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PubMedDate not supplied

Prostaglandins as modulators of the inflammatory response in the rat.

E-type PGs, injected in rat skin at a low dose concentration (1-5 ng ml-) proved not to release vasoactive amines from local mast cell, enhance increase in vascular permeability evoked by hypersensitivity endogenous inflammatory reactions (passive cutaneous anaphylaxis and reversed passive Arthus) or by intradermal injection of histamine and bradykinin. The possible role of PGE1 and PGE2 as modulators of the inflammatory response is discussed.

Amines↗
PubMed1976

[Influence of antilymphocyte sera on the development of experimental allergic encephalomyelitis].

Experimental allergic encephalomyelitis (EAE) was induced in guinea pigs by sensitization of myelinomas of homologous or heterologous (rabbit) brain in the complete Freund's adjuvant. Antilymphocytic serum (ALS) obtained by immunization of rabbits with the lymphocytes of the lymph nodes of guinea pigs was injected subcutaneously for 3--6 days at the early periods before or after the sensitization. ALS produced a marked inhibitory action on the development of the neurological signs of EAE and of histological changes in the form of demyelinization and perivascular cell infiltration in the lumbo-sacral and cervical portions of the spinal cord. Administration of ALS beginning from the 3rd--5th day before the sensitization or from the date of the EAE induction proved to be the most effective. When the injections were started from the 7th or the 12th day after the sensitization an increase in the incidence of the disease occurred in the grooups. A fall of morbidity correlated with a reduction of percentage of positive skin tests in response to the intradermal injection of a homologous myelin. No reduction in the production of the complement-fixing, antibodies to the heterologous antigen was seen in the animals given ALS. This pointed to the participation of cell factors in the development of the pathological process.

Animals↗
PubMed1978

A comparison of the hematogenous cell infiltrate evoked by lymphokine injection with that of delayed hypersensitivity reactions.

Lymphokine preparations of high potency obtained by in vitro assay were employed in vivo to determine whether they could produce inflammatory responses showing a cellular infiltrate that qualitatively or quantitatively resembled responses of delayed hypersensitivity. Hematogenous cell infiltrates in guinea pig skin were characterized in terms of the number and types of participating cells following intradermal injection of either lymphokines or an antigen (PPD) to which the animals exhibited delayed hypersensitivity. The dose of lymphokine or PPD per skin test site was selected on the basis of comparable ability to enhance vascular permeability. Delayed hypersensitivity responses showed, as expected, a persistent mononuclear cell exudate both in dermis and subcutis, but most notable in the dermis, during the 24 hours following antigen injection. In contrast, the response to lymphokine over the same period was characteristically neutrophilic and principally in the subcutis. There was no pronounced mononuclear cell infiltrate at any time throughout the reaction to lymphokine. It is concluded that preformed lymphokine produces a pattern of increased vascular permeability appropriate to a mediator of delayed hypersensitivity reactions, provided there is sustained secretion of this material. The ability of lymphokine to cause carbon labeling of dermal capillaries is also pertinent to a mediator of delayed hypersensitivity. The absence of significant mononuclear cell accumulation suggests that the in vitro chemotactic activity of lymphokine toward mononuclear cells may be more important for retention of mononuclear cells in the extravascular connective tissue space than for their selective accumulation.

Animals↗
PubMed1980

Anti-allergy properties of PRD-92 Ea in guinea pig and rat.

The effects of PRD-92 Ea were examined on the increased plasma protein extravasation in the skin of guinea pig and rat elicited by specific antigens and spasmogenic mediators. PRD-92 Ea was found to be a potent inhibitor of rat PCA reactions when administered intradermally, intravenously or orally. This compound did not antagonize the local inflammatory responses of histamine, bradykinin or 5HT. This implies that in vivo PRD-92 Ea acts predominantly as an anti-allergy agent rather than a spasmogen antagonist. At high concentrations PRD-92 Ea directly increased vascular permeability when injected intradermally (greater than 250 micrograms/site) or administered by aerosol into the lung (greater than 10%). The importance of investigating such direct irritant actions of similar new drugs is discussed.

Administration, Oral↗
PubMed2006

Inhibitory effect of the polyinosinic-polycytidylic acid/cationic liposome on the progression of murine B16F10 melanoma.

Cellular proteins, retinoic acid inducible gene-I and Toll-like receptor 3, sense dsRNA including polyinosinic-polycytidylic acid (PIC) to stimulate innate immune response. The local administration of PIC has been demonstrated to be effective in anti-tumor immunotherapy. However, the effects of PIC delivered cross the cell membrane have not yet been examined. To address this issue, we used a complex of PIC and cationic liposome (PIC liposome) and examined its anti-tumor effects in vitro and in vivo. PIC liposome could directly suppress the growth of B16F10 melanoma in vitro and repeated peritumoral injections of PIC liposome inhibited melanoma growth in a dose-dependent manner. This treatment induced tyrosinase-related protein-2 (TRP-2)-tetramer(+) CD8(+) cells in the lymph nodes. As the mechanism for its anti-tumor immune response, we showed that the intradermal injection of PIC liposome induced the maturation of dendritic cells (DC). Moreover, the intratumoral injection of immature DC after treatment with PIC liposome significantly increased the number of TRP-2-specific IFN-gamma-producing cells in the lymph nodes as well as spleen, which resulted in an augmentation of the anti-tumor immune response. These studies demonstrate the potential of peritumoral injection of PIC liposome as immunotherapy for malignant melanoma.

Animals↗
PubMed1995

Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors.

Recently, there has been renewed interest in the concept of tumor vaccines using genetically engineered tumor cells expressing a variety of cytokines to increase their immunogenicity. Human MCP-1 (JE) is a potent chemoattractant and activator of monocytes and T lymphocytes and thus a good candidate gene for a tumor vaccine. We therefore evaluated the efficacy of vaccines consisting of irradiated tumor cells transduced with the murine MCP-1 gene in the syngeneic 9L gliosarcoma brain tumor model. 9L cell lines stably expressing murine MCP-1 (9L-JE) and control cell lines expressing neomycin 3' phosphotransferase (9L-Neo) were generated by infection with a Moloney murine leukemia retroviral vector. Fisher 344 rats were immunized with intradermal injections of 5 x 10(5) or 2 x 10(6) irradiated (5000 cGy) 9L-JE, 9L-Neo, and wild-type 9L (9L-WT) cells. Two weeks later immunized and non-immunized animals were challenged with various doses of intradermal (5 x 10(6)-5 x 10(7) or intracerebral (2 x 10(4)-5 x 10(5) 9L-WT cells. Intradermal tumors grew in all non-immunized animals. No tumors grew in animals immunized with irradiated 9L-JE or 9L-Neo cells and challenged with inocula of fewer than 5 x 10(5) 9L-WT cells. With higher inocula up to 10(7) cells, tumors appeared in all the animals, but subsequently regressed in the immunized animals. Tumors in animals immunized with 9L-JE were always smaller than tumors in the other groups. In addition, only the 9L-JE vaccine protected against tumor inocula of 5 x 10(7) cells. Thus vaccination with MCP-1-expressing cells was able to protect animals against at least a 100-fold larger number of challenge tumor cells than vaccination with control cells. In contrast to studies with intradermal tumors, immunization with 9L-JE and 9L-Neo produced only minimal protection against intracerebral tumors. There was no significant difference between the 9L-JE and 9L-Neo vaccines in intracerebral challenge. This study suggests that tumor vaccines expressing cytokine genes such as MCP-1 can increase the antitumor response. However, the protective effect of these vaccines appears to be largely limited to intradermal tumors rather than intracerebral tumors.

Animals↗
PubMed1983

Cellular infiltrate in situ and response kinetics of human intradermal and epicutaneous tuberculin reactions.

Monoclonal antibodies used in the avidin-biotin-peroxidase complex (ABC) method and a histochemical azo-dye method for acid alpha-naphthyl acetate esterase (ANAE) were used to identify T lymphocytes and their functional subpopulations, B cells, and mononuclear phagocytes in tuberculin-test reactions. At 6 and 24 hr up to 52% of all dermal inflammatory cells in situ were T6+, whereas at 72 hr no T6+ cells were observed in the dermis. This suggests that in the initial phases of tuberculin reactions the epidermal Langerhans cells are mobilized to the perivascular spaces in the dermis. At 6, 24, and 48 hr T3+ T lymphocytes usually formed the main inflammatory cell type in situ. The high proportion of Ia+ T lymphocytes and the variations in the local proportion and numbers of T4+ and T8+ cells suggest that T cells play an active role in the generation of a positive tuberculin reaction. At 72 hr T-pattern ANAE+ lymphocytes accounted for 64 +/- 9 and 35 +/- 10% of all cells in situ in epicutaneous and intradermal tuberculin reactions, respectively (P less than 0.05). The corresponding values for M-pattern ANAE+ macrophages were 27 +/- 9 and 53 +/- 10% (P less than 0.10). This indicates that the recruitment of mononuclear phagocytes is delayed if tuberculin is applied epicutaneously rather than injected intradermally.

Humans↗
PubMedDate not supplied

The effect of ebselen on polymorphonuclear leukocyte and lymphocyte migration to inflammatory reactions in rats.

Ebselen, a selinyl organic compound with anti-inflammatory properties was found by us previously to inhibit in vitro human polymorphonuclear leukocyte (PMNL) adhesion to and migration through umbilical vein endothelium monolayers. Here we investigated in rats the effect of ebselen on PMNL and spleen T lymphocyte (SPLT) migration to inflamed joints induced by intra-articular (i.a) injection of recombinant murine tumor necrosis factor alpha (mTNF alpha) and to dermal inflammatory reactions. Inflammation was induced in the carpal and talar joints of rats by intra-articular (i.a.) injection (100 ng) of mTNF alpha once daily for 2 days. Corresponding joints in the opposite limb received diluent. Simultaneously, the rats were treated p.o. with either ebselen (100 mg/kg/day) or indomethacin (2 mg/kg/day) or vehicle for 2 days. Dermal inflammation was induced by intradermal injection (0.05 ml) of inflammatory stimuli. Accumulation of 51Cr-labelled rat blood PMNL, 111In-labeled SPLT, and extravasation of 125I-labelled human serum albumin (HSA) in the joints and in skin sites were measured. Treatment of rats with ebselen inhibited by 33-65% PMNL migration to the mTNF alpha inflamed joints, and to dermal inflammation induced by zymosan activated serum (ZAS; containing C5adesArg), endotoxin (LPS), mIL-1 beta and mTNF alpha. Migration of SPLT to dermal inflammation induced by interferon gamma (IFN gamma), poly-inosine-cytosine (poly I:C) and LPS was also significantly inhibited (22-33%), but SPLT migration into the inflamed joints was not effected by ebselen. Indomethacin treatment of rats also inhibited PMNL migration into the inflamed joints, but unlike ebselen, indomethacin inhibited only ZAS induced dermal PMNL accumulation. In contrast to ebselen, indomethacin inhibited SPLT migration into the inflamed joints as well as to the dermal inflammation induced by poly I:C and a delayed-type hypersensitivity reaction (DTH). In addition, treatment of rats with indomethacin significantly inhibited plasma protein (125I-HSA) extravasation in the inflamed joints and the dermal inflammatory reaction induced by ZAS, but ebselen had no such effect. In conclusion, ebselen appears to have a distinct antiinflammatory mechanism of action from indomethacin and the PMNL findings are consistent with a direct inhibitory action on PMNL activation and PMNL transendothelial migration as observed previously in vitro.

Analysis of Variance↗
PubMed1995

LPS-induced 111In-eosinophil accumulation in guinea-pig skin: evidence for a role for TNF-alpha.

Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria with powerful pro-inflammatory activities. Although the mechanisms involved in LPS-induced neutrophil accumulation have been studied extensively, few reports have focused on the effects of LPS on eosinophil infiltration. In this study we have used an in vivo model of local 111In-eosinophil accumulation in the guinea-pig to investigate the mechanisms of LPS-induced eosinophilia. Using a 4-hr in vivo test period, the intradermal injection of LPS (50-1000 ng/site) led to a marked and dose-dependent accumulation of 111In-eosinophils into guinea-pig skin sites. Time-course experiments revealed that this cell infiltration was delayed in onset, becoming significant 1 hr after the intradermal administration of LPS. The slow development of the response and its sensitivity to the locally administered protein synthesis inhibitor, actinomycin D, suggested that the LPS-induced 111In-eosinophil accumulation in vivo is mediated by the generation of de novo proteins. The intravenous pretreatment of guinea-pigs with a soluble tumour necrosis factor-alpha (TNF-alpha) receptor fusion protein (TNFR-IgG, 1 mg/kg), potently inhibited the 111In-eosinophil accumulation induced by LPS. Our results demonstrate that LPS can induce 111In-eosinophil accumulation in vivo in guinea-pig skin, and that this process is mediated by TNF-alpha.

Animals↗
PubMed2004

Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization.

Although the PI3K (phosphatidylinositol 3-kinase) pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in neural plasticity. It is unknown whether the PI3K pathway can mediate pain hypersensitivity. Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals. We examined the activation of PI3K in primary sensory DRG neurons by these inflammatory agents and the contribution of PI3K activation to inflammatory pain. We further investigated the correlation between the PI3K and the ERK (extracellular signal-regulated protein kinase) pathway. Capsaicin and NGF induce phosphorylation of the PI3K downstream target AKT (protein kinase B), which is blocked by the PI3K inhibitors LY294002 and wortmannin, indicative of the activation of PI3K by both agents. ERK activation by capsaicin and NGF was also blocked by PI3K inhibitors. Similarly, intradermal capsaicin in rats activated PI3K and ERK in C-fiber DRG neurons and epidermal nerve fibers. Injection of PI3K or MEK (ERK kinase) inhibitors into the hindpaw attenuated capsaicin- and NGF-evoked heat hyperalgesia but did not change basal heat sensitivity. Furthermore, PI3K, but not ERK, inhibition blocked early induction of hyperalgesia. In acutely dissociated DRG neurons, the capsaicin-induced TRPV1 current was strikingly potentiated by NGF, and this potentiation was completely blocked by PI3K inhibitors and primarily suppressed by MEK inhibitors. Therefore, PI3K induces heat hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent manner. The PI3K pathway also appears to play a role that is distinct from ERK by regulating the early onset of inflammatory pain.

Androstadienes↗
PubMed1994

Antitumor effect of intratumoral administration of biological response modifiers: induction of immunosuppressive acidic protein, a type of alpha 1-acid glycoprotein, in mice.

The antitumor effects of biological response modifiers (BRMs) in an experimental mouse model, the "double grafted tumor system" were analyzed. Male BALB/c mice received simultaneous inoculations of Meth-A fibrosarcoma cells on the right flank (10(6) cells) and left flank (2 x 10(5) cells) on day 0, and BRMs were injected intratumorally into the right tumor on days 3, 4 and 5. PSK (a protein-bound polysaccharide preparation), interleukin-1 (IL-1) and cepharanthin (CR) cured not only the right, but also the left, non-treated tumor in a double grafted tumor system. OK-432 (a Streptococcus preparation) and BCG and tumor necrosis factor (TNF) cured the right tumor and inhibited the growth of the left tumor. Lentinan (a polysaccharide preparation) and IL-6 inhibited neither the right nor the left tumor. Immunosuppressive acidic protein (IAP) in serum was increased transiently soon after intradermal injection of PSK, CR, OK-432 and TNF in BALB/c mice. Lentinan, however, did not induce IAP. IAP in serum was gradually increased after intradermal inoculation of Meth-A tumor in BALB/c mice. The biochemical difference between PSK-induced IAP (early, inflammatory IAP) and Meth-A-induced IAP (late, tumor-induced IAP) was investigated by crossed affinity immunoelectrophoresis with concanavalin A. IAP of murine serum was separated into 4 peaks. IAP in normal mouse was rich in high-mannose type sugar chain (Peak 3) and contained no hybrid-type sugar chain (Peak 4), which was present in inflammatory and tumor-induced IAP. Inflammatory IAP was rich in biantennary sugar chain (Peak 2) and tumor-induced IAP was rich in tri-tetraantennary sugar chain (Peak 1).

Animals↗
PubMed1984

Immunity to transplantable nitrosourea-induced neurogenic tumors. III. Systemic adoptive transfer of immunity.

The effect of intravenously injected tumor immune spleen cells on growth of 3 X 10(5) gliosarcoma T9 cells injected intradermally (ID) or intracerebrally (IC) into sublethally irradiated CDF rats was evaluated. Spleen cells from donor rats with sufficient immunity to reject 5 X 10(5) T9 cells inhibited the growth of T9 cells mixed with spleen cells in a ratio of 1:25 and injected ID, but could not act after intravenous transfer. However, donor rats which had rejected increasing T9 challenge doses up to 1 X 10(7) cells produced immune spleen cells which, upon IV transfer, could inhibit growth of ID T9 challenge but not of EB-679, an unrelated glioma, in recipient rats. Rejection of IC T9 challenge was also obtained after IV transfer, in recipients of such "hyperimmune" spleen cells, but was less (60% maximum) than that noted after ID T9 challenge (100% maximum). The removal of B cells from the transferred spleen cells did not affect the results, suggesting that the specific immunity was mediated by T cells. We conclude that the special immunological circumstances of tumors growing in the brain renders them less accessible to rejection by systemically transferred immune cells, but it is nevertheless possible to effect a significant incidence of rejection of syngeneic tumor growth in the brain by the intravenous transfer of hyperimmune spleen cells.

Animals↗
PubMed1998

Tuberculin-induced delayed-type hypersensitivity reaction in a model of hu-PBMC-SCID mice grafted with autologous skin.

We have developed an animal model to study human delayed-type hypersensitivity reactions. Previous studies in humans have shown after tuberculin injection the presence of a mononuclear cell infiltration, with almost no eosinophils, associated with a preferential Th-1-type cytokine profile. Human skin graft obtained from tuberculin-reactive donors was grafted onto the back of severe combined immunodeficient mice. After healing, mice were reconstituted intraperitoneally with peripheral mononuclear cells. Tuberculin and diluent were injected intradermally, and skin biopsies were performed 72 hours later. Skin grafts were divided into two parts, one for immunohistochemistry and one for in situ hybridization studies. Immunohistochemistry was performed on cryostat sections using the alkaline phosphatase anti-alkaline phosphatase technique. In the tuberculin-injected sites as compared with the diluent-injected sites, there were significant increases in the number of CD45+ pan leukocytes and CD4+, CD8+, CD45RO+ T cells but not in CD68+ monocytes/macrophages and EG2 or MBP+ eosinophils. The activation markers CD25 and HLA-DR were up-regulated in the tuberculin-injected sites. In situ hybridization was performed using 35S-labeled riboprobes for interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-5. After tuberculin injection, a preferential Th-1-type cytokine profile was observed with significant increases in the numbers of IL-2 and IFN-gamma mRNA-expressing cells. These results are similar to those reported after tuberculin-induced delayed-type hypersensitivity in humans, suggesting that this model might be useful to study cutaneous inflammatory reaction.

Animals↗
PubMed1997

Massive infiltration of basophilic cells in inflamed tissue after injection of RANTES.

Regulated upon activation normal T expressed and secreted (RANTES) is a new inducible protein member of the human C-C branch of chemokines. RANTES is a potent monocyte and lymphocyte chemoattractant and is a mediator of inflammatory responses. In these studies we found that RANTES 10 ng/50 microl chemoattracts basophilic cells in a dose-dependent manner 4 h after an intradermal injection in rat skin sites, as revealed by optic microscopy. Moreover, in biopsy specimens from rat skin injection sites histamine release was significantly higher (P < 0.05) than in controls (PBS 50 microl) after 4 h from RANTES treatment. The presence of basophilic cells in rat skin injection sites after RANTES-treatment was also confirmed by electron microscopy studies. In addition, histidine decarboxylase (HDC) mRNA was increased in rat skin sites injected with RANTES compared to sites injected with PBS (controls). Our report describes additional biological activities for RANTES, suggesting that this human chemoattractant protein may play a fundamental role in histamine and HDC generation, along with basophilic cell recruitment.

Animals↗
PubMed1975

A preliminary report on the effects of methanol extraction residue of BCG (MER) on cancer patients.

Twenty-seven patients with malignant neoplasia were injected intradermally with the methanol extraction residue (MER) fraction of tubercle bacilli. Two schedules of treatment were used: every other week and once a month; 1-10 courses of MER were administered to the patients. The skin reactivity to 3 recall antigens, as well as to the injected MER itself, was used to monitor the immune response. Improvement of skin reactivity occurred in 9 of 18 patients tested with recall antigens. Five of 6 patients treated every other week improved in their immune capacity whereas only 4 of 12 patients improved on the monthly schedule. Thus, repeated injections given every other week were more effective in increasing the cutaneous reactivity than monthly injections of MER. The side-effects of MER treatment were tolerable.

Antigens, Bacterial↗
PubMed1991

Alpha-macroglobulin-like plasma inactivator for Vibrio vulnificus metalloprotease.

The metalloprotease produced by Vibrio vulnificus (VVP) is known to be quickly inactivated by plasma proteins which belong to the class of alpha-macroglobulins in vitro at a molar ratio of 1:1. But the in vivo potential of the inactivators has not been studied. Macroalbumin (MA), a member of alpha-macroglobulins in guinea pig plasma, was found to inactivate VVP by means of physical entrapment in vitro. In vivo actions of VVP, permeability-enhancing and hemorrhagic actions, were greatly augmented by simultaneous injection of the antibody against MA, which had no effect on in vitro proteolytic action toward azocasein. The interstitial-tissue space in the normal guinea pig skin contains a negligible amount of MA. However, sufficient MA was present in the extravascular fluid collected after the intradermal injection of VVP. Besides, in the extravascular fluid, VVP formed a complex with MA and no inactivator other than MA was found. These results indicate that plasma MA leaked from the vascular system owing to the permeability-enhancing and hemorrhagic actions of VVP, resulting in inactivation of VVP in situ.

Animals↗
PubMed1992

Effects of antihistamines on cutaneous reactions and influx of eosinophils after local injection of PAF, kallikrein, compound 48/80 and histamine in patients with chronic urticaria and healthy subjects.

The effects of one week's daily treatment with dexchlorpheniramine (3 + 3 mg x 2) and loratadine (10 mg x 2) on the cutaneous reactions to putative mediators of urticarial reactions were studied in healthy subjects and in patients with chronic urticaria. Biopsy specimens were taken from skin with delayed reactions and studied immunohistochemically for the presence of eosinophilic cationic protein (ECP). In healthy subjects both antihistamines significantly decreased the weal and flare induced by histamine and the histamine releaser compound 48/80. They also reduced the flare seen after injection of PAF (platelet activating factor) and kallikrein. In patients with chronic urticaria the delayed reactions to PAF and kallikrein were larger than in healthy subjects. The immediate flare seen after injection of histamine, 48/80 and PAF, and the delayed reaction to 48/80, were significantly decreased by treatment with loratadine. No correlation was found between the clinical response and test reactions. In the group of healthy subjects, eosinophils were increased in the skin of all subjects after intradermal injection of 100 micrograms of PAF and in 50% after 1 microgram of PAF, but no eosinophils were seen after injection of 1 ng of PAF. In patients with chronic urticaria the eosinophils were increased at all sites where 1 ng of PAF had been injected and also at a limited number of sites of injection of histamine, 48/80, kallikrein and saline. Treatment with the antihistamines had no effect on the influx of eosinophils in the skin.

Adult↗
PubMed1974

Formation of multinucleate giant cells in organized epitheloid cell granulomas.

Organized epithelioid cell granulomas were produced experimentally by injecting intradermally dilute suspensions of zirconium and beryllium salts into individuals who had been previously sensitized to these metals. Biopsies were obtained at intervals of between 5 days and 13 months later, and the specimens were fixed and prepared for light and electron microscopy. Tritiated thymidine was injected into a number of the granulomas; the biopsy specimens were secured from 40 minutes to 2 or more weeks later, and the tissues were processed for light microscopic autoradiography. Giant cells occurred commonly, both within organized tubercles and in relation to areas of necrosis, and had markedly different cytoplasmic features from typical secretory epithelioid cells which enabled them to be readily recognized at scanning magnifications. The characteristic hallmark of these giant cells was the presence of myriads of small mitochondria adjacent to nuclei with numerous membrane-lined vesicles in the center of the cell. Giant cells occurred mainly in edematous disrupted tubercles. In these tubercles, epithelioid cells contained cytoplasmic components more like giant cells. Direct evidence of cell fusion was not seen, although fusion of membranes seemed to occur between cells having similar cytoplasmic features. The failure to find labeled nuclei in any giant cells 40 minutes after injection of tritiated thymidine indicates that normal nuclear division does not occur within giant cells. We postulate that epithelioid cells containing vesicles develop in damaged and necrotic areas, and that mainly this type of epithelioid cell fuses to form giant cells.

Autoradiography↗