S. Kotani

Publication List Details

Period

1985 - 1988

Number

89

Co-Authors

Immunopathological activities of extracellular products of Streptococcus mitis, particularly a superantigenic fraction.

Matsushita, K, Fujimaki, W, Kato, H, Uchiyama, T, Igarashi, H, Ohkuni, H, ...

Previously, we prepared extracellular products, fractions F-1 and F-2 of Streptococcus mitis 108, an isolate from the tooth surface of an infant, and showed that F-1 exhibited inflammatory...

beta-Lactam resistance in Serratia marcescens: comparison of action of benzylpenicillin, Apalcillin, Cefazolin, and ceftizoxime.

Takata, N, Suginaka, H, Kotani, S, Ogawa, M, Kosaki, G

The intrinsic mechanisms of resistance to beta-lactam antibiotics in Serratia marcescens IFO 12648 were investigated, comparing the action of benzylpenicillin, apalcillin, cefazolin, and ceftizoxime....

Isolation and purification of Flavobacterium alpha-1,3-glucanase-hydrolyzing, insoluble, sticky glucan of Streptococcus mutans.

Ebisu, S, Kato, K, Kotani, S, Misaki, A

Studies were made on the physical and chemical properties of polysaccharides synthesized by cell-free extracts of Streptococcus mutans, Streptococcus sanguis, and Streptococcus sp. and their...

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195.

Hui, G S, Tam, L Q, Chang, S P, Case, S E, Hashiro, C, Siddiqui, W A, ...

The Plasmodium falciparum major merozoite surface protein (gp195) is a protective antigen against lethal malaria. However, increasing evidence indicates that the efficacy of a malaria vaccine will...

Macrophages are stimulated by muramyl dipeptide to induce polymorphonuclear leukocyte accumulation in the peritoneal cavities of guinea pigs.

Nagao, S, Nakanishi, M, Kutsukake, H, Yagawa, K, Kusumoto, S, Shiba, T, ...

N-Acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide [MDP]) injected intraperitoneally significantly increased the number of cells entering the peritoneal cavity of guinea pigs primed with...

Immunobiological activities of a porin fraction isolated from Fusobacterium nucleatum ATCC 10953.

Takada, H, Ogawa, T, Yoshimura, F, Otsuka, K, Kokeguchi, S, Kato, K, ...

From Fusobacterium nucleatum ATCC 10953 cell envelope fraction whose inner membranes had been removed by treatment with sodium N-lauroyl sarcosinate, an outer membrane protein (37,000 Mr in a native...

Immunobiological activities of synthetic lipid A analogs with low endotoxicity.

Kotani, S, Takada, H, Takahashi, I, Ogawa, T, Tsujimoto, M, Shimauchi, H, ...

Synthetic lipid A analogs, beta(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each...

Requirement of a properly acylated beta(1-6)-D-glucosamine disaccharide bisphosphate structure for efficient manifestation of full endotoxic and associated bioactivities of lipid A.

Takahashi, I, Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Shiba, T, ...

Several synthetic acylated glucosamine monophosphates, with structures corresponding to the nonreducing or reducing moiety of the lipid A of the Escherichia coli or Salmonella minnesota type, and a...

Analgesic effects of N-acetylmuramyl-L-alanyl-D-isoglutamine in decreasing the acetic acid-induced abdominal-writhing response.

Ogawa, T, Kotani, S

A new pharmacological action of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) is described. Pretreatment of male ddY mice with MDP, but not its biologically inactive analogs, significantly decreased...

Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: adaptability to various vehicles and pyrogenicity.

Tsujimoto, M, Kotani, S, Kinoshita, F, Kanoh, S, Shiba, T, Kusumoto, S

Thirteen 6-O-acyl-N-acetylmuramyl-L-alanyl-D-isoglutamines (6-O-acyl-MDPs), including four inactive D-isoasparagine and L-isoglutamine analogs, were tested for their pyrogenicity and...

Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: dose-response and local reactions observed with selected compounds.

Tsujimoto, M, Kotani, S, Shiba, T, Kusumoto, S

6-O-(2-Tetradecylhexadecanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutamine (B3O-MDP) and 6-O-(3-hydroxy-2-docosylhexacosanoyl)-MDP (BH48-MDP) were examined for immunopotentiating activity in stimulating...

Low endotoxic activities of synthetic Salmonella-type lipid A with an additional acyloxyacyl group on the 2-amino group of beta (1-6) glucosamine disaccharide 1,4'-bisphosphate.

Kotani, S, Takada, H, Takahashi, I, Tsujimoto, M, Ogawa, T, Ikeda, T, ...

A synthetic lipid A (Salmonella type, compound 516), beta (1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, with three acyloxyacyl groups and one hydroxyacyl group, i.e.,...

Synthetic Salmonella-type lipid A antigen with high serological specificity.

Kasai, N, Arata, S, Mashimo, J, Okuda, K, Aihara, Y, Kotani, S, ...

A synthetic compound (compound 516), beta(1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated by (R)-3-hexadecanoyloxytetradecanoyl, (R)-3-hydroxytetradecanoyl,...

Immunopharmacological activities of a synthetic counterpart of a biosynthetic lipid A precursor molecule and of its analogs.

Takada, H, Kotani, S, Tsujimoto, M, Ogawa, T, Takahashi, I, Harada, K, ...

Synthetic lipid A analogs (compounds 404 through 406) were examined for their immunopharmacological activities. These compounds had two amide-bound and two ester-bound (R)-3-hydroxytetradecanoyl...

Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant.

Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Takahashi, I, Ikeda, T, ...

A synthetic compound (506), beta (1-6) D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated at 2'-amino and 3'-hydroxyl groups with (R)-3-dodecanoyloxytetradecanoyl and...

Granuloma formation by muramyl dipeptide associated with branched fatty acids, a structure probably essential for tubercle formation by Mycobacterium tuberculosis.

Emori, K, Nagao, S, Shigematsu, N, Kotani, S, Tsujimoto, M, Shiba, T, ...

Muramyl dipeptide, which does not induce epithelioid granuloma when injected alone dissolved in phosphate-buffered saline, could induce extensive granulomas in guinea pigs when chemically conjugated...

Acute joint inflammation in mice after systemic injection of the cell wall, its peptidoglycan, and chemically defined peptidoglycan subunits from various bacteria.

Koga, T, Kakimoto, K, Hirofuji, T, Kotani, S, Ohkuni, H, Watanabe, K, ...

The systemic injection of an aqueous suspension of cell wall or its peptidoglycan (PG)-rich sonicate derived from group A streptococcus and Lactobacillus casei induced acute joint lesions in BALB/c,...

Immunobiologically active lipid A analogs synthesized according to a revised structural model of natural lipid A.

Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Harada, K, Mori, Y, ...

Synthetic lipid A analogs which have two amide-bound and two ester-bound (R)-3-hydroxytetradecanoyl groups at the C-2 and -2' and C-3 and -3' positions of beta(1-6)glucosamine disaccharide mono- or...

Enhancement of dengue virus type 2 replication in mouse macrophage cultures by bacterial cell walls, peptidoglycans, and a polymer of peptidoglycan subunits.

Hotta, H, Hotta, S, Takada, H, Kotani, S, Tanaka, S, Ohki, M

The effects of bacterial cell walls, peptidoglycans, and a water-soluble polymer of peptidoglycan subunits on dengue virus type 2 replication in cultured mouse peritoneal macrophages were studied....

Immunobiological activities of synthetic lipid A analogs and related compounds as compared with those of bacterial lipopolysaccharide, re-glycolipid, lipid A, and muramyl dipeptide.

Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Mori, Y, Sakuta, M, ...

Thirteen acylated and phosphorylated derivatives of beta-1,6-linked glucosamine disaccharide (lipid A analogs), which were synthesized after the structural model of Salmonella-type lipid A, and seven...

Novel biological property of pertussis toxin: chemotactic activity on human monocytes.

Ogawa, T, Takada, H, Kotani, S, Sato, H, Sato, Y

Pertussis toxin isolated from Bordetella pertussis phase I strain Tohama enhanced the migration of human blood monocytes in an assay with a multiwell chemotaxis assembly. The monocyte migration...

Isolation and serotyping of Streptococcus mutans from teeth and feces of children.

Hamada, S, Masuda, N, Kotani, S

Streptococcus mutans were detected in the feces from 10 of 29 caries-active patients, aged 4 to 9 years. The percentage of S. mutans to the total counts of facultatively anaerobic streptococci on...

Isolation and immunobiological classification of Streptococcus sanguis from human tooth surfaces.

Hamada, S, Torii, M, Tsuchitani, Y, Kotani, S

A total of 113 pure cultures of Streptococcus sanguis were obtained from dental plaque samples of 64 subjects. All isolates synthesized glucan from sucrose, elaborated peroxide, and were...

Cytokine induction by extracellular products of oral viridans group streptococci.

Takada, H, Kawabata, Y, Tamura, M, Matsushita, K, Igarashi, H, Ohkuni, H, ...

During an etiological study of Kawasaki disease (mucocutaneous lymph node syndrome [MCLS]), we found that dominant viridans streptococcal strains on tooth surfaces and in the throat of both MCLS...

Somnogenic activities of synthetic lipid A.

Cady, A B, Kotani, S, Shiba, T, Kusumoto, S, Krueger, J M

Bacterial infections and various immune response modifiers, including endotoxin and its lipid A moiety, alter sleep duration. The purpose of this study is to amplify our understanding of lipid A...

Liberation of serotonin from rabbit blood platelets by bacterial cell walls and related compounds.

Harada, K, Kotani, S, Takada, H, Tsujimoto, M, Hirachi, Y, Kusumoto, S, ...

A study was made on the activity of various bacterial cell walls and peptidoglycans to liberate serotonin from rabbit blood platelets. All of the test cell walls or peptidoglycans prepared from 27...

Stimulation of migration of human monocytes by bacterial cell walls and muramyl peptides.

Ogawa, T, Kotani, S, Fukuda, K, Tsukamoto, Y, Mori, M, Kusumoto, S, ...

Bacterial cell walls, water-soluble fragments of the wall peptidoglycan, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), and 6-O-acyl derivatives of MDP were examined for migration-stimulating...

Purification and quantitative chemical analysis of cell wall peptidoglycans of Leptotrichia buccalis.

Fukuhara, H, Umemoto, T, Sagawa, H, Kato, K, Kotani, S

Peptidoglycans of Leptotrichia buccalis ATCC 14201 and ATCC 19616 were isolated by extraction with sodium dodecyl sulfate and subsequent digestion of the sodium dodecyl sulfate-insoluble residue with...

Adherence of Streptococcus sanguis clinical isolates to smooth surfaces and interactions of the isolates with Streptococcus mutans glucosyltransferase.

Hamada, S, Torii, M, Kotani, S, Tsuchitani, Y

Streptococcus sanguis isolated from human dental plaque were grown in Todd-Hewitt broth. Cells were collected by centrifugation and lyophilized after extensive washing with water. The cell-associated...

Contractile effects of bacterial cell walls, their enzymatic digests, and muramyl dipeptides on ileal strips from guinea pigs.

Ogawa, T, Kotani, S, Tsujimoto, M, Kusumoto, S, Shiba, T, Kawata, S, ...

Cell walls isolated from four bacterial species (Streptococcus pyogenes, Lactobacillus plantarum, Streptomyces gardneri, and Nocardia corynebacteriodes), which exhibited the adjuvant effect of...

Role of thymus for N-acetyl muramyl-L-alanyl-D-isoglutamine-induced polyarthritis and granuloma formation in euthymic and athymic nude rats or in neonatally thymectomized rats.

Kohashi, O, Pearson, C M, Tamaoki, N, Tanaka, A, Shimamura, K, Ozawa, A, ...

A synthetic adjuvant, N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP), produced extremely severe polyarthritis with almost 100% incidence in Rowett euthymic rnu/+ rats, but the same dose of MDP (100...

Chemical and biological properties of a peptidoglycan isolated from Treponema pallidum kazan.

Umemoto, T, Ota, T, Sagawa, H, Kato, K, Takada, H, Tsujimoto, M, ...

A peptidoglycan layer of Treponema pallidum kazan was isolated by solubilization of whole cells with 1% warm sodium dodecyl sulfate and subsequent digestion of an insoluble residue with proteases....

Mechanism of synergistic action of a combination of ampicillin and dicloxacillin against a beta-lactamase-producing strain of Citrobacter freundii.

Mizoguchi, J, Suginaka, H, Kotani, S

The mechanism of synergistic activity of a combination of ampicillin and dicloxacillin was studied on beta-lactamase-producing Citrobacter freundii GN346 and its derived beta-lactamaseless mutant...

Stimulation of the reticuloendothelial system of mice by muramyl dipeptide.

Tanaka, A, Nagao, S, Nagao, R, Kotani, S, Shiba, T, Kusumoto, S

Muramyl dipeptide (MDP), a part of bacterial cell wall peptidoglycans, was active as adjuvant and stimulated the reticuloendothelial system (RES) of mice to increase its phagocytic function. A series...

Inhibition of macrophage migration by muramyl peptides.

Nagao, S, Tanaka, A, Yamamoto, Y, Koga, T, Onoue, K, Shiba, T, ...

In the capillary tube migration system a synthetic muramyl dipeptide (MDP; N-acetylmuramyl-L-alanyl-D-isoglutamine), a part of bacterial cell wall peptidoglycans, inhibited the migration of...

Macrophage activation by bacterial cell walls and related synthetic compounds.

Takada, H, Tsujimoto, M, Kato, K, Kotani, S, Kusumoto, S, Inage, M, ...

Activation of peritoneal macrophages from guinea pigs by various bacterial cell walls, M-1 endo-N-acetylmuramidase enzymatically digested bacterial cell walls and synthetic muramyl dipeptides was...

Synergistic effect of polyriboinosinic acid:polyribocytidylic acid and either bacterial peptidoglycans or synthetic N-acetylmuramyl peptides on production of adjuvant-induced arthritis in rats.

Kohashi, O, Kotani, S, Shiba, T, Ozawa, A

Lewis rats developed polyarthritis after a single injection of a water-in-oil emulsion containing various peptidoglycans (PGs) derived from Lactobacillus plantarum. A copolymer of polyriboinosinic...

Preparation of arthritogenic hydrosoluble peptidoglycans from both arthritogenic and non-arthritogenic bacterial cell walls.

Kohashi, O, Pearson, C M, Watanabe, Y, Kotani, S

Cell wall lytic enzyme (Kyowa lytic no. 2 enzyme) liberated arthritogenic hydrosoluble peptidoglycans from both arthritogenic and non-arthritogenic bacterial cell walls. From these cell walls,...

Adjuvant activity of synthetic N-acetylmuramyl peptides in rats.

Tanaka, A, Saito, R, Sugiyama, K, Morisaki, I, Kotani, S

The minimal adjuvant-active structure in bacterial cell wall peptidoglycan for the induction of delayed hypersensitivity in rats (WKA) was the N-acetylmuramyl dipeptides (N-acetylmuramyl...

Arthritis-inducing ability of a synthetic adjuvant, N-acetylmuramyl peptides, and bacterial disaccharide peptides related to different oil vehicles and their composition.

Kohashi, O, Tanaka, A, Kotani, S, Shiba, T, Kusumoto, S, Yokogawa, K, ...

A synthetic adjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), failed to produce polyarthritis with a wide dose range in a water-in-oil emulsion of mineral oil such as liquid paraffin, Drakeol,...

Lipophilic derivative of muramyl dipeptide is more active than muramyl dipeptide in priming macrophages to release superoxide anion.

Pabst, M J, Cummings, N P, Shiba, T, Kusumoto, S, Kotani, S

Mouse peritoneal macrophages, when treated with a lipophilic derivative of muramyl dipeptide either in vitro or in vivo by intraperitoneal injection, showed a more than fivefold increase in their...

Immunological activities of Capnocytophaga cellular components.

Murayama, Y, Muranishi, K, Okada, H, Kato, K, Kotani, S, Takada, H, ...

Whole cells of a clinical isolate (strain S-3) of the genus Capnocytophaga were divided into cell envelope (CE) and cytoplasm (CP) fractions by mechanical disintegration followed by differential...

Immunopathological activities of extracellular products of Streptococcus mitis, particularly a superantigenic fraction.

Matsushita, K, Fujimaki, W, Kato, H, Uchiyama, T, Igarashi, H, Ohkuni, H, ...

Previously, we prepared extracellular products, fractions F-1 and F-2 of Streptococcus mitis 108, an isolate from the tooth surface of an infant, and showed that F-1 exhibited inflammatory...

beta-Lactam resistance in Serratia marcescens: comparison of action of benzylpenicillin, Apalcillin, Cefazolin, and ceftizoxime.

Takata, N, Suginaka, H, Kotani, S, Ogawa, M, Kosaki, G

The intrinsic mechanisms of resistance to beta-lactam antibiotics in Serratia marcescens IFO 12648 were investigated, comparing the action of benzylpenicillin, apalcillin, cefazolin, and ceftizoxime....

Isolation and purification of Flavobacterium alpha-1,3-glucanase-hydrolyzing, insoluble, sticky glucan of Streptococcus mutans.

Ebisu, S, Kato, K, Kotani, S, Misaki, A

Studies were made on the physical and chemical properties of polysaccharides synthesized by cell-free extracts of Streptococcus mutans, Streptococcus sanguis, and Streptococcus sp. and their...

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195.

Hui, G S, Tam, L Q, Chang, S P, Case, S E, Hashiro, C, Siddiqui, W A, ...

The Plasmodium falciparum major merozoite surface protein (gp195) is a protective antigen against lethal malaria. However, increasing evidence indicates that the efficacy of a malaria vaccine will...

Macrophages are stimulated by muramyl dipeptide to induce polymorphonuclear leukocyte accumulation in the peritoneal cavities of guinea pigs.

Nagao, S, Nakanishi, M, Kutsukake, H, Yagawa, K, Kusumoto, S, Shiba, T, ...

N-Acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide [MDP]) injected intraperitoneally significantly increased the number of cells entering the peritoneal cavity of guinea pigs primed with...

Immunobiological activities of a porin fraction isolated from Fusobacterium nucleatum ATCC 10953.

Takada, H, Ogawa, T, Yoshimura, F, Otsuka, K, Kokeguchi, S, Kato, K, ...

From Fusobacterium nucleatum ATCC 10953 cell envelope fraction whose inner membranes had been removed by treatment with sodium N-lauroyl sarcosinate, an outer membrane protein (37,000 Mr in a native...

Immunobiological activities of synthetic lipid A analogs with low endotoxicity.

Kotani, S, Takada, H, Takahashi, I, Ogawa, T, Tsujimoto, M, Shimauchi, H, ...

Synthetic lipid A analogs, beta(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each...

Requirement of a properly acylated beta(1-6)-D-glucosamine disaccharide bisphosphate structure for efficient manifestation of full endotoxic and associated bioactivities of lipid A.

Takahashi, I, Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Shiba, T, ...

Several synthetic acylated glucosamine monophosphates, with structures corresponding to the nonreducing or reducing moiety of the lipid A of the Escherichia coli or Salmonella minnesota type, and a...

Analgesic effects of N-acetylmuramyl-L-alanyl-D-isoglutamine in decreasing the acetic acid-induced abdominal-writhing response.

Ogawa, T, Kotani, S

A new pharmacological action of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) is described. Pretreatment of male ddY mice with MDP, but not its biologically inactive analogs, significantly decreased...

Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: adaptability to various vehicles and pyrogenicity.

Tsujimoto, M, Kotani, S, Kinoshita, F, Kanoh, S, Shiba, T, Kusumoto, S

Thirteen 6-O-acyl-N-acetylmuramyl-L-alanyl-D-isoglutamines (6-O-acyl-MDPs), including four inactive D-isoasparagine and L-isoglutamine analogs, were tested for their pyrogenicity and...

Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: dose-response and local reactions observed with selected compounds.

Tsujimoto, M, Kotani, S, Shiba, T, Kusumoto, S

6-O-(2-Tetradecylhexadecanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutamine (B3O-MDP) and 6-O-(3-hydroxy-2-docosylhexacosanoyl)-MDP (BH48-MDP) were examined for immunopotentiating activity in stimulating...

Low endotoxic activities of synthetic Salmonella-type lipid A with an additional acyloxyacyl group on the 2-amino group of beta (1-6) glucosamine disaccharide 1,4'-bisphosphate.

Kotani, S, Takada, H, Takahashi, I, Tsujimoto, M, Ogawa, T, Ikeda, T, ...

A synthetic lipid A (Salmonella type, compound 516), beta (1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, with three acyloxyacyl groups and one hydroxyacyl group, i.e.,...

Synthetic Salmonella-type lipid A antigen with high serological specificity.

Kasai, N, Arata, S, Mashimo, J, Okuda, K, Aihara, Y, Kotani, S, ...

A synthetic compound (compound 516), beta(1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated by (R)-3-hexadecanoyloxytetradecanoyl, (R)-3-hydroxytetradecanoyl,...

Immunopharmacological activities of a synthetic counterpart of a biosynthetic lipid A precursor molecule and of its analogs.

Takada, H, Kotani, S, Tsujimoto, M, Ogawa, T, Takahashi, I, Harada, K, ...

Synthetic lipid A analogs (compounds 404 through 406) were examined for their immunopharmacological activities. These compounds had two amide-bound and two ester-bound (R)-3-hydroxytetradecanoyl...

Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant.

Kotani, S, Takada, H, Tsujimoto, M, Ogawa, T, Takahashi, I, Ikeda, T, ...

A synthetic compound (506), beta (1-6) D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated at 2'-amino and 3'-hydroxyl groups with (R)-3-dodecanoyloxytetradecanoyl and...

Granuloma formation by muramyl dipeptide associated with branched fatty acids, a structure probably essential for tubercle formation by Mycobacterium tuberculosis.

Emori, K, Nagao, S, Shigematsu, N, Kotani, S, Tsujimoto, M, Shiba, T, ...

Muramyl dipeptide, which does not induce epithelioid granuloma when injected alone dissolved in phosphate-buffered saline, could induce extensive granulomas in guinea pigs when chemically conjugated...