共查询到20条相似文献,搜索用时 22 毫秒
1.
R N Lausch J Sofranko S O Prather 《Journal of immunology (Baltimore, Md. : 1950)》1975,115(3):682-687
The role of serum factors in tumor immunity to cells transformed by PARA-(defective SV40)-adenovirus 7 was investigated. It was found that sera from SV40-sensitized hosts did not block the specific cytotoxicity of SV40-sensitized spleen cells for PARA-7 cells. However, such sera could collaborate with nonsensitized spleen cells to produce specific killing. This activity could be absorbed out by PARA-7 cells but not by cells transformed by cytomegalovirus. The activity of sera from hamsters bearing tumor isografts depended upon when, after transplantation, the specimens were obtained. Sera collected greater than or equal to 10 days after grafting completely blocked immune spleen cell cytotoxicity and did not mediate target cell killing in the presence of normal spleen cells. Sera obtained at an earlier time, i.e., 3 to 6 days after transplantation, consistently were active in the antibody-dependent cellular cytotoxicity test and exhibited reduced or no blocking of antibody-independent cellular cytotoxicity. Thus, there appears to be an inverse correlation in the capacity of serum from tumor bearing hosts to block effector cell cytotoxicity and mediate antibody-dependent cellular cytotoxicity. 相似文献
2.
Spleen cells from LSH hamsters inoculated with xenogeneic, allogeneic, or syngeneic (PARA-7) tumor cells were assayed for their ability to mediate direct cell-mediated cytotoxicity (DCMC) and lectin-dependent cell-mediated cytotoxicity (LDCC) in a 4-hr chromium release assay. Spleen cells from animals immune to xenogeneic or allogeneic cells demonstrated specific DCMC against homologous target cells in the absence of Con A and nonspecific LDCC against both homologous and heterologous target cells in the presence of Con A. Spleen cells from animals bearing syngeneic PARA-7 tumors (TBA) failed to express DCMC against homologous or heterologous target cells; however, significant lysis of all target cells occurred in the presence of Con A. LDCC was not detectable when nonsensitized spleen cells from normal animals were employed. The LDCC reaction was dependent on the concentration of Con A and the number of effector cells present in the reaction. The development of LDCC effector cells in the TBA appeared to parallel the development of both DCMC and LDCC effector cells in immune animals. 相似文献
3.
Antibody-dependent cellular cytotoxicity mediated by murine lymphocytes activated in recombinant interleukin 2 总被引:6,自引:0,他引:6
E Shiloni A Eisenthal D Sachs S A Rosenberg 《Journal of immunology (Baltimore, Md. : 1950)》1987,138(6):1992-1998
The incubation of murine splenocytes in recombinant interleukin 2 (RIL 2) gives rise to lymphokine-activated killer (LAK) cells that can lyse fresh, NK-resistant tumor cells but not normal cells in 4-hr 51Cr-release assays. Lysis by this IL 2-activated cell population was enhanced up to 100-fold by prior reaction of target cells with specific antisera reactive with antigens on the target cells. This antibody-dependent cellular cytotoxicity (ADCC) also resulted in lysis of fresh normal target cells, which are not usually susceptible to LAK lysis. The ADCC was evident after 24 hr of incubation of splenocytes in RIL 2, but peak lytic activity was reached after 3 to 4 days of incubation. The concentrations of RIL 2 needed for the in vitro activation of the effectors in order to attain maximal ADCC was between 100 and 3000 U/ml and parallel the IL 2 concentrations required to generate LAK cells. ADCC mediated by IL 2-activated splenocytes was completely blocked by anti-FcR monoclonal antibodies. Although antisera directed against MHC antigens were used in most experiments, anti-B16 monoclonal antibodies have also shown the ability to induce ADCC mediated by RIL 2-activated syngeneic and allogeneic cells. Treatment of the precursor splenocyte populations with anti-asialo GM1 and complement eliminated the direct LAK activity and the antibody-dependent cytotoxicity, suggesting that both direct and indirect tumor cell lysis may be caused by the same effector cell. ADCC mediated by LAK cell populations represents another possible mechanism for the in vivo therapeutic effects of these cells. 相似文献
4.
A R Alsheikhly B W?hlin T Andersson P Perlmann 《Journal of immunology (Baltimore, Md. : 1950)》1984,132(6):2760-2766
The effect of Parotis virus on antibody-dependent cellular cytotoxicity in vitro (ADCC) of human lymphocytes was investigated in a 51Cr-release assay and, at the effector cell level, in an ADCC plaque assay. Target cells were bovine or chicken erythrocytes, which are not susceptible to natural cytotoxicity (NK) of human lymphocytes. They were not killed when incubated with virus-treated lymphocytes in the absence of antibodies. Treatment of the lymphocytes or the target cells with small amounts of virus, however, resulted in a very significant enhancement of ADCC. The same results were obtained with live or UV-inactivated virus, suggesting that enhancement was a passive phenomenon not requiring infection. Enhancement was already significant after 3 hr of incubation, indicating that it was independent of endogenously released interferon. Enhancement of ADCC by virus was due to effector cell recruitment rather than due to the increase of the cytotoxic potential of the individual K cell. The highest frequency of effector cells was present in Percoll fractions enriched in large granular lymphocytes (LGL). Virus treatment resulted in recruitment of effector cells carrying T cell markers such as the T3 antigen (OKT3+), receptors for sheep erythrocytes, or Fc receptors for IgM. In contrast, the absolute number of K cells carrying the HNK-1 marker (Leu-7) or receptors for C3 fragments was not changed by the virus. It is concluded that Parotis virus enhances ADCC by improving effector cell-target cell contacts, resulting in recruitment of effector cells with T cell characteristics. Recruitment is accompanied by a significant reduction of the antibody concentration needed for ADCC induction. This virus-mediated enhancement of ADCC may be of importance for protection of the host in the early phases of a virus infection in which the amounts of anti-viral IgG antibodies capable of inducing cellular cytotoxicity may yet be very small. 相似文献
5.
Normal peritoneal cells or spleen cells from C57BL mice could not lyse SRBC in an ADCC assay. After intraperitoneal injection of Adriamycin, BCG or thioglycolate the ADCC of peritoneal cells toward antibody-coated SRBC was elevated to 30% in contrast to the ADCC of spleen cells. However, peritoneal cells but not spleen cells of mice immunized with allogenic tumor cells (DBA SL2) showed ADCC levels at least two times higher than the levels observed after stimulation by other agents. Maximal ADCC levels (55.8%) were observed 10 to 15 days after immunization. Direct cytotoxicity towards SRBC increased to a maximum of 17.7% at 9 days after immunization. The effector cells in this system are thought to be macrophages, for ADCC activity was only present in the plastic-adherent cell fraction. Cell to cell contact was necessary for ADCC to occur; nonsensitized erythrocytes were not lysed when added to a mixture of effector cells and sensitized erythrocytes. Concentrations of antibody of 1 pg/ml were sufficient to induce ADCC, and effector cell to target cell ratios could be as low as 0.05. The finding that macrophages of mice immunized with allogenic tumor cells exhibit higher ADCC levels than macrophages elicited in other ways can contribute to the investigation of combined cancer therapy with antibodies and biological response modifiers. 相似文献
6.
The nature of the cell types capable of mediating mitogen-induced cellular cytotoxicity (MICC) and antibody-dependent cellular cytotoxicity (ADCC) was investigated utilizing effector cells from athymic nude and euthymic heterozygous control littermate mice as well as Sephadex anti-Fab immunoabsorbent column purified spleen cell populations from normal (CS7BL/6) mice. Chicken erythrocytes (CRBC) and the mouse lymphoma, EL-4, were used as target cells in both cytotoxicity assays. MICC utilizing CRBC targets was mediated by several effector cell types whereas MICC utilizing EL-4 lymphoma targets was T-cell dependent. ADCC against both CRBC and EL-4 lymphoma targets occurred independently of the presence of T-cells. In addition, effector cell populations incapable of mediating MICC against EL-4 lymphoma targets were capable of mediating ADCC against the same EL-4 targets. Thus, utilizing the appropriate target cells, EL-4 but not CRBC, a sharp distinction can be made between the effectors for ADCC and MICC: ADCC is T-cell independent while MICC is dependent on the presence of mature thymus-derived cells. Furthermore these studies demonstrate that the nature of the target cell employed in MICC and ADCC reactions plays a critical role in defining the types of effector cells capable of mediating these cytotoxicity reactions. 相似文献
7.
W/Fu rats inoculated with the syngeneic Gross-virus induced lymphoma, (C58NT)D, had transient lymphocyte-mediated specific cytotoxicity against the tumor cells at 7–15 days after tumor injection. Spleen cells 40 days after immunization (spleen 40) were unreactive by a direct 4-hr 51Cr release assay, but activity appeared after in vitro culture of these spleen eclls by themselves for 18–24 hr. The nature of the cells involved in the activation of cytotoxicity and the characteristics of the effector cells themselves were studied. Significant differences were seen in the cell types involved in the activation phase and the effector phase. Activation appeared to require the cooperation of three cell types. Induction of activity was lost by treatment of cells with ATS plus complement, by passage over an EAC-column, or by treatment with carbonyl iron. Thus, T cells, CRL and macrophages were necessary for full activation of cytotoxicity in spleen 40. In contrast, after activation, only CRL seemed to be required for cytotoxicity, and treatment wih ATS or carbonyl iron had little effect. The effector cell detected after in vitro activation was quite distinct from that seen in the direct cytotoxicity assay with spleen cells at 10 days after tumor cell inoculation. The early, direct cytotoxic reactivity was dependent on T cells, being eliminated by treatment with ATS and complement but not by EAC columns or carbonyl iron. It appears therefore that the in vitro activation is a separate mechanism for cytotoxicity against tumor cells, rather than a simple recovery of T cells from in vivo inhibition. 相似文献
8.
Murine antibody-dependent cellular cytotoxicity to herpes simplex virus-infected target cells. 总被引:6,自引:0,他引:6
S Kohl D L Cahall D L Walters V E Schaffner 《Journal of immunology (Baltimore, Md. : 1950)》1979,123(1):25-30
Freshly collected peritoneal cells (PC) and cultured spleen cells (SC) (but not fresh SC) from nonimmune mice could mediate antibody-dependent cellular cytotoxicity (ADCC) against herpes simplex virus (HSV)-infected cells in the presence of mouse or human sera containing antibody to HSV. PC also demonstrated variable natural killer cell cytotoxicity to infected cells. Both PC and cultured SC required high concentrations of antibody and high effector to target cell ratios for optimal ADCC. The time kinetics of the reaction appeared to depend on the state of activation of the effector cells. In both PC and SC populations, ADCC activity was limited to adherent cells, and was profoundly inhibited by particulate latex or silica. The murine effector cell found in PC and SC able to mediate ADCC to HSV-infected cells appears to be a macrophage. 相似文献
9.
Fc gamma receptors play a dominant role in protective tumor immunity against a virus-encoded tumor-specific antigen in a murine model of experimental pulmonary metastases
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Simian virus 40 (SV40) large tumor antigen (Tag) represents a virus-encoded tumor-specific antigen expressed in many types of human cancers and a potential immunologic target for antitumor responses. Fc receptors are important mediators in the regulation and execution of host effector mechanisms against conditions including infectious diseases, autoimmunity, and cancer. By examining tumor protection in SV40 Tag-immunized wild-type BALB/c mice using an experimental pulmonary metastasis model, we attempted to address whether engagement of the immunoglobulin G Fc receptors (FcgammaRs) on effector cells is necessary to mediate antitumor responses. All immunized BALB/c FcgammaR-/- knockout mice developed anti-SV40 Tag antibody responses prior to experimental challenge with a tumorigenic cell line expressing SV40 Tag. However, all mice deficient in the activating FcgammaRI (CD64) and FcgammaRIII (CD16) were unable to mount protective immunologic responses against tumor challenge and developed tumor lung foci. In contrast, mice lacking the inhibitory receptor FcgammaRII (CD32) demonstrated resistance to tumorigenesis. These results underscore the importance of effector cell populations expressing FcgammaRI/III within this murine tumor model system, and along with the production of a specific humoral immune response, antibody-dependent cell-mediated cytotoxicity (ADCC) may be a functioning mechanism of tumor clearance. Additionally, these data demonstrate the potential utility of ADCC as a viable approach for targeting vaccination strategies that promote FcgammaRI/III scavenging pathways against cancer. 相似文献
10.
The effect of feeding xenoserum (xs) on cytolytic cell activity induced by parenteral injection was examined in C3H/N mice. Spleen cells were cultured with xs and then assayed for cytolytic activity against a panel of 51Cr-labeled YAC-1, AKR-A, or P815 target cells. Prior feeding resulted in significant suppression of responses stimulated by injection and culture. The induction of these responses was antigen specific for xs whereas the effector stage represented polyclonal activation of cytolytic cells. Some effector cells were lysed by either anti-Lyt 2 or anti-NK- 1.2 and complement and some were blocked by anti-Lyt 2 or anti-T200 in the cytotoxicity assay. Thus, both cytolytic T and NK-like cells were suppressed by antigen feeding. Activity of TH cell-derived factors which enhance cytolytic activity ("promoter" factor, interferon, and interleukin 2) also was diminished in culture supernatants of cells from mice fed soluble antigens. The conclusion that polyclonal cytolytic responses induced by soluble antigen can be regulated by prior enteric stimulation is made. 相似文献
11.
Cytotoxic effector lymphocytes were induced by in vitro immunization of lymph node and spleen cells from AKR-mice (H-2k) and from BALB/c-mice (H-2d) to syngeneic SV40-transformed fibroblasts. The T cell-dependent cytotoxicity was specific for target cells expressing the same H2-specificity as the immunizing cells. Nontransformed fibroblasts as stimulator cells did not induce efficient cytotoxicity to transformed or nontransformed target cells. Incubation with phytohemagglutinin during the sensitization period modified the specificity of the T cell-mediated lysis of syngeneic SV40-transformed fibroblasts: allogeneic as well as syngeneic target cells were destroyed by these effector cells. However, the polyclonal stimulant activates preferentially cytotoxicity to H2-matched target cells. The in vitro generation of cytotoxic effector cells was restricted to living SV40-transformed fibroblasts as immunizing cells; it was not possible to immunize lymphocytes in the presence of membrane proteins prepared from the SV40-transformed cells. The cytotoxicity of the in vitro immunized lymphocytes was inhibited by incubation with membrane protein preparations from syngeneic or allogeneic SV40-transformed fibroblasts. 相似文献
12.
The role of HLA-DR determinants in monocyte-macrophage presentation of herpes simplex virus antigen to human T cells 总被引:1,自引:0,他引:1
Spleen cell killing of target cells can manifest through spleen cell-target cell interaction in the presence of mitogenic lectin, lectin-dependent cell-mediated cytotoxicity (LDCC). Spleen cells from C57B1/6 mice immunized with C3H mouse cells were found to be capable of cytotoxicity against autologous and other C57B1/6 spleen cells in the presence of Con A. Thus, alloimmune spleen cells are capable of an anti-self cytotoxic response in the presence of mitogenic lectin, antiautologous LDCC. Antiautologous LDCC is blocked by preincubation of cytotoxic cells with colchicine, an inhibitor of the cytotoxic effector mechanism. Analysis of alloimmune spleen cell subpopulations suggests that the antiautologous LDCC cell is an immature alloimmune cytotoxic cell (prekiller cell). Potent LDCC was found in alloimmune spleen cell preparations depleted of alloimmune cytotoxic T cells (killer-depleted) by three passes on allogeneic cell monolayers genetically identical with the immunizing cell. However, some LDCC effectors were also found to adhere to the adsorbing target, suggesting that there is some maturational diversity among LDCC effectors. 相似文献
13.
Lei Wu Anastasia Parton Ling Lu Mary Adams Peter Schafer J. Blake Bartlett 《Cancer immunology, immunotherapy : CII》2011,60(1):61-73
We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity
(ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their
solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma)
were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated
with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1
or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP
3 antibodies. Differences between groups were assessed using unpaired and paired Student’s t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity
against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of
NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited
ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype
antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D–NKG2D ligand interactions,
but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of
potential biomarkers predictive of clinical benefit. 相似文献
14.
The development of the immune response to xenogeneic tumor cells and the mechanism of potentiation of cell-mediated cytotoxicity (CMC) by xenoantiserum were investigated. The kinetics of potentiation of CMC resembled, both qualitatively and quantitatively, the kinetics of antibody-dependent cellular cytotoxicity (ADCC) of target cells treated with the same xenoantisera. Varying proportions of immune and nonimmune effector cells did not influence the amount of lysis of antibody-treated tumor cells. It would appear, therefore, that spleens from immunized animals contained cell populations that were capable of mediating both CMC and ADCC. Potentiation of CMC would appear to result from the preferential expression of ADCC effector cells; interaction of CMC effector cells was apparently hindered by the presence of antibody on the tumor cell surface. Immune complexes formed in antibody excess may also modify ADCC and the potentiation of CMC. 相似文献
15.
Cells of the J774 macrophage cell line are primed for antibody-dependent cell-mediated cytotoxicity following exposure to gamma-irradiation. 总被引:1,自引:0,他引:1
Activation of macrophages (M phi) for host defense against tumor cells follows a sequence of priming events followed by an initiating stimulus that results in production and release of cytotoxic molecules that mediate target cell killing. We have developed a model to study specific macrophage cytotoxicity in vitro utilizing a cultured murine M phi cell line, J774. Specific cytotoxicity of cultured human gastrointestinal tumor cells is achieved in the presence of murine IgG2a monoclonal antibody (mAb) 17-1-A. The ability of these cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) is greatly enhanced following gamma-irradiation. ADCC can be demonstrated at mAb 17-1-A concentrations greater than or equal to 1 microgram/ml and effector/target cell ratios greater than or equal to 2. Exposure to doses greater than or equal to 10 Gy of gamma-irradiation increases ADCC threefold. Varying the duration from J774 M phi exposure to gamma-irradiation until addition of antibody-coated target cells showed that the primed state for ADCC is stable for at least 8 days but approximately 24 hr is required for complete development of the primed state. mAb-dependent target cell death begins 8 hr after addition of mAb and labeled target cells to primed effector cells and is complete by 24 hr. Incubation of unirradiated J774 M phi effector cells with recombinant murine interferon-gamma (rmIFN-gamma) also results in enhanced ADCC, but the extent of target cell killing achieved is less than that following priming by gamma-irradiation. Concomitant priming of gamma-irradiated J774 M phi with rmIFN-gamma increases the extent of ADCC. Further study of irradiated J774 cells may elucidate the molecular pathways utilized by M phi for achieving and maintaining the primed state for ADCC. Irradiated J774 cells will also provide a homogenous, stably primed cell type in which to examine the mechanism(s) of cytotoxicity employed by tumoricidal M phi. 相似文献
16.
Anti-renal cell carcinoma chimeric antibody G250: cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity 总被引:2,自引:0,他引:2
Liu Z Smyth FE Renner C Lee FT Oosterwijk E Scott AM 《Cancer immunology, immunotherapy : CII》2002,51(3):171-177
The chimeric monoclonal antibody cG250 targets the G250 antigen, a transmembrane protein which is expressed on renal carcinoma cells and is identical to the MN/CAIX antigen. In vitro studies have previously demonstrated that cG250 induces antibody-dependent cellular cytotoxicity (ADCC) of G250-positive targets. In order to investigate the upregulation of ADCC mediated by cG250, ADCC was examined using effector cells cultured in the presence or absence of the cytokines interferon-gamma (IFN-gamma), interferon-alpha isoforms IFN-alpha (2a) and IFN-alpha (2b) and interleukin-2 (IL-2), and the time course of effects over a 7-day period was determined. Renal cell carcinoma lines expressing high (SK-RC-52) and low (SK-RC-09) G250 antigen levels were used as target cells, and freshly isolated peripheral blood mononuclear cells (PBMC) from a healthy donor were used as the effector cells. PBMC were incubated with the respective cytokine at a range of concentrations or with a media alone control for a period of 7 days. The ADCC activity mediated by cG250 or control isotype matched huA33 with the different PBMC treatment groups was assessed in triplicate daily. Corresponding lymphokine activated killing (LAK) activity was measured concurrently for each treatment group. Chimeric G250 specifically recognised G250 antigen on high and low expressing cell lines SK-RC-52 and SK-RC-09, and mediated specific in vitro ADCC of both lines. In the absence of cytokine stimulation, the specific ADCC of cG250 declined rapidly within three days. IL-2 strongly enhanced and maintained cG250-mediated ADCC activity and K562 cytotoxicity when applied to PBMC in culture for seven days. IFN-gamma also enhanced the ADCC of cG250 throughout the study period, but was not as effective as the IL-2 treatment, and the SK-RC-09 line displayed lower specific cytotoxicity than the SK-RC-52 cell line. In contrast, IFN-alpha 2a and 2b increased cG250-mediated ADCC and K562 cytotoxicity for only three days of the study period. The potent and sustained immune effector activity observed with cG250 and cytokines in this in vitro study suggests that the combination immunotherapy of cG250 with cytokines such as IL-2 shows promise in the treatment of renal cell carcinoma (RCC). 相似文献
17.
Neutrophils and mononuclear cells (MNC) can mediate antibody-dependent cellular cytotoxicity (ADCC) against cancer cells.
To study cytotoxicity and growth inhibition of neuroblastoma cells by neutrophils and MNC with chimeric anti-disialoganglioside
(GD2) monoclonal antibody (mAb) ch14.18, we developed digital image microscopy scanning (DIMSCAN) assays that measure fluorescence
of target cells in 96-well plates after 6–18 h (cytotoxicity assay) or 7 days (growth assay). Neuroblastoma cell lines (GD2-positive:
SMS-KCN, SMS-LHN, LA-N-1; GD2-negative: SK-N-SH) were preloaded with calcein acetoxymethyl ester for the cytotoxicity assay
or labeled in situ after 7 days of culture with fluorescein diacetate in the growth assay. Fluorescence, as quantified by
DIMSCAN, was correlated with neuroblastoma cell number in both assays (100–2000 cells/well). In the cytotoxicity test, both
neutrophils and MNC effectively mediated ADCC of GD2-positive but not GD2-negative neuroblastoma cell lines. Cytotoxicity
of both neutrophils and MNC increased with effector to target cell (E:T) ratio (5–50:1) and mAb ch.14.18 dose (0.1–10 μg/ml).
ADCC of neutrophils, but not MNC, increased with addition of GM-CSF. Neutrophils, especially with rhGM-CSF, significantly
suppressed growth of GD2-positive cell lines at a high E:T ratio (50:1) and mAb dose (10 μg/ml). Without antibody, neutrophils
inhibited growth of one cell line (LA-N-1) but stimulated growth of two others (SMS-KCN, SMS-LHN). If neuroblastoma cells
did not express GD2 (SK-N-SH), neutrophils stimulated growth whether or not antibody was present. Neutrophil culture supernatants
increased growth of SK-N-SH, LA-N-1, and SMS-KCN cells, and MNC culture supernatants increased growth of SK-N-SH. In conclusion,
neutrophils can mediate cytotoxicity and growth inhibition with a chimeric anti-GD2 antibody but also can promote tumor cell
growth if antibody is not present or if GD2 is not expressed.
Received: 18 November 1998 / Accepted: 24 September 1999 相似文献
18.
Rob N. de Jong Frank J. Beurskens Sandra Verploegen Kristin Strumane Muriel D. van Kampen Marleen Voorhorst Wendy Horstman Patrick J. Engelberts Simone C. Oostindie Guanbo Wang Albert J. R. Heck Janine Schuurman Paul W. H. I. Parren 《PLoS biology》2016,14(1)
IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell–expressed antigen. 相似文献
19.
Spleen cell populations stimulated in vitro with as few as 1000 tumor cells produce cytotoxic effector cells. Syngeneic as well as allogeneic spleen cells respond to DBA mastocytoma tumor cells. There is a significant cellular immune response to allogeneic tumor cells 72 hr after exposure to antigen. By contrast, the response of DBA spleen cells to DBA mastocytoma tumor cells is first detectable at 120 hr following exposure to antigen. C57BL/6 spleen cells immunized against DBA mastocytoma antigen kill both DBA mastocytoma tumor cells and normal cells from DBA animals. DBA spleen cells immunized against DBA mastocytoma antigen kill only the DBA mastocytoma tumor cells, and not normal cells from DBA animals. 相似文献
20.
Spleen cells removed from immunized mice specifically kill allogeneic lymphoma cells in vitro, but in the presence of specific antigen nonspecific target cell growth inhibition also occurs. Only the specific target cell killing was found to be θ-sensitive, the nonspecific cytotoxicity was caused by a population of θ-resistant, adherent, and AMS-sensitive cells. Nonspecific cytotoxic effects were caused by spleen cells from normal mice after incubation with endotoxin, and these effects were inhibited by removal of the adherent cells. 相似文献