bluuebunny/crossref_metadata_2025 huggingface dataset:
CHRONIC ALLOGENEIC DISEASE
Authors: Lewis Robert M. , Armstrong Martine Y. K. , André-Schwartz Janine , Muftuoglu Asuman , Beldotti Lorraine , Schwartz Robert S.
Published: June 2004

Glomerulonephritis, often accompanied by the nephrotic syndrome, developed in CAF1 mice following the administration of spleen cells from normal BALB/c mice. The renal lesion was membranous glomerulonephritis. When studied with fluorescein-conjugated antisera to either mouse gamma globulin or ß1C-globulin, the glomeruli contained beaded and irregular deposits of these immunoproteins. The ultrastructure of the lesion was characterized by thickening of the glomerular basement membranes and the presence of electron-dense subepithelial deposits. Acid eluates of the diseased kidneys contained gamma globulin that failed to bind to sections of normal kidneys. These findings conform to the type of nephritis provoked by immune complexes. They indicate that this type of immune injury can be based on the reaction of intolerant immunocytes to normal antigens.
CELLULAR EVENTS IN THE IMMUNE RESPONSE
Authors: Raidt Donald J. , Mishell R. I. , Dutton Richard W.
Published: June 2004

Cell suspensions from the spleens of normal mice or mice injected with sheep erythrocytes were separated on a discontinous bovine serum albumin density gradient. Four bands or subpopulations were obtained and were assayed for antibody-forming cells, and for antigen-sensitive precursor cells. The antibody-forming cells were assayed by the hemolytic plaque assay and the antigen-sensitive precursors were assayed by the number of plaque-forming cells which developed after 3 or 5 day's culture with antigen. It was found that both antibody-forming cells and their precursors were present in the denser region of the gradient when spleen cell suspensions were taken from unimmunized mice. In contrast, both antibody-forming cells and precursors floated to the top in cell suspensions from mice sacrificed 1, 2, or 3 days after antigen injection. The change in density was detectable as early as 12 hr and was complete by 18 hr. The cell which changed in density was specific for the antigen that brought about that change. The significance of these findings is discussed.
CELL TO CELL INTERACTION IN THE IMMUNE RESPONSE
Authors: Mitchell G. F. , Miller J. F. A. P.
Published: June 2004

The number of discrete hemolytic foci and of hemolysin-forming cells arising in the spleens of heavily irradiated mice given sheep erythrocytes and either syngeneic thymus or bone marrow was not significantly greater than that detected in controls given antigen alone. Thoracic duct cells injected with sheep erythrocytes significantly increased the number of hemolytic foci and 10 million cells gave rise to over 1000 hemolysin-forming cells per spleen. A synergistic effect was observed when syngeneic thoracic duct cells were mixed with syngeneic marrow cells: the number of hemolysin-forming cells produced in this case was far greater than could be accounted for by summating the activities of either cell population given alone. The number of hemolytic foci produced by the mixed population was not however greater than that produced by an equivalent number of thoracic duct cells given without bone marrow. Thymus cells given together with syngeneic bone marrow enabled irradiated mice to produce hemolysin-forming cells but were much less effective than the same number of thoracic duct cells. Likewise syngeneic thymus cells were not as effective as thoracic duct cells in enabling thymectomized irradiated bone marrow-protected hosts to produce hemolysin-forming cells in response to sheep erythrocytes.

Irradiated recipients of semiallogeneic thoracic duct cells produced hemolysin-forming cells of donor-type as shown by the use of anti-H2 sera. The identity of the hemolysin-forming cells in the spleens of irradiated mice receiving a mixed inoculum of semiallogeneic thoracic duct cells and syngeneic marrow was not determined because no synergistic effect was obtained in these recipients in contrast to the results in the syngeneic situation. Thymectomized irradiated mice protected with bone marrow for a period of 2 wk and injected with semiallogeneic thoracic duct cells together with sheep erythrocytes did however produce a far greater number of hemolysin-forming cells than irradiated mice receiving the same number of thoracic duct cells without bone marrow. Anti-H2 sera revealed that the antibody-forming cells arising in the spleens of these thymectomized irradiated hosts were derived, not from the injected thoracic duct cells, but from bone marrow.

It is concluded that thoracic duct lymph contains a mixture of cell types: some are hemolysin-forming cell precursors and others are antigen-reactive cells which can interact with antigen and initiate the differentiation of hemolysin-forming cell precursors to antibody-forming cells. Bone marrow contains only precursors of hemolysin-forming cells and thymus contains only antigen-reactive cells but in a proportion that is far less than in thoracic duct lymph.
PERSISTENCE OF STREPTOCOCCAL GROUP A ANTIBODY IN PATIENTS WITH RHEUMATIC VALVULAR DISEASE
Authors: Dudding Burton A. , Ayoub Elia M.
Published: June 2004

Antibody levels to streptococcal Group A and A-variant carbohydrates were determined using a radioactive immune precipitation technique on patients with rheumatic fever, with and without valvular disease, on patients with post-streptococcal acute glomerulonephritis, and on age-matched controls. During the acute phase of the above illness, the means of the antibody levels to both carbohydrate antigens were equally elevated and were significantly higher than the normal controls. When Group A antibody levels were determined on sera obtained at intervals of 5–12 months and 1–5 yr after the acute illness) it was found that the antibody levels declined within the normal range at the 5–12 month interval in patients with glomerulonephritis as well as in patients with rheumatic fever in whom no valvular involvement had complicated the disease, i.e., patients with pure Sydenham's chorea. However, in patients with rheumatic valvulitis, who had been on penicillin prophylaxis after the last acute episode, the A antibody level showed little decline from the level obtained during the acute illness. The elevated antibody level in patients with rheumatic valvulitis, including patients with Sydenham's chorea with valvulitis, persisted for periods of at least 1 yr and up to 20 yr after the last acute attack. The pattern of the decline of the antibody levels to the A-variant carbohydrate as well as of the antibody titers to the other streptococcal antigens tested, ASO and anti-DNase B, was similar in all patients studied regardless of the presence of valvular disease. These findings suggest that prolonged persistence of the Group A antibody is a phenomenon peculiar to patients with rheumatic valvular disease. Whether this persistence is involved in the pathogenesis or is an outcome of the valvular disease remains to be determined.
MEDIATORS OF INFLAMMATION IN LEUKOCYTE LYSOSOMES
Authors: Janoff A. , Scherer J.
Published: June 2004

The present study demonstrates that a granule fraction derived from human polymorphonuclear leukocytes possesses elastinolytic activity, and that the latter can be separated from the collagenase present in these cells. Properties of the human leukocyte elastase differ sufficiently from those of pancreatic elastases of different species as to suggest that the former enzyme is a distinct and separate entity. Thus, soybean trypsin inhibitor and salivary kallikrein inhibitor (Trasylol) fail to inhibit elastolysis by the pancreatic enzyme, but do inhibit the leukocyte elastinolytic agent. Elastolysis by human leukocyte granule extract does not show significant salt inhibition, whereas that catalyzed by pancreatic elastase is markedly reduced when ionic strength is increased to physiological levels. The leukocyte granule extract is at least 10 times more resistant to serum elastase inhibitor than is the purified pancreatic enzyme. Both enzymes show optimal elastolysis above pH 8.5, but the leukocyte factor still retains 50% of its maximal elastolytic activity at pH 6–7; whereas the activity of the pancreatic enzyme falls to 10% or less of its maximal value under the same conditions. The foregoing characteristics of the human leukocyte elastase suggest that it, rather than pancreatic (serum) elastase, may mediate pathological elastolysis during acute arteritis in man. In keeping with this suggestion, the present experiments also show that elastica staining of human arterial vessels is reduced by incubation of tissues with human leukocyte granule extracts in vitro.
QUANTITATIVE STUDIES ON THE MIXED LYMPHOCYTE INTERACTION IN RATS
Authors: Wilson Darcy B. , Blyth Janet L. , Nowell Peter C.
Published: June 2004

The proliferative interaction of cultured rat lymphocytes of immunogenetically disparate origin—the mixed lymphocyte interaction—was employed as an experimental model to examine the initial stages of the immune response mechanism. Using mixed cultures of cells derived from parental strain and F1 hybrid rats, in which only the parental lymphocytes respond, the following observations were made on the magnitude and kinetics of the reaction.

After initiation of the cultures, there was a latent period of approximately 40 hours during which time no mitotic activity was detected.

This inactive phase was followed by a period of proliferation in which previously nondividing cells entered the mitotic cycle for the first time. Activity in the cultures, as detected by incorporation of radioactive thymidine and measured by radioautography or scintillation spectrometry, increased exponentially with a doubling time (T2) of 9–10 hr.

In this exponential proliferative phase, lasting approximately 100 hr, the dividing cells underwent a series of rapid sequential divisions with a generation time (Tc) of 8 hr, and few, if any, dropped out of the mitotic cycle.

In addition to the cells which first entered mitosis at the beginning of the proliferative phase and then proceeded through multiple divisions, significant numbers of new, previously nondividing cells continued to enter the mitotic cycle during the entire exponential growth phase. The total number of these newly responsive, first division cells throughout the total culture period amounted to 1–3% of the original parental cell inoculum. This is a surprisingly large proportion of peripheral blood lymphocytes with demonstrable reactivity to a particular antigen system, if it is assumed that these first division cells in vitro are functionally related to the hypothetical antigen-sensitive cells which proliferate and differentiate into immunological effector cells. At present there is no entirely satisfactory explanation for this large number of reactive cells in the mixed lymphocyte interaction.
THE INDIVIDUAL ANTIGENIC SPECIFICITY OF ANTIBODIES TO STREPTOCOCCAL CARBOHYDRATES
Authors: Braun Dietmar G. , Krause Richard M.
Published: June 2004

Although a single electrophoretically uniform antibody component with specificity for the group carbohydrate may comprise the bulk of the γ-globulin in rabbits immunized with streptococcal vaccines, this is not always the case. Not infrequently, electrophoresis may reveal multiple antibody components. Nevertheless, it has been feasible by various preparative procedures to isolate from a single antiserum at least two antibody components with similar reactivity for the carbohydrate both of which are electrophoretically monodisperse. Light chains from such antibodies reveal a restricted pattern when examined by disc electrophoresis.

Antibodies to streptococcal carbohydrates have been examined for their individual antigenic specificity. Goats were immunized with isolated Group C and Group A-variant antibodies raised in rabbits. Individual antigenic specificity of these antibodies was brought out by absorption of the goat anti-antiserum with Fr II of pooled normal rabbit sera. Additional absorption of the goat anti-antisera with Fr II diminished but did not eliminate the reactivity for the homologous antibody.

Immunoelectrophoretic studies with papain fragments of purified streptococcal antibodies localized the specificity to the Fab fragment. Specificity was not confined to the isolated light chains of the antibody.
A SUBCLASS OF HUMAN γA-GLOBULINS (γA2) WHICH LACKS THE DISULFIDE BONDS LINKING HEAVY AND LIGHT CHAINS
Authors: Grey Howard M. , Abel Carlos A. , Yount William J. , Kunkel Henry G.
Published: June 2004

The γA2-subgroup of γA-globulins, previously delineated by antigenic studies, was found to differ strikingly from other immunoglobulins in the manner in which the polypeptide chains are bound together. The heavy and light chains were not linked to each other by disulfide bonds. Instead the light chains were disulfide linked to one another, and were present in the γA2-molecule as disulfide bridged L-L dimers.

Antisera specific for γA2-proteins indicated the occurrence of two different antigenic types in all normal sera as well as saliva and colostrum. Both of these showed the unique interchain disulfide linkage. Quantitative analyses indicated higher levels of γA2-proteins in external secretions.
HISTOPATHOLOGICAL EFFECTS IN MICE OF HETEROLOGOUS ANTILYMPHOCYTE SERUM
Authors: Taub Robert N. , Lance Eugene M.
Published: June 2004

The effects of heterologous rabbit anti-mouse lymphocyte antiserum on the morphology of lymphoid and other tissues was investigated in CBA mice.

The lymphoid tissues exhibited characteristic changes specific for ALS treatment, which were an invariable accompaniment to its immunosuppressive effects. These consisted of peripheral lymphopenia occurring at some time during a course of ALS treatment and persistent depletion of small lymphocytes in lymph node paracortical areas and splenic follicular periarteriolar zones. The thymic histology was generally well preserved.

It is suggested that the relevant lesions reflect a rapid depletion of the pool of recirculating lymphocytes, possibly by a primary cytotoxic effect exerted on cells peripheral to lymphoid tissue.

Other histologic features attendant to the administration of ALS were accounted for as consequences of immunization of ALS recipients to rabbit serum constituents or by the deleterious effects of antibodies directed against tissues other than lymphoid cells.
CELLULAR DIFFERENTIATION AND THE AGING PROCESS IN CARTILAGINOUS TISSUES
Authors: Shulman Herbert J. , Meyer Karl
Published: June 2004

Primary cell cultures of differentiated chondrocytes were shown to produce chondroitin-4-sulfate as the predominant mucopolysaccharide, with suggestive evidence for the synthesis of keratan sulfate and possibly chondroitin-6-sulfate.

Chicken embryonic cartilage was shown to be composed mainly of chondroitin-4-sulfate, with a small amount of chondroitin-6-sulfate, but essentially no keratan sulfate.

These findings were compared to the data of others, and a hypothesis explaining the aging process in cartilage in terms of cellular differentiation was presented.
STUDIES ON THE SENSITIZATION OF ANIMALS WITH SIMPLE CHEMICAL COMPOUNDS
Authors: Macher Egon , Chase Merrill W.
Published: June 2004

In light of knowledge of the rate and route of dispersal of allergenic chemicals from ear sites (0.25 µg of picryl chloride, or 2:4 dinitrochlorobenzene in 0.25 µg and 5.0 µg amounts), dispersal was interrupted at selected times by ear excision. The animals exposed in this manner to different, tiny amounts of allergen were tested for development of contact type hypersensitivity.

Both of these allergenic chemicals left the local ear site in about three phases of successively lengthening "half-lives." In the first phase, the escape rate was high. The principal pathway of escape was not via the lymphatics but via the blood vessels. Ear excisions made at 24 hr after injection of 0.25 µg of picryl chloride (PCl) or at 12 hr after injection of 5.0 µg of dinitrochlorobenzene (DNCB) essentially blocked onset of delayed type hypersensitivity, hence the first fraction to escape (80% of PCl, 98% of DNCB) was not used for sensitization. This large fraction serves rather to set up a state of specific tolerance, for these individuals showed extensive deficits in their ability to respond to a later sensitizing course. Also the ability to form hapten-specific antibody appeared nearly completely suppressed. Injections of allergen into the blood stream or directly in auricular nodes, in an amount approximating that which escaped early from the ear, also led to the same degrees of unresponsiveness—sometimes full, sometimes partial tolerance. The same types of specific tolerance were secured also by injecting subsensitizing doses into the ear, without excision, or into the flank and by contact tests applied to the flank.

The allergen remaining in the ear after the early outflow, particularly between 12–24 hr and 3–4 days, appeared to constitute the sensitizing depot. The longer this depot was available to the animals the greater the immunological "information" for sensitization was picked up until the depot had served its full function around the 4th day. "Peripheral sensitization" was clearly demonstrable.

The eventual degree of sensitivity attained by the animals was a resultant of two immunologic processes which occurred independently—tolerogenic effects of escaped chemical on the one hand and on the other the sensitizing effect of the local sensitizing depot of allergen bound in the ear tissue.
IMMUNOLOGICAL INDUCTION OF INCREASED VASCULAR PERMEABILITY
Authors: Henson P. M. , Cochrane C. G.
Published: June 2004

Passive cutaneous anaphylaxis (PCA) reactions were produced in rabbits by antibodies to bovine serum albumin. Two types of antibodies were found, each inducing increased vascular permeability, but by means of different mediation systems.

One of these antibodies required the presence of complement, platelets, and neutrophils for the induction of the PCA reaction, which was inhibited by antihistamine. This antibody was heat stable, sedimented in the 7S region, and was found in both fast and slow electrophoretic fractions of rabbit γ-globulin.

Homocytotropic antibody was also detected. The PCA reactions induced by this type of antibody did not require platelets or neutrophils and were not inhibited in rabbits depleted of C3 with cobra venom factor. The lesions were, however, prevented by administration of antihistamine.
CELL SEPARATION ON ANTIGEN-COATED COLUMNS
Authors: Wigzell Hans , Andersson Birger
Published: June 2004

Glass and plastic bead columns coated with antigenic protein molecules were used as an immunological filter for cell populations containing immune cells of relevant specificity. A selective elimination of these immune cells from the passing cell suspension was regularly noted and it approached, in some experiments, complete abolition of the specific immune reactivity of the filtered cell population. This specific retention of immune cells by antigenic columns could be selectively blocked by the presence of free antigen molecules in the medium during filtration. The results obtained support the concept of a cell-associated antigen-specific receptor being present on the outer surface of immune cells, displaying the same antigen-binding specificity as the potential product of the cell, the humoral antibody. Using the present bead column system, results were obtained indicating that this receptor was an active product of the immune cells and not any passively adsorbed, cytophilic antibody.

Antigenic bead columns may very well constitute a tool for the production in vitro of cell populations being specifically deprived of immune reactivity and allow detailed analysis of the characteristics of the cell-associated antibody of immune cells.
LYSOSOMAL AND ULTRASTRUCTURAL CHANGES IN HUMAN "TOXIC" NEUTROPHILS DURING BACTERIAL INFECTION
Authors: McCall Charles E. , Katayama Isao , Cotran Ramzi S. , Finland Maxwell
Published: June 2004

"Toxic" neutrophils from humans with severe bacterial infections, identified by the presence of Döhle bodies, "toxic" granules, and vacuoles were shown to differ from normal neutrophils both in ultrastructure and in lysosome activity.

Döhle bodies were identified as lamellar aggregates of rough endoplasmic reticulum. Toxic granules corresponded to the azurophilic granules usually identified by Romanowsky stains only in neutrophil precursors. By electron microscopy such granules were large, electron-dense, and peroxidase positive; they could usually be distinguished from the smaller, less dense, "specific" granules also present in control neutrophils, but in the latter they became visible by light microscopy only after prolonged staining or following fixation with glutaraldehyde. These observations suggest that toxic granules represent an abnormal staining reaction of the large dense granules in the toxic cells, and not phagocytized material, newly formed abnormal granules or autophagic bodies.

Alkaline phosphatase activity was significantly greater in toxic neutrophils than in normal ones; 80% of the activity of both was located in the lysosome fraction. Beta glucuronidase was normal. Total acid phosphatase was normal, but the percentage located in the nonlysosome fraction of toxic neutrophils was increased, suggesting that lysosomes were "labilized."

Formation of neutral red vacuoles in supravitally stained preparations, an index of lysosome activity, occurred more rapidly in toxic neutrophils. This reaction paralleled degranulation and the formation of clear vacuoles in unstained wet mounts and could be blocked by colchicine, a lysosome stabilizer, or enhanced by procedures which activate lysosomes. "Autophagic" vacuoles were observed by electron microscopy in some toxic neutrophils.

These observations are discussed in relation to the concept that the "toxic" neutrophils in severe bacterial infection reflect cellular immaturity and/or stimulation or degeneration.
THE INHIBITION OF PLASMIN, PLASMA KALLIKREIN, PLASMA PERMEABILITY FACTOR, AND THE C'1r SUBCOMPONENT OF THE FIRST COMPONENT OF COMPLEMENT BY SERUM C'1 ESTERASE INHIBITOR
Authors: Ratnoff Oscar D. , Pensky Jack , Ogston Derek , Naff George B.
Published: June 2004

The fraction of human serum designated as C'1 esterase inhibitor is known to inhibit the action of C'1 esterase, a plasma kallikrein, and PF/Dil, an enzyme in plasma enhancing cutaneous vascular permeability. In the present study, C'1 esterase inhibitor has been found to block the actions of plasmin and the C'1r subcomponent of the first component of complement, and to retard the generation of PF/Dil. No inhibition of blood clotting or of the generation of plasmin was demonstrable.
IMMUNOCHEMICAL STUDIES OF FOOT-AND-MOUTH DISEASE
Authors: Cowan K. M.
Published: June 2004

Three antigenic variants of foot-and-mouth disease virus, type A, strain 119, were demonstrated in Ouchterlony analyses utilizing serum collected from guinea pigs 7 days postinfection (DPI). Such antisera contain antibodies of the 19S class. Guinea pig antisera that contained antibodies of the 7S class were unable to distinguish between the antigenic variants. Similarly, 19S antibody was able to demonstrate antigenic differences in trypsin- and chymotrypsin-treated viruses that were not detected by 7S antibody-containing antisera.

One of the antigenic variants of virus is apparently the wild type and is tentatively considered to have two antigenic determinant groupings termed the a- and b-sites (140S-ab). The 140S-ab variant was the sole or predominant antigenic type produced in guinea pigs and in large plaque-forming- and tissue culture-low passage sources of the virus. Another antigenic variant appears to possess only the b-site (140S-b) and was the major constituent in tissue culture-high passage virus preparations. The third variant, a small plaque former, was also devoid of the a-site and contains an antigenic determinant that is related to, but not identical with, the b-site. This variant appears to be a minor constituent of tissue culture-high passage virus.

7-DPI serum could be absorbed with a suitable concentration of tissue culture-high passage virus to remove antibody reactive with the b-determinant site. This absorbed serum still precipitated 140S-ab virus by virtue of still containing antibody reactive with the a-determinant site; however, the neutralizing activity was eliminated. This suggests that the b-site is critical with respect to neutralization while the a-site is noncritical.
ANTIGEN-REACTIVE CELLS IN NORMAL, IMMUNIZED, AND TOLERANT MICE
Authors: Armstrong W. D. , Diener E. , Shellam G. R.
Published: June 2004

The numbers of antigen-reactive cells (ARC) responding to a purified protein, the polymer of S. adelaide flagellin, have been assayed in cell populations derived from several lymphoid tissues of mice. The assay, which employs the cell transfer into lethally irradiated mice, indicates that there is a response of ARC in bone marrow in the absence of thymus cells. This suggests that the immune response to this protein antigen is not thymus dependent.

The presence of relatively large numbers of ARC in Peyer's patches argues for their direct participation in the immune response in the adult mouse.

The kinetics of ARC and antibody-forming cells in the early primary response employing the transfer system is described. The numbers of ARC declined during the first 2 days of the immune response, but by day 6 had increased to about five times the number in unprimed spleen cells. The rise is believed to be a result of the primary injection of antigen and therefore may be described as memory; however, these experiments have not been able to further elucidate any specific qualities of the "memory cell."

Tolerance induction in C57BL/Brad mice produced by repeated injections of a cyanogen bromide digest of the antigen is described. The ARC or its precursor is shown to be the site of the lesion of tolerance by direct investigation.
THE EFFECT OF NEURAMINIDASE ON THE FATE OF TRANSFUSED LYMPHOCYTES
Authors: Woodruff Judith J. , Gesner Bertram M.
Published: June 2004

Evidence has been obtained that incubation of rat lymphocytes with neuraminidase, prior to intravenous transfusion into allogeneic or syngeneic recipients, alters the distribution of the cells. Many enzyme-treated lymphocytes initially become trapped in the liver, and there is a decrease in the selective accumulation of these cells in the lymph nodes and spleen. Subsequently, many enzyme-altered cells emigrate from the liver, concentrate in lymph nodes, and recirculate to the lymph. The results suggest that sialic acid constituents of the lymphocyte surface play a critical role in ensuring the normal distribution of these cells in the body. The findings also imply that reactions involving surface sialic acid can markedly alter the fate of lymphocytes without "killing" the cells.
THE BACTERIAL INDUCTION OF HOMOGRAFT SENSITIVITY
Authors: Rapaport Felix T. , Markowitz A. S. , McCluskey Robert T.
Published: June 2004

Immunization of rabbits with Group A Type 12 streptococcal cell membranes has elicited serum antibodies which have the ability to cause rapid rejection of skin allografts in guinea pigs. Intradermal injection of such antisera has resulted in skin reactions characterized by prominent polymorphonuclear leukocyte infiltrates, similar to those noted in the Arthus reaction. The combined use of membrane antisera and epinephrine has resulted in hemorrhagic necrosis of the skin of guinea pigs.

The ability of membrane antisera to exert these effects appears to be dependent upon the presence in the host tissues of antigen(s) shared by or cross-reacting with streptococcal membrane antigens. Such cross-reacting antigens may have a group distribution in the outbred guinea pig population.

The results highlight the potential biological importance of antigens present in the Group A streptococcal membrane in the induction of altered tissue reactivity in the mammalian host.
STUDIES ON THE ENTRY OF VIRUSES INTO THE CENTRAL NERVOUS SYSTEM OF MICE VIA THE CIRCULATION
Authors: Sellers Margret I.
Published: June 2004

The inhalation of CO2 exerted a selective action on the entry of viruses into the CNS of mice via the circulation. In 6 wk old animals, the infectivity of poliovirus, vaccinia, and vesicular stomatitis viruses was enhanced, whereas the entry of herpesviruses and of a neurotropic influenza virus was not affected. However, in 3 to 4 wk old mice, inhalation of the gas enhanced the infectivity of all the viruses. To explain the relationship of age to the animals' response to CO2, it was proposed that CO2 inhalation, by increasing the rate of cerebral blood flow, served to increase the exposure of some extraneural cell(s) to virus, possibly the cerebrovascular endothelial cell, in which virus replicated and reached the brain parenchyma by direct extension of the infectious process. Consequent to maturation, the postulated target cell developed resistance to certain viruses, while its susceptibility to others remained unchanged.

Inoculation of adrenalin or serotonin simultaneously with virus into the circulation enhanced the CNS infectivity of all the viruses tested in both 4 wk and 6 wk age groups of mice. The enhancing effects were completely inhibited by the action of an α-adrenergic blocking agent; it was therefore concluded that hemodynamic changes produced by the contractile response of the smooth muscle cells in the vessel walls mediated the enhancing effect. It was suggested that a vasopressor response invoked in the peripheral vessels, with a consequent increase in cerebral blood flow, increased virus dosage to the CNS. In addition, a direct effect of the vasoactive amine on the cerebral vessels, resulting in the disruption of an anatomical "barrier", was considered as a contributory factor in increasing the transfer of virus to the CNS from the circulation.
AUTOANTIBODIES TO COLON IN GERMFREE RATS MONOCONTAMINATED WITH CLOSTRIDIUM DIFFICILE
Authors: Hammarström Sten , Perlmann Peter , Gustafsson Bengt E. , Lagercrantz Rutger
Published: June 2004

Germfree rats monocontaminated with the anaerobic microorganisms Clostridium difficile or another Clostridium species (strain G 62) produce auto-antibodies to colon antigen. The antigen can be extracted with phenol water from the feces of germfree rats. Antibodies, demonstrable by means of passive hemagglutination of antigen sensitized sheep erythrocytes appear after monocontamination for 35 days or longer. The indirect immunofluorescence techniques, applied to sections of germfree rat colon, gave positive mucosal staining. The staining was similar to that obtained with sera from patients with ulcerative colitis or from rats immunized with rabbit colon. No antibodies were found in the sera of germfree rats, germfree rats monocontaminated with various other bacteria, conventional rats of germfree origin, or conventional Sprague-Dawley rats.

Although the anti-colon antibodies of the Clostridium infected rats reacted with the same feces extract as the antibodies of ulcerative colitis patients or of rabbit colon immunized rats, their specificity was different. While the latter cross-react with polysaccharide from E. coli O14, those from the Clostridium-infected exgermfree rats did not. Rats monocontaminated with Cl. difficile also developed antibodies to this organism, but no cross-reaction between Cl. difficile antigen and colon antigen could be demonstrated. This speaks against breakage of tolerance by cross-reacting bacterial antigen as the cause of autoimmunity in these rats. Other possible mechanisms for autoantibody production in this model are immunogenic alteration of gastrointestinal mucins by bacterial degradation, adjuvant effects of bacterial products, or both.
THE EFFECTS OF ENDOTOXIN ON VASCULAR ENDOTHELIUM
Authors: McGrath J. M. , Stewart G. J.
Published: June 2004

This study was undertaken to develop a technique for the preparation of sheets of endothelial cells and to investigate the effects of bacterial endotoxin on large numbers of cells from continuous sheets of vascular endothelium.

Rabbits were divided into one control and two experimental groups. The experimental animals received intracardially an LD50 dose of Escherichia coli endotoxin. 1 and 24 hr postinjection, the vessels of the animals were perfused with glutaraldehyde in Millonig's buffer with methylene blue as a marker.

Pieces of mesentery containing arteries were postfixed in buffered glutaraldehyde, dehydrated, and placed in acetone (to remove fat deposits). The surrounding connective tissue was stripped from the mesenteric arteries, and segments of the vessels were slit longitudinally, flattened out, and firmly affixed to a sheet of cork with fine mounting pins. A 3% solution of Formvar in ethylene dichloride was pipetted onto the luminal surfaces of the vessels. The endothelial cells were impregnated with and adhered to the Formvar and, after soaking overnight in 10 N NaOH, could be stripped from the vessel walls as monolayers. Sheets of Formvar-impregnated cells were temporarily mounted on glass slides in aqueous methylene blue and examined by phase and bright-field microscopy. Methylene blue stained the nuclei a deep blue and the cytoplasm faintly, but cell outlines were indistinct.

Endothelial sheets from control rabbits had smooth, elliptical nuclei oriented parallel to the longitudinal axis of the cells and irregularly distributed over a smooth background with faint longitudinal striations.

Essentially every cell in endothelial sheets from endotoxin-injected animals appeared to be severely damaged. Cell sheets from 24 hr posttreatment animals exhibited the same type of, but more extensive, damage than that observed in 1 hr posttreatment animals. The most prominent features of the damaged endothelium were distorted nuclei, apparent nuclear vacuolization, and missing nuclei.

Unstained platelets and plaques were present on the surfaces of the specimens from the experimental animals only. Stained and unstained red blood cells were also dispersed over the luminal surfaces of the endotoxin-treated vessels.
STUDIES ON HUMAN ANTIBODIES
Authors: Moreno Carlos , Kabat Elvin A.
Published: June 2004

Human antibodies to blood group A substance were purified by absorption on columns of insoluble polyleucyl hog blood group A + H substance and eluted first with N-acetylgalactosamine and then with an A active reduced pentasaccharide ARL0.52. The γM and γG antibodies in these eluates were separated by density gradient centrifugation. The antibodies were studied for their relative capacities to be inhibited by various blood group A active oligosaccharides. Antibodies eluted by the N-acetylgalactosamine could be inhibited by N-acetylgalactosamine, as well as by lower concentrations of A active tri- and pentasaccharides, while those eluted by the pentasaccharide ARL0.52 could only be inhibited by the two oligosaccharides, but not by N-acetylgalactosamine, indicating that the N-acetylgalactosamine eluate had more antibodies with smaller size combining sites than the ARL0.52 eluate. Measurements by equilibrium dialysis gave values ranging from 2 x 103 to 1 x 105 M–1 and the values obtained with the ARL0.52 eluate were somewhat higher than those with the GalNAc eluate. Only one of three anti-A sera had γM anti-A in the ARL0.52 eluate, while all three had γM in the N-acetylgalactosamine eluate. Data on the precipitating, hemagglutinating, complement fixing, hemolytic properties of the eluted antibodies, and of their content of κ and λ light chains are given.
THE INFLUENCE OF IMMUNOLOGICALLY COMMITTED LYMPHOID CELLS ON MACROPHAGE ACTIVITY IN VIVO
Authors: Mackaness G. B.
Published: June 2004

It has been shown that the immune response of mice to infection with L. monocytogenes gives rise to a population of immunologically committed lymphoid cells which have the capacity to confer protection and a proportionate level of delayed-type hypersensitivity upon normal recipients. The cells were most numerous in the spleen on the 6th or 7th day of infection, but persisted for at least 20 days. Further study revealed that the immune cells must be alive in order to confer protection, and free to multiply in the tissues of the recipient if they are to provide maximum resistance to a challenge infection. The antibacterial resistance conferred with immune lymphoid cells is not due to antibacterial antibody; it is mediated indirectly through the macrophages of the recipient. These become activated by a process which appears to depend upon some form of specific interaction between the immune lymphoid cells and the infecting organism. This was deduced from the finding that immune lymphoid cells from BCG-immunized donors, which were highly but nonspecifically resistant to Listeria, failed to protect normal recipients against a Listeria challenge unless the recipients were also injected with an eliciting dose of BCG. The peritoneal macrophages of animals so treated developed the morphology and microbicidal features of activated macrophages. It is inferred that acquired resistance depends upon the activation of host macrophages through a product resulting from specific interaction between sensitized lymphoid cells and the organism or or its antigenic products. Discussion is also made of the possibility that activation of macrophages could be dependent upon antigenic stimulation of macrophages sensitized by a cytophilic antibody.
THE EFFECT OF ANTI-LYMPHOCYTE GLOBULIN ON CELL-MEDIATED RESISTANCE TO INFECTION
Authors: Mackaness G. B. , Hill William C.
Published: June 2004

The specificity of anti-lymphocyte globulin (ALG) has been used to analyze an immune mechanism which is mediated by immunologically committed lymphoid cells to the apparent exclusion of humoral antibody. Rabbit antimouse lymphocyte globulin completely suppressed the immunity which can be passively transferred with Listeria-immune lymphoid cells from actively infected donors. When prospective donors were given a single dose of 1.0 mg of ALG, it remained active against immune lymphoid cells transferred 24 hr later; yet immune cells in the spleens of donors could not be inactivated in situ by even larger doses of ALG given 24 hr prior to cell harvest. In keeping with this finding, the immunity to reinfection with Listeria was not suppressed by a single dose of ALG, indicating that the immunologically active cells in the spleen are not accessible to intravenously administered ALG. On the other hand, protracted treatment with ALG did abolish most of the memory of a previous infection in intact animals. From this and other evidence, it was concluded that immunologically committed cells are vulnerable to attack by ALG only if they circulate. While in circulation, they make contact both with ALG and the phagocytic elements of the reticuloendothelial system which appear to be responsible for their destruction.

Four lines of evidence indicated that the suppression of anti-Listeria resistance with ALG depends upon destruction of immune lymphoid cells and not to any action it has on host macrophages. It is possible to infer from this that immunity to L. monocytogenes depends upon a two cell system in which the donor lymphoid cells provide the immunological reactivity to the organism and recipient macrophages provide the mechanism through which resistance is expressed. Accompanying papers provide additional support for this view, and reasons for believing that delayed-type hypersensitivity and acquired cellular resistance are mediated by the same population of immunologically committed lymphoid cells.
THE EFFECTS OF HETEROLOGOUS ANTI-THYMOCYTE SERA IN MICE
Authors: Mandel Mark A. , Asofsky Richard
Published: June 2004

A quantitative graft-vs.-host (GVH) assay was used to compare the reactivity of spleen cells from germfree (GF) and conventionally reared (CV) mice against allogeneic tissue before and after treatment with rabbit anti-mouse thymocyte serum (ATS) and its IgG fraction (AT-IgG). AT-IgG produced a far greater and longer lasting suppression of this reactivity in GF than in CV mice. Moreover, CV mice recovered from suppression twice as rapidly as did GF mice. In both groups, the rate of recovery was exponential. These results suggest that recovery from the suppressive effects of ATS or AT-IgG was the result of generation of new cells.

Transfer of mice born and initially reared in a conventional animal room to germfree isolators, with subsequent maintenance on the same diet that the germfree mice received, did not change the reactivity of their spleen cells in the assay used nor their susceptibility to AT-IgG. Removal of GF mice to a conventional animal room resulted in a prompt reduction in susceptibility to AT-IgG. The possibility that this might be related to the elaboration of a plasma factor affecting lymphocyte stability was discussed.

Spleen cells taken from GF mice at various times after such "conventionalization" showed a transient but marked hyperreactivity to tissues of the allogeneic recipients. The amount of reduction in reactivity of spleen cells from such mice treated with AT-IgG was always proportional to the activity of spleen cells from comparable untreated mice. It was suggested that the increased reactions evoked should be ascribed to an adjuvant effect rather than to specific immunologic sensitization.

Blood lymphocyte counts correlated very poorly with the state of suppression, confirming previous observations. It was also shown that while AT-IgG had little or no effect on blood granulocyte counts in both GF and CV mice, marked reductions in circulating granulocytes followed administration of AT-IgG during the period of increased granulocytopoiesis that resulted from conventionalization. This demonstrated that AT-IgG can produce functional impairment of target cells other than lymphocytes.
CELLS INVOLVED IN THE IMMUNE RESPONSE
Authors: Richter M. , Abdou N. I.
Published: June 2004

Bone marrow cells obtained from rabbits of one allotype were injected into irradiated rabbits of a different allotype. The recipients were also injected with sheep red blood cells, and their spleen cells were tested for plaque-forming capacity 7 days later. Spleen cells of all recipients gave large numbers of plaques as did spleen cells incubated with antiserum, directed toward donor allotype. However, incubation of the recipient spleen cells with antiserum directed toward recipient allotype completely suppressed plaque formation. These results demonstrate that antibody-formation in irradiated recipients of transferred lymphoid cells is a property of the recipient animal and that the antibody-forming cell is relatively irradiation-resistant.

It was also demonstrated that only viable normal bone marrow cells are capable of transferring antibody-forming capacity to irradiated recipient rabbits. Neither sonicates nor heat-killed preparations of normal rabbit bone marrow cells possessed this capacity.
HUMAN IMMUNITY TO THE MENINGOCOCCUS
Authors: Goldschneider Irving , Gotschlich Emil C. , Artenstein Malcolm S.
Published: June 2004

Susceptibility to systemic meningococcal disease is related to a selective deficiency of humoral antibodies to pathogenic strains of meningococci. In a study of the age-specific incidence of meningococcal meningitis in the United States, it was found that the proportion of individuals with serum bactericidal activity to meningococci of serogroups A, B, and C was reciprocally related to the incidence of disease. The prevalence of bactericidal activity was highest at birth and among adults, and lowest in infants between 6 and 24 months of age.

Sera from 51 of 54 prospective cases of meningococcal disease among military recruits were deficient in antibodies to homologous and heterologous strains of pathogenic meningococci as determined by serum bactericidal activity and indirect immunofluorescence. Such sera, however, could support the bactericidal activity of purified human gamma globulin (Cohn fraction II), and such individuals could respond immunologically to infection with meningococci. The implication is that susceptible persons are deficient in antimeningococcal antibodies because they have not received significant exposure to meningococcal antigens in the past.

The fate of individuals who lack bactericidal antibodies to pathogenic meningococci was determined during an outbreak of group C meningitis among military recruits. The incidence of disease was found to be primarily associated with the incidence of exposure of susceptibles to the pathogenic strains. Whereas 81.5% of the presumed susceptibles acquired a meningococcal strain, only 24.1% acquired an organism similar to the prevalent disease-producing strains. Of the exposed susceptibles, 38.5% developed systemic meningococcal disease.
HUMAN IMMUNITY TO THE MENINGOCOCCUS
Authors: Goldschneider Irving , Gotschlich Emil C. , Artenstein Malcolm S.
Published: June 2004

Results of the present study suggest that natural immunity to meningococcal disease is initiated, reinforced, and broadened by intermittent carriage of different strains of meningococci throughout life.

In young adults, carriage of meningococci in the nasopharynx is an efficient process of immune sensitization. 92% of carriers of serogroup B, C, or Bo meningococci were found to develop increased titers of serum bactericidal activity to their own meningococcal isolate, and 87% developed bactericidal activity to heterologous strains of pathogenic meningococci. The rise in bactericidal titer occurred within 2 wk of onset of the carrier state, and was accompanied by an increase in titer of specific IgG, IgM, and IgA antibodies to meningococci.

In early childhood, when few children have antibodies to pathogenic meningococci, active immunization seems to occur as a result of carriage of atypical, nonpathogenic strains.

Immunity to systemic meningococcal infection among infants in the neonatal period is associated with the passive transfer of IgG antibodies from mother to fetus.

The antigenic determinants which initiate the immune response to meningococci include the group-specific C polysaccharide, cross-reactive antigens, and type-specific antigens.
HUMAN IMMUNITY TO THE MENINGOCOCCUS
Authors: Gotschlich Emil C. , Goldschneider Irving , Artenstein Malcolm S.
Published: June 2004

Purified meningococcal polysaccharides were administered to army recruits. No adverse reactions were observed in 145 men who received group C polysaccharide, and in 53 men who were injected with group A polysaccharide. Hemagglutinating and bactericidal activity developed in the sera of all individuals with the exception of two recruits injected with A polysaccharide.

During the 6 wk period of observation, the proportion of unvaccinated recruits who acquired group C meningococci in the three companies studied was 38, 42, and 69 per cent. A significantly lower proportion of the individuals vaccinated with group C polysaccharide acquired group C meningococci; 4.6, 24, and 31 per cent respectively.