. They were, however, small in number, and did not play an inportant role in the development and progression of the disease. The phagocytic activity of the common endothelial cells was nearly similar to that in normal condition. The activity of the mesangial cells was markedly enhanced. The endothelium-like cells were syncytial and frequently transformed into multinuclear giant cells. The cytoplasm was stained basophilic and contained numerous filament-like structures. Their phagocytic activity was not uniform. Some of them took no carbon granule, some took various amount of granules which were frequently arranged in rosette-like pattern. From the histologic findings of the nephriticc rabbits treated with predonisolone, it was suggested that these endothelium-like cells were originated.d from mesangial cells. 4) The large "endothelial cells" appeared in the nephritic glomeruli were not a single kind of cells. In the stages soon before and after the onset of the nephritis, the majority of them were the common endothelial cells, and in the severest stage, the endothelium-like cells. In the lasting stage and thereafter, they were composed of miscellaneous ; namely degenerating endothelium-like clls
Article
The ultrastructural changes in the glomerulus of rats with Aminonucleoside (AN) and Anti-kidney serum (AKS) nephrosis, which showed the similar clinical condition, especially in degree of proteinuria, were studied by electron microscopy. The materials, fixed in osmium tetroxide and embedded in epon epoxy resin, were sectioned with glass knives on a Portor-Blum microtome. The sections were stained with lead tartrate and examined with electron microscope. The results were obtained as follows. (1) The stage before the appearance of proteinuria: In AN nephrosis, the fine structure of the glomerulus was normal in appearance. In AKS nephrosis, swelling of the endothelial cytoplasm and disarray of the fenestration were slightly observable, but no structural changes were detected in the mesangium, the basement membrane, and the epithelium. (2) The stage immediately after the appearance of proteinuria: In AN nephrosis, the glomerulus showed almost normality in appearance, except for the epithelium in which the foot processes were occasionally lost, forming a broad cytoplasmic layer on the basement membrane. In AKS nephrosis, the endothelium was swollen and its fenestration were reduced in number. The mesangium was slightly proliferated, and the irregularities of thickness and electron density were seen in the basement membrane. The cytoplasm of epithelium showed no significant changes, but the foot processes were occasionally lost as seen in AN nephrosis. (3) The stage of mild nephrosic syndrome: In AN nephrosis, swelling and vacuolation of the endothelium, and proliferation of the mesangium were very slightly recognized. The basement membrane showed partially slight irregularities in thickness and electron density. There was increase of vesicles, vacuoles and dense bodies in the epithelium, the foot processes of which were moderately lost, forming a denser continuous cytoplasmic sheet over the basement membrane. Many micropinocytotic invaginations also occured in it. In AKS nephrosis, the endothelium was swollen, and partially separated from the basement membrane, where the Lamina densa was directly exposed to the blood. The basement membrane changed in appearance more prominently. The cytoplasm and foot processes of epithelium showed changes similar to those in mild AN nephrosis. (4) The stage of severe nephrotic syndrome: In AN nephrosis, the epithelium, the mesangium, and the basement membrane were similar in appearance to those in mild nephrotic stage, but the epithelial cytoplasmic changes were more prominent and the foot processes were remarkably lost. In AKS nephrosis, the changes of the endothelium, the mesangium, and the basement membrane were more advanced than those in mild nephrotic stage. The cytoplasm and foot processes of epithelium showed the similar changes to those in severe AN nephrosis. Although there were remarkable differences in structural pattern of the endothelium, the mesangium, and the basement membrane between AN and AKS nephrosis, the epithelium showed the similar changes in structure between them. The loss of the foot processes were well correlated with degree of proteinuria, and were nearly the same in degree between both nephrosis, though they showed the similar condition. It seems likely that the pathogenesis of proteinuria in the nephrotic syndrome is attributed to the increased permeability of the glomerular capillary wall, which resulted from the aprimary damage of the basement membrane, probably followed by epithelial changes.
Chapter
Die Hämagglutination hat nicht nur ein wissenschaftliches Interesse bez. Fragen der Genetik und Rassenkunde, sowie der chemischen Natur der mannigfachen sog. Gruppen-und Faktorensubstanzen im Stroma der Blutzellen and a., sondern auch ein großes praktisches Interesse für die Bluttransfusion, für den Vaterschaftsnachweis und andere forensische Aufgaben.
Chapter
Diseases now known to be manifestations of allergy or altered reactivity have undoubtedly existed throughout human history, but their nature and relationship to each other have been understood only in the past fifty years. There are records dating from antiquity of a casual relationship between exposure to innocuous substances and the production of minor or severe clinical disorders. Before the present century it was not suspected that such a diversity of disease conditions could be caused by allergic hypersensitivity; nor was there any suspicion that a vast number of environmental substances, which are in themselves relatively harmless, can produce distresssing and even fatal disease through their capacity to induce the allergic state. It has been estimated that approximately ten per cent of our population have such common clinical allergies as asthma, hay fever, allergic rhinitis, atopic eczema, urticaria, angioneurotic edema and gastro-intestinal allergy. These are usually caused by non-infectious antigens of environmental or extrinsic origin. However, the pathologic changes of chronic infection often may be caused, in large part, by an allergic response of the host to the invading micro-organism. Furthermore, the morphologic and physiologic changes which characterize the so-called “collagen diseases”, glomerulonephritis, rheumatic fever and encephalomyelitis, are thought by some to result from autoantibody production to antigens present in the individual’s own tissues. In erythroblastosis fetalis, antibodies derived from the mother pass through the placenta to combine with antigens on the erythrocytes of the fetus. The degeneration of homologous skin and other tissue grafts may be also attributed to the formation by the recipient of antibodies to the grafted tissue.
Chapter
Antikörper haben bekanntlich Globulineigenschaft mit einer zusätzlichen chemischen Affinität zu Molekülen, die ihrerseits als Antigen die Bildung der Antikörper in bestimmten dazu geeigneten Körperzellen veranlaßt haben. Ein Antigen ist in allgemeinster Fassung definiert als eine Substanz, die im Körper als fremd empfunden wird, und die der Körper zu eliminieren oder sonstwie unschädlich zu machen versucht. Nach Ehiilichs Formulierung als „Horror autotoxicus“ soll in einem Organismus kein Antikörper gegen arteigenes und ganz sicher kein Antikörper gegen körpereigenes Gewebe entstehen können. Da dies aber doch der Fall sein kann und Auto-Antikörper tatsächlich vorkommen, so ist das Ehrliohsche Dogma, wie wir später sehen, einzuschränken.
Article
The change of urinary prostaglandin (PGE) excretion was studied in experimental glomerulonephritic rats (Masugi nephritis) and the effects of ouabain and chlorothiazide on urinary PGE excretion in nephritic rats were examined. Experimental glomerulonephritis was induced in rats by the intravenous injection of anti-kidney serum obtained from rabbits immunized with the homogenate of rat kidney. The urinary PGE was measured by the bioassay using rat stomach fundus strip. Urinary PGE and urinary electrolytes in nephritic and normal rats were determined. There was positive relationship between urinary PGE and urinary electrolytes in both kinds of rats. The urinary PGE and sodium excretion was increased in nephritic rats by ouabain (10 mg/kg), but not in normal rats. The potassium and chloride excretion was significantly increased in both nephritic and normal rats by ouabain. The diuretic effect of clorothiazide (15 mg/kg) was more significantly recognized in nephritic rats than in normal rats. But there was little change in urinary PGE excretion by chlorothiazide in both nephritic and normal rats. The reduction of urinary PGE excretion in nephritic rats may be due to a decrease of PGE biosynthesis in the renal medulla and/or a diminished secretion of PGE into renal tubules, both accompanied with the disturbance of glomerular function.
Article
Chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel diseases, and others typically stimulate a systemic response of the entire body. This response has a uniform character in many diseases because common pathways are switched on. The uniform response regulates systemic energy and water provision. However, long-term application of this program leads to typical disease sequelae such as fatigue / depressive symptoms, sleep disturbances, anorexia, malnutrition, muscle wasting - cachexia, cachectic obesity, insulin resistance, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal axis, elevated sympathetic tone, hypertension, volume expansion, decreased parasympathetic tone, inflammation-related anemia, bone loss, hypercoagulability, circadian rhythms of symptoms, and disease exacerbation by stress . The Origin of Chronic Inflammatory Systemic Diseases and Their Sequelae demonstrates concepts of neuroendocrine immunology, energy and water regulation, and evolutionary medicine in order to show that the uniform response that regulates systemic energy and water provision, has been positively selected for acute physiological responses and short-lived disease states, but is a misguided program in chronic inflammatory diseases and aging.
Chapter
This chapter discusses the roots of and routes to autoimmunity. Ehrlich developed the first general theoretical concept of specific immunity and natural self-tolerance. His side-chain receptor theory, with its striking similarities to the current selection theory of acquired immunity, proposed that cells involved in immune responses produced sessile “side-chain” receptors that were initially anchored to the cell. The attachment of an antigenic molecule to a receptor stimulates the formation by the cell of new receptors, and there is production of the same receptors by additional cells in the body, “activated cells” and “memory cells” in later usage. The production of a surplus of receptors resulted in these being shed as free particles—antibodies—that bind antigen in the circulation. Autoimmune Diseases was published as a theoretical and clinical science description of autoimmunity and disease. The theoretical basis comprised Burnet's clonal selection theory of acquired immunity that includes deletion in embryonic life of any potential self-reactive immunocytes.
Article
The principal objective of this investigation was to define the roles of injected and autogenous, kidney-localizing antibodies in the pathogenesis of rat nephrotoxic nephritis by relating data obtained with fluorescent antibody techniques to clinical and histologic observations. Such an analysis of the nephritis that developed in 28 rats after injection with the crude γ-globulin fraction of nephrotoxic serum has led us to the following conclusions:— The renal localization of nephrotoxic antibodies is primarily and, perhaps, exclusively in the membranes of the glomerular tufts. These antibodies are demonstrable, as antigens, in the glomeruli for up to 3 months after injection. In the acute stage of the nephritis, non-antibody, autogenous globulins are present in the glomerular tufts, probably as components of edema fluid. From 6 and 9 days to 3 months after injection, autogenous antibodies are localized in the glomerular tufts in a pattern that corresponds closely to that of the nephrotoxins. The essential requirements for the operation of the mechanism postulated by Kay are fulfilled in rat nephrotoxic nephritis.
Article
Studies have been carried out to determine the distribution of antigen capable of inducing the formation in rabbits of antibodies nephrotoxic for the rat. The results indicate that the antigen is present both in cortex and medulla of rat kidney. It can be extracted to a limited extent with saline. It is non-dialyzable and destroyed by boiling. The nephrotoxic serum antigen is also present in rat lung and placenta, in amounts roughly comparable to that in kidney, and in a number of other rat organs in smaller amounts. These various tissues not only are capable of stimulating the production of nephrotoxic antibodies, but each tissue is also able to absorb the nephrotoxic antibodies induced by injections of other rat tissues. These studies indicate that the nephrotoxic serum antigen in various rat tissues is the same or closely related. The nephrotoxic serum antigen of the rat is distinct from that of the dog and the rabbit, but there appears to be a cross-reaction between the nephrotoxic serum antigens of the rat and mouse. It is concluded that the nephrotoxic serum antigen is not a specific component of kidney; it is neither limited to kidney in its distribution within the rat, nor is the rat antigen present in kidney tissue of 2 other species examined. Rather, it is probable that the antigen is to a large extent specific for tissue of a given species. The preponderance of renal injury following injections of the anti-organ sera presumably is due to the occurrence in the kidney of large amounts of the antigen in positions of physiological importance in which it is exposed directly to the circulating antibodies.
Article
Mit Hilfe des Parabioseversuches läßt sich die Nephrotoxin-(Masugi-) Nephritis der Ratte in derselben Weise wie bei Verwendung genetisch differenter Tiere auch auf Inzuchtratten übertragen. Dieses Resultat weist darauf hin, daß genetische Inkompatibilitäten im Sinne der „Transplantationsimmunität“ bei der vorliegenden Übertragung keine Rolle spielen. Die Übertragungsreaktion muß vielmehr als Folge der Einwirkung des Blutes nierenkranker Tiere auf gesundes Nierengewebe angesehen werden.
Article
The nephrotic syndrome is characterized by intermittent edema associated with considerable proteinuria, with low concentrations of certain plasma proteins, especially albumin and gamma globulin, and with hyperlipemia. The nephrotic syndrome may occur as a phase of classical glomerulonephritis or as part of certain systemic diseases not primary in the kidney. However, there is compelling evidence to support the belief that in children the nephrotic syndrome may, and almost always does, occur as a disease of unknown etiology but distinct from the glomerulonephritis associated with infection by the hemolytic streptococcus. The fact that the mortality rate does not change abruptly from childhood to adulthood suggests that apart from those few cases occurring as a stage of glomerulonephritis or as a part of certain systemic diseases, the nephrotic syndrome represents the same disease in adults as in children. Proteinuria in patients with the nephrotic syndrome is attributed to an alteration in the glomerular membrane which permits large amounts of protein to pass into the glomerular fluid, and the primary cause of hypoproteinemia is ascribed to urinary excretion of protein. In patients with the nephrotic syndrome, the concentration in serum of the low density beta lipoproteins rich in triglycerides, cholesterol, and phospholipids is usually increased. The cause of these alterations is not known, but recent evidence suggests that they may be related to the urinary loss of plasma albumin. Edema in patients with the nephrotic syndrome is due to renal tubular reabsorption of filtered sodium chloride and water in excess of that required to maintain a normal volume of extracellular fluid. The question of whether the primary alteration is a reduction in glomerular filtration rate or an increase in tubular reabsorption has not been resolved. A review of the course of patients with the nephrotic syndrome emphasizes the chronic nature of the disease. The median time from onset to recovery varied from 22 to 57 months in different age groups, with great variability within groups. In the group of patients who died, the median time from onset to death ranged from 29 to 82 months. The corrected mortality was slightly over 40 per cent in the group of patients under 10 years of age and increased with age to 86 per cent in patients over 30 years of age. Although general measures in treatment are of great practical importance, of greater significance at the present time are the problems concerning the use of corticotropin or adrenocortical steroids. Present evidence suggests that these agents should be used to induce diuresis and that they should be given for a prolonged period thereafter.
Article
Consideration on autoimmunity began, as did immunology itself, around year 1900, first with Ehrlich's doctrine of 'horror autotoxicus', then interpreted as 'autoimmunity cannot happen'. Yet by 1904 the antibody nature of the autohemolysin responsible for cold hemoglobinuria was described, and soon confirmed, but without generating any durable concept on autoimmunization as a cause of disease. Reasons included Ehrlich's doctrine, the particular directions that immunology was to take after the initial advances, and a greater preoccupation with bodily responses to extrinsic rather than autologous substances. So, during 1915-1945, autoimmunity underwent a long eclipse despite, during this time, some potentially telling studies relating to brain, kidney and other diseases. The 'awakening' dates from 1945 when a general theoretical concept did appear feasible. Knowledge accrued from applications of several research undertakings mostly for purposes quite unrelated to the proof of autoimmunization: the use of adjuvants; the Coombes anti-globulin reaction; the Waaler-Rose rheumatoid factor; Hargraves' LE cell; the Witebsky-Rose experimental induction of thyroiditis with autologous thyroid gland, and others. By the early 1960s resistance to the idea of autoimmunization had weakened, perhaps hastened by a monograph on autoimmune disease published in 1963, and surely by the consensus reached at a large international conference published as proceedings in 1965. This present conspectus arbitrarily concludes at year 1965, recognizing that the history of autoimmunity even now is far from over.
Article
Attention is called to the fact that bacteria may be preserved for a long time by desiccation in the frozen state. It has been shown that it is necessary to maintain the frozen condition until desiccation is complete; if the fluid melts before the moisture is completely removed, the organisms are killed, probably because of the concentration of the salts upon the surface of the bacteria. By the simple expedient of immersing the tubes of organisms in glycerol contained in a desiccator and subsequently keeping the whole apparatus in a salt-ice mixture until drying is complete, the organisms are easily maintained in the frozen state, and dry properly. Bacteria preserved in this manner retain their cultural, biochemical, and immunological characters for prolonged periods.
Article
1. The sera of rabbits injected repeatedly with the nucleoproteins, globulins, and albumins of the liver and kidney of the dog give no evidence in vitro or in vivo experiments of organ affinity. The precipitin test offers no proof of the specificity of these sera for the proteins employed as antigens. 2. The anaphylaxis reaction applied to the same proteins indicates a slight relative organ affinity but no specificity as far as the respective protein fractions are concerned. The relative organ affinity resides, rather, in the globulin and albumin fractions than in the nucleoprotein fraction. Dog serum used both as a sensitizing and an intoxicating agent gives rise to very active cross reactions with organ proteins, thus failing to support the theory of organ or of protein specificity. 3. These results do not support the view put forward that nucleoproteins play an important part in the course of production of cytotoxic immune sera.
Article
(1) The cytotoxins are not specific. (2) The changes occurring after the injection of different cytotoxins are similar and do not vary in kind. (3) The changes do, however, vary in degree in the following order, the one having the most marked effect being placed first, etc.: (a) Haemolymphotoxin, (b) Splenotoxin, (c) Lymphotoxin, (d) Endotheliotoxin, (e) Nephrotoxin, (f) Hepatotoxin. (4) Nephrotoxin causes the most specific change. (5) The haemolymph glands play some important part in the production of eosinophiles. The haemolytic action of haemolymphotoxic serum is greater than that of other cytotoxic sera. (6) The histological changes which are observed in every case are secondary to the haemolytic factor present in all cytotoxic sera.
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