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PubMed1982

T cell-mediated cytotoxicity against HBsAg-coated Chang cells in patients with chronic hepatitis: evidence for cytotoxicity mediated by delayed hypersensitivity T cell reaction.

T lymphocytes from 7 (21%) of 34 patients with chronic hepatitis showed positive cytotoxicity against HBsAg-coated Chang cells. This positivity was observed in HBsAg-negative patients having positive blast transformation responses to HBsAg, as well as in patients convalescing and recovered from acute B hepatitis. Levels of S-GPT in these patients were not different from those showing no cytotoxicity. T cell-mediated cytotoxicity against HBsAg-coated hepatocytes in HBsAg-negative patients thus may have no significant pathogenetic role in destruction of hepatocytes and may represent anamnestic response of sensitized T lymphocytes to HBsAg. Positive cytotoxicity against HBsAg-coated Chang cells was also found in 3 of 17 patients with HBsAg-positive chronic hepatitis. All positive cases exhibited blast transformation responses to HBsAg and low HBsAg titers in their sera. Levels of S-GPT in these patients were significantly higher than in those showing no cytotoxicity, suggesting possible presence of T cell-mediated liver cell damage in these patients. T lymphocytes from asymptomatic HBsAg carrier showed no cytotoxicity to HBsAg-coated hepatocytes and no blast transformation responses of lymphocytes to HBsAg. From the results of the parallel occurrence of T cell-mediated cytotoxicity and blast transformation responses to HBsAg, and of presence of lymphotoxin in the supernatant co-cultured HBsAg and cytotoxicity-positive lymphocytes, it seemed likely that T cell-mediated cytotoxicity in our system might be mediated by lymphokine produced by T cells as a result of delayed hypersensitivity reaction in vitro.

Cells, Cultured↗

PubMed1975

Subpopulations of multiparous rat lymph-node cells cytotoxic for rat tumour cells and capable of suppressing cytotoxicity in vitro.

Lymph-node cells (LNC) from multiparous pregnant rats were separated on columns prepared from nylon wool, and tested for cytotoxicity against target tumour cells. Reactivity of LNC towards hepatoma D23 and mammary carcinoma AAF57 was demonstrated in cell populations retained on the nylon wool, and not with cells eluted from the column. Although only 25% of the samples of unfractionated LNC were cytotoxic for tumour cells, retained cell fractions were cytotoxic in 11 out of 12 tests (p = less than 0.05). Similarly retained LNC were also cytotoxic for 15-day-old embryo cells but not for normal adult rat fibroblasts. Using multiparous rat serum it was shown that the reactivity of the retained LNC population could be abrogated in eight out of 11 tests (p = less than 0.05). The LNC population recovered from the nylon wool constituted 28 to 35% of the original LNC preparation, and consisted of 60-70% Ig-bearing cells together with a subpopulation of cells responding to soluble PHA. Separation of multiparous LNC on glass beads coated with rat Ig and then rabbit anti-rat Ig (in excess) also demonstrated the retained cell population to be cytotoxic against tumour cells. Approximately 17-20% of the original cell population was recovered from cells retained on the column, and consisted of an enriched Ig-bearing cell population (65-80% Ig-bearing cells) and LNC responsive to PHA. Carbonyl iron treatment of multiparous rat LNC was found to remove detectable cytotoxicity from multiparous rat LNC preparations. The cytotoxicity of multiparous rat LNC retained on nylon wool was also abolished following incubation with carbonyl iron. Definite conclusions as to the nature of the effector cell cannot be drawn from this test, since carbonyl iron treatment was found to remove not only phagocytic cells from LNC preparations but also a proportion of other cell populations including Ig-bearing lymphocytes... In addition to detecting a cytotoxic LNC population reactive towards tumour-associated embryonic antigens (retained fractions from nylon-wool column separation), a subpopulation of multiparous rat LNC was demonstrated in cell fractions eluted from the nylon wool which was shown to suppress the cytotoxicity of the retained multiparous LNC population. The exact nature of this subpopulation of LNC and the mechanism of action is at present not known.

Animals↗

PubMed1982

Effect of interleukin 2 on cytotoxic effectors: I. Short-term culture of the cytotoxic effectors and the in vivo anti-tumor activity of the cultured effectors isolated from tumor site.

The effects of interleukin 2 (IL2) on the in vitro and in vivo activity of cytotoxic T cells have been studied. IL2 was produced by W/Fu rat spleen cells cultured with concanavalin A. The IL2 thus prepared gave an optimal T-cell growth-promoting effect at a concentration of 5-20% equivalents of the original preparation. In the primary syngeneic mixed lymphocyte/tumor cell cultures (MLTC) against FBL-3 tumor cells, the addition of IL2 failed to generate a cytotoxic response. However, the cytotoxic response could be generated in MLTC by addition of exogenous macrophages. On the other hand, IL2 could maintain the growth of performed cytotoxic T cells for 3 to 5 weeks. These cytotoxic T cells were generated either by in vitro sensitization (MLC or MLTC) or by in vivo sensitization of B6 mice against a syngeneic tumor FBL-3. In short-term cultures, augmentation of the cytotoxic activity was seen after 10 days' culturing with IL2. The antigenic specificity of the cytotoxic reaction was altered after 28-35 days in culture, and the effectors broadly reactive. When growing a nonadherent population of lymphocytes isolated from FBL-3 ascites tumor, supplementation with IL2 selectively promoted the growth of a T-cell population, resulting in the elimination of the contaminating tumor cells. These purified T cells were highly cytotoxic for FBL-3 cells in vitro and also possessed strong in vivo anti-tumor activity against FBL-3 cells in the adoptive transfer experiments. The present study demonstrates that short-term culture (2-3 weeks) in IL2 promotes the growth of T cells and augments their cytotoxic activity with the appropriate antigenic specificity. IL2 also promoted the selective growth of T cells isolated from tumor site and these T cells showed augmented in vitro and in vivo anti-tumor activity.

Animals↗

PubMed2001

Phylogeny of natural cytotoxicity: cytotoxic activity of coelomocytes of the purple sea urchin, Arbacia punctulata.

Coelomocyte-mediated nonspecific cell cytotoxic activity against human and murine target cells by the purple sea urchin Arbacia punctulata was investigated in vitro. Cytotoxic activity toward target cells was shown to be mediated by different coelomocyte populations isolated by discontinuous density gradient centrifugation. The population of phagocytic amebocytes showed the strongest cytotoxic activity and the highest binding to human NK markers by cytometry analysis. Our immunophenotypic studies showed that A. punctulata phagocytic amebocytes are CD14(+), CD56(+), CD158b(+), CD3(-), CD4(-), CD8(-), and CD16(-). The cytotoxic activity was independent of experimental incubation temperatures, required viable effector cells, and required cell-cell contact between the effector and target cells. Sodium azide significantly decreased coelomocyte cytotoxicity, indicating that cytotoxicity is metabolically dependent, and EDTA reduction of cytotoxic activity is consistent with the involvement of divalent cations in the cytotoxic process. These data describe a population of sea urchin coelomocytes (the phagocytic amebocyte) that are CD14(+), CD56(+), and CD158b(+), with cytotoxic activities.

Animals↗

PubMed1986

Lymphocyte-induced macrophage cytotoxicity. III. Induction of specific macrophage cytotoxicity is independent of lipopolysaccharide.

The induction of specific macrophage cytotoxicity by allo-sensitized T cells in vitro is shown to be independent of the presence of lipopolysaccharide (LPS). This contrasts with the induction of macrophage cytotoxicity by Macrophage Activating Factor (MAF). The specific macrophage cytotoxicity could be induced in LPS-free medium (less than l ng/ml). Addition of LPS to the macrophages did not increase the cytotoxicity. Addition of LPS-binding polymyxin B to the macrophages before and during the induction of cytotoxicity did not reduce the specific macrophage cytotoxicity. Macrophages obtained from the LPS-unresponsive mouse strain C3H/HeJ were rendered cytotoxic by the allo-sensitized lymphocytes to the same extent as the macrophages from LPS-responsive C3HeB/Fe and C57BL mice. This indicates that the induction of macrophage cytotoxicity by MAF is different from the induction of specific macrophage cytotoxicity by Specific Macrophage Arming Factor (SMAF).

Animals↗

PubMed1974

Cytotoxic immune cells with specificity for defined soluble antigens. IV. Antibody as mediator of specific cytotoxicity.

Spleen cells from mice immunized against ovalbumin (OA) or dinitrophenylated mouse serum albumin (DM) were found to be specifically cytotoxic in vitro towards target cells (chicken red blood cells) coated with these antigens. Inhibition of specific cytotoxicity was observed when free soluble antigen was added to the incubation mixtures. DM-immune cell cytotoxicity could be specifically and completely inhibited by DNP-lysine and was thus shown to be hapten specific. Complete and specific inhibition was also observed for OA-immune cell cytotoxicity using OA as inhibitor, but compared with the inhibition curves obtained with DNP-lysine, the OA cytotoxicity inhibition curves were shifted by a factor of about one hundred towards lower molar inhibitor concentrations. Very similar results were observed when the serum antibodies of DM- and OA-immune animals were analyzed by passive hemagglutination inhibition. With increasing time after immunization, both cytotoxicity inhibition curves and agglutination inhibition curves, shifted to lower antigen or hapten concentrations. Specific cytotoxicity against antigen-coated target cells was induced in nonimmune spleen cells (a) by serum from immune animals, and (b) by supernatants from in vitro immune cell cultures. In both instances, the factor which induced antigen-specific cytotoxic activity could be absorbed on anti-mouse Ig columns, thus demonstrating its immunoglobulin nature. The ability of target cell bound antibodies to induce cytotoxicity in nonimmune spleen cells was restricted to the 7S antibody class.

Animals↗

PubMed1981

The antibody-independent cytotoxic activity of normal circulating human leucocytes. II. Failure to demonstrate effector cell-target cell interaction and target cell specificity of the circulating cytotoxic-enhancing factor.

The naturally-occurring antibody-independent cellular cytotoxic activity (NOCC) of normal circulating human monocytes and neutrophils was investigated employing a number of erythrocytes and the K-562 cell line as target cells simultaneously. The identity of the effector cell(s) was shown to be dependent upon or be a function of the type of target cell selected for the assay system. A number of erythrocyte targets (rabbit, horse, sheep and ox erythrocytes) were lysed to varying degrees by neutrophils and monocytes and not by lymphocytes. Irrespective of the red blood cell (RBC) target, the effector monocyte invariably possessed receptors for both C'3 and the Fc of IgG. In contrast, the cytotoxic cells using the K-562 target cell were lymphocytes. Monocytes and neutrophils were inactive. The cytotoxic-enhancing activity in normal human serum exhibits specific and non-specific properties which suggests that more than one factor is involved. With respect to the monocyte cytotoxic cells, only the rabbit erythrocytes could totally absorb the serum factor in a specific fashion. Absorption of the serum with horse, sheep or ox erythrocytes resulted in a significant loss of potentiating activity with respect to all of the erythrocyte targets but a more marked loss of activity using the absorbing erythrocytes as targets. With respect to the polymorphonuclear leucocyte effector cells, only the rabbit RBC were capable of specifically absorbing out the cytotoxic-enhancing factor present in the normal human serum. Absorption of the serum with sheep, horse or ox RBC resulted in total cross-absorption of the enhancing factor. Chicken and human RBC, which do not serve as targets for the NOCC assay, could not absorb out the cytotoxic-enhancing factor with respect to any of the target erythrocytes. The composition of the soluble serum factor(s) is under current investigation but it is not an immunoglobulin since pure serum albumin can substitute for normal serum in the NOCC assay. The mechanism of erythrocyte lysis by the cytotoxic monocyte was investigated. Mononuclear cells were incubated with target cell monolayers and with target cells under optimal rosetting conditions. No interaction between the effector and target cells could be detected. The monocytes did not adhere to the target cell monolayer nor did they form rosettes with the target cells. Thus, the results fail to corroborate or support the assumption that the cytotoxic activity of the monocyte is dependent upon conventionally-detectable receptors. Erythrophagocytosis was not observed to any significant degree under the assay conditions used. Therefore, the nature of the interaction between the cytotoxic monocyte and the erythroid target cell which results in lysis of the target cell remains to be elucidated.

Cell Line↗

PubMed2000

Granule exocytosis, and not the fas/fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4(+) as well as CD8(+) cytotoxic T lymphocytes in humans.

We investigated the cytotoxicity mechanisms of alloantigen-specific human CD4(+) and CD8(+) cytotoxic T lymphocytes (CTLs) using cells from family members with the Fas gene mutation. Alloantigen-specific CD4(+) and CD8(+) CTL bulk lines and clones were generated from 2 individuals by stimulation of their peripheral blood lymphocytes with allogeneic Fas(-/-) or Fas(+/-) cell lines that were established from B-lymphocytes of a patient with Fas deficiency and her mother, respectively. Both CD4(+) and CD8(+) CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas(-/-) and Fas(+/-) cells to almost the same degree. The cytotoxicity of CD4(+) and CD8(+) CTLs appeared to be Ca(2+)-dependent and was completely inhibited by concanamycin A, an inhibitor of perforin-mediated cytotoxicity. Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand, perforin, and granzyme B were all detected in these CD4(+) CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4(+) CTL clones that showed Fas-independent cytotoxicity were T(H)0, as determined by their cytokine production profile. These data, obtained with the use of a novel experimental system, clearly show that the main pathway of cytotoxicity mediated by alloantigen-specific human CD4(+) as well as by CD8(+) CTLs is granule exocytosis, and not the Fas/Fas ligand system.

Anti-Bacterial Agents↗

PubMed1983

Antibody-dependent cell-mediated cytotoxicity and spontaneous cell-mediated cytotoxicity against cells infected with porcine transmissible gastroenteritis virus.

The objective of this study was to determine whether porcine peripheral blood leukocytes and intestinal intraepithelial leukocytes can mediate antibody-dependent cell-mediated cytotoxicity and spontaneous cell-mediated cytotoxicity against target cells infected with transmissible gastroenteritis virus. Peripheral blood leukocytes collected from six young adult pigs and intraepithelial leukocytes from a further five pigs were used as effector cells in chromium release assays against PK-15 cells persistently infected with transmissible gastroenteritis virus. Both peripheral blood leukocytes and intraepithelial leukocytes were capable of mediating antibody-dependent cell-mediated cytotoxicity and spontaneous cell-mediated cytotoxicity against PK-15 transmissible gastroenteritis cells. While the peripheral blood leukocytes mediated lower levels of specific 51Cr release in spontaneous cell-mediated cytotoxicity than in antibody-dependent cell-mediated cytotoxicity, the intraepithelial leukocytes were more effective in spontaneous cell-mediated cytotoxicity than antibody-dependent cell-mediated cytotoxicity.

Animals↗

PubMed1974