Biomedical subjects
Publications and source records attributed to I Nakashima.
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When Klebsiella pneumoniae capsular polysaccharide (CPS-K) from type 1, Kasuya strain, was injected intraperitoneally (i.p.) immediately before i.p. bacterial challenge, the survival time of mice infected with Salmonella enteritidis NUB 1 (virulent strain) was shortened and the mortality rate for mice infected with S. enteritidis NUB 31 (avirulent strain) was enhanced. The promotion of infection with S. enteritidis NUB 1 by CPS-K depended upon its dose, the effect of CPS-K being demonstrable up to as little as 0.2 mug per mouse. In the case of S. enteritidis NUB 31, the effect of CPS-K was detectable only when more than 20 mug per mouse was injected. As a result of enumeration of bacterial populations in the peritoneal washing, blood, liver and spleen, it was revealed that CPS-K promoted in vivo growth of S. enteritidis NUB 1 and NUB 31. In addition, CPS-K enhanced the mortality rate in mice infected with Streptococcus pyogenes or Streptococcus pneumoniae. The peak CPS-K effect on infection with S. enteritidis NUB 1 was seen when given immediately before bacterial challenge. The active substance responsible for the infection-promoting effect of CPS-K was neutral CPS-K, which is distinct from the O antigen and from acidic CPS-K (the type-specific capsular antigen). Preparations of neutral CPS-K isolated from the other three strains of K. pneumoniae exhibited a marked infection-promoting effect comparable with that of preparations from the Kasuya strain. Neutral CPS-K, with identical antigenicity to that from the Kasuya strain, has already been found to exert a strong adjuvant effect on antibody responses to various antigens in mice. No parallelism exists between infection-promoting activity and adjuvant activity of neutral CPS-K.
The neutral fraction (neutral CPS-K) of Klebsiella pneumoniae capsular polysaccharide (CPS-K) from type 1, Kasuya strain, has already been reported as the active substance responsible for the strong adjuvant effect of CPS-K. The present results demonstrate that neutral CPS-K exhibits further common biological activities with lipopolysaccharide (LPS) isolated from Salmonella enteritidis. The intensity of the lethality in mice of neutral CPS-K by the intraperitoneal route is very similar to that of LPS. Its lethality for mice by the intravenous (i.v.) route is significantly stronger than that of LPS, because the degree of increase in the sensitivity to their lethality by i.v. challenge is smaller for LPS than for neutral CPS-K. The intensity of the pyrogenicity of neutral CPS-K in rabbits is approximately one-tenth of that of LPS as judged by the minimal pyrogenic doses and fever indices. The skin-preparatory potency of neutral CPS-K for the dermal Shwartzman phenomenon in rabbits is also approximately one-tenth of that of LPS compared on the basis of the minimal skin-preparatory doses. When injected i.v., neutral CPS-K exhibits a provocative effect on hemorrhagic reactions in skin sites prepared with neutral CPS-K or LPS.
In normal mice, the total count of peritoneal leukocytes was markedly decreased after intraperitoneal (i.p.) injection of the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) depending on the dosage injected. This decrease was mainly due to the depletion of macrophages, and a decrease in the number of lymphocytes occurred to a lesser extent. CPS-K in relatively smaller doses mobilized polymorphonuclear neutrophilic leukocytes (PMN) into the peritoneal fluid but it decreased them transiently in larger doses. In mice infected i.p. with a virulent strain of Salmonella enteritidis, there was an abundant emigration of PMN into the peritoneal fluid. When 200 mug of CPS-K was injected i.p. immediately before bacterial challenge, emigration of PMN was markedly delayed for 48 hr after infection. Associated with this suppressed emigration of PMN, the numbers of macrophages and lymphocytes in the peritoneal fluid were significantly less in mice treated with CPS-K than those in untreated control mice for 48 hr after infection. The numbers of both cell-associated and extracellular bacteria in the peritoneal fluid were markedly greater in mice treated with CPS-K than those in untreated control mice. In both in vivo and in vitro experiments, ingestion of bacteria by macrophages and PMN was not blocked by CPS-K or neutral CPS-K, the active substance responsible for the infection-promoting effect of CPS-K. It appeared that CPS-K somehow impaired the intraphagocytic bactericidal activity.
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Using the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a polyclonal B-cell activator (PBA) and sheep red blood cells (SRBC) as a T cell-dependent antigen, we compared the ability of PBA and antigen to differentiate (generate antibody-forming cells, AFC) and proliferate (generate immunological memory) virgin B cells and B memory cells. In vitro CPS-K induced the differentiation of IgM virgin B cells, IgM B memory cells and IgG B memory cells to AFC, as well as or better than SRBC. The differentiation of B memory cells to AFC by CPS-K did not require the participation of macrophages or T cells, whereas the action of SRBC depended strictly upon the helper actions of these cells. The responsiveness to CPS-K and SRBC of normal and antigen-primed spleen cells as judged by anti-SRBC PFC responses in vitro was markedly decreased after stimulation of virgin B cells and B memory cells in vivo by CPS-K injection into normal or primed mice but greatly increased after the injection of SRBC. The decrease in the responsiveness to CPS-K of spleen cells from mice treated with CPS-K appeared principally due to exhaustion of the functions of B cells and B memory cells. From the present data it has been concluded that the signals required for the differentiation and proliferation of B cells of B memory cells are different from each other, the signal for differentiation being provided by either antigen (SRBC) or PBA (CPS-K), while the signal for proliferation only by antigen.
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A close correlation was observed between body weight and length of the survival time of mice inoculated intravenously (i.v.) with Cryptococcus neoformans (p less than 0.001). An endotoxic substance of C. neoformans (Cr-ET) increased the susceptibility of mice to i.v. infection of C. neoformans only when more than 50 mug of Cr-ET was injected i.v. 24 hours before infection. Intraperitoneal (i.p.) administration of dimethyl sulfoxide which is found to enhance bacterial infection did not enhance death rate of mice infected i.p. with C. neoformans.
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With the use of the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a powerful adjuvant, high precipitin responses could be induced in mice to syngeneic eyeball extracts and thyroid gland extracts which were normally nonimmunogenic. Only very weak responses were induced to eyeball extracts by Freund's complete adjuvant. Repeated administrations of the antigens mixed with CPS-K at time intervals of 30 days (more than twice for the eyeballs or more than three times for the thyroid glands) were required for induction of high precipitin responses. Antibody responses detectable by the immunofluorescent technique could be induced to syngeneic lymphoid tissue extracts by injecting the mixture of antigen and CPS-K more than five times at time intervals of 30 days. These findings suggest that repeated stimulation by autoantigens together with such a strong adjuvant as CPS-K can terminate natural tolerance against autoantigens.
The capsular polysaccharide of Klebsiella pneumoniae (CPS-K) type 1, Kasuya strain, induces interferon production in the blood of mice when injected intravenously. CPS-K resembles bacterial endotoxin (lipopolysaccharide) in the time pattern of interferon production, with peak levels 2h after injection. CPS-K on a weight basis exhibits a more potent interferon-inducing effect than lipopolysaccharide. The active substance responsible for the interferon-inducing activity of CPS-K is the neutral CPS-K antigen which is antigenically distinct from the O antigen and from acidic CPS-K (the type-specific capsular antigen). Neutral CPS-K from the Kasuya strain has been already found to exhibit a strong adjuvant effect on antibody responses to various antigens in mice. Preparations of neutral CPS-K from other strains of K. pneumoniae, of which adjuvant action is only very weak, exhibit interferon-inducing activity similar to the preparation from the Kasuya strain. Heterologous and homologous tolerance to re-induction of interferon is produced by a prior injection (one each) of LPS, neutral CPS-K, and acidic CPS-K. No simple correlation exists between the inducing and tolerogenic capabilities of these substances.
A study was performed to clarify the roles of primary and secondary injections of antigen and adjuvant (capsular polysaccharide of Klebsiella pneumoniae, CPS-K) in induction of antibody responses and in the development of immunological memory in mice to bovine serum albumin (BSA). A primary injection of BSA alone neither induced significant primary antibody response nor increased immunological memory for a secondary antibody response but, if primary injections of BSA and CPS-K were performed simultaneously, high antibody responses were induced. Moreover, a prior injection of BSA alone or CPS-K alone decreased the level of primary antibody response and the degree of increase in memory following the subsequent injection of BSA mixed with CPS-K. In contrast, a secondary injection of BSA alone into mice once primed with a mixture of BSA and CPS-K elicited very high secondary type antibody response and increased secondarily the memory for a tertiary antibody response. Injection of CPS-K simultaneously with or shortly before or after the secondary injection of BSA did not increase the level of the secondary antibody response and the degree of the secondary increase in memory. Augmentation of the secondary antibody response was elicited by simultaneous injection of CPS-K only when the secondary response was induced inadequately by a suboptimum or supraoptimum dose of antigen.
In mice primed with a mixture of bovine serum albumin (BSA) and adjuvant (capsular polysaccharide of Klebsiella pneumoniae (CPS-K)) cell-associated immunological memory was increased secondarily after a second injection of BSA alone, whereas a primary injection of BSA alone into normal unprimed mice did not result in detectable memory. The optimum antigen doses for expression of the primary and secondary memories of adoptively transferred cells from unboosted primed donors or boosted donors in in vivo culture systems were very similar, although those observed in intact mice were very different, as reported previously. The size of the secondary memory of adoptively transferred cells from boosted donors was more than ten times greater than that of the primary memory of adoptively transferred cells from unboosted primed donors. The lag period for increase of the secondary memory was shorter than that for the primary memory. Both primary and secondary memories increased during a long period (up to 3 months) after the antigenic stimulus. From the results of this study it was concluded that cell-associated immunological memory could be amplified in a secondary fashion upon contact with a second stimulus.
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