scholarly journals Extracellular cytolysis by activated macrophages and granulocytes. I. Pharmacologic triggering of effector cells and the release of hydrogen peroxide.

1979 ◽  
Vol 149 (1) ◽  
pp. 84-99 ◽  
Author(s):  
C F Nathan ◽  
L H Brukner ◽  
S C Silverstein ◽  
Z A Cohn
Keyword(s):  
Trypan Blue ◽  
Response Curve ◽  
Target Cells ◽  
Activated Macrophages ◽  
Lymphoma Cells ◽  
Effector Cells ◽  
Proteose Peptone ◽  
Standard Assay ◽  
Different Types ◽  
J774 Cells

Lymphoma cells were rapidly lysed by activated macrophages and granulocytes in the presence of PMA. Release of 51Cr from lymphoma cells correlated closely with their destruction as viewed by scanning electron microscopy, and with reduction in the number of trypan blue-excluding cells. The standard assay involved 51 Cr release measured at 4.5 h, but injury appeared to be complete in 1 h. Of eight different types of effector cells tested, only those releasing abundant H2O2 in response to PMA were effective, that, is BCG-, C. parvum-, or casein-activated macrophages, or thioglycollate-elicited granulocytes. Normal macrophages, J774 cells, or macrophages elicited with thioglycollate broth or proteose-peptone were ineffective. BCG-activated macrophages and granulocytes caused 50% specific release of 51Cr from P388 lymphoma cells at E:T ratios between 1.4 and 4.5, and from mouse erythrocytes at E:T ratios of 0.017 to 0.025. 10 types of target cells varied widely in their susceptibility to lysis by reagent H2O2, with one-half maximal lysis occurring at H2O2 concentrations ranging from 3.63 X 10(-6) M to 3.85 X 10(-5) M. Effector cells were expected to generate approximately that much H2O2 during the period of injury. Susceptibility of the target cells to lysis by PMA-triggered granulocytes correlated closely with their sensitivity to H2O2 (r = 0.98). The membrane-active agents LPS and digitonin, which did not trigger H2O2 release, did not trigger cytotoxicity. The dose-response curve for triggering of H2O2 release by PMA was identical to that for triggering cytotoxicity. These results provided strong circumstantial evidence for the importance of H2O2 in extracellular cytolysis by activated macrophages and granulocytes when pharmacologically triggered.

scholarly journals Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity.

1979 ◽  
Vol 149 (1) ◽  
pp. 100-113 ◽  
Author(s):  
C F Nathan ◽  
S C Silverstein ◽  
L H Brukner ◽  
Z A Cohn
Keyword(s):  
Superoxide Dismutase ◽  
Spatial Relation ◽  
Target Cells ◽  
Activated Macrophages ◽  
Lymphoma Cells ◽  
Bacille Calmette Guerin ◽  
Effector Cells ◽  
Marked Inhibition ◽  
Necessary And Sufficient ◽  
Quench Singlet Oxygen

When deprived of oxygen, Bacille Calmette-Guérin (BCG)-activated macrophages no longer lysed P388 lymphoma cells. Both H2O2 release and cytotoxicity by BCG-activated macrophages and by granulocytes triggered with phorbol myristate acetate (PMA) were markedly inhibited when the glucose concentration in the medium was reduced to 0.03 mM or less, or if glucose were replaced with galactose. Catalase abolished PMA-triggered cytotoxicity by both types of effector cells, whereas superoxide dismutase had no effect. Ferricytochrome C reduced the cytotoxicity of BCG-activated macrophages, an effect which was largely reversed by superoxide dismutase. 10 drugs, thought to quench singlet oxygen and/or scavenge hydroxyl radical, did not affect cytotoxicity in this system. Neither azide nor cyanide reduced cytolysis, but there was marked inhibition by lactoperoxidase and iodide. This suggested that cytotoxicity was not dependent upon myeloperoxidase, and that lactoperoxidase may have diverted H2O2 from the oxidation of target cells to oxidation of substances in serum. Mouse erythrocytes, although sensitive targets, interfered with the cytolysis of lymphoma cells, probably by competition for H2O2. Starch particles with covalently bound glucose oxidase resembled macrophages in their spatial relation to the target cells and in the flux of H2O2 they generated from their surface, but were not expected to produce any other potentially toxic products. Such particles lysed lymphoma cells, and the lysis was prevented by catalase. Neither arginase nor thymidine appeared to be involved in cytolysis by BCG-activated macrophages under the conditions used. These findings demonstrated that release of H2O2 was both necessary and sufficient for cytolysis by BCG-activated macrophages and by granulocytes when pharmacologically triggered.

Monocyte Colony-Stimulating Factor Enhances Rituximab-Dependent Cellular Cytotoxicity by Monocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2533-2533
Author(s):  
Akiyoshi Takami ◽  
Shigeru Shimadoi ◽  
Yukio Kondo ◽  
Hirokazu Okumura ◽  
Shinji Nakao
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Lymphoma Cells ◽  
Effector Cells ◽  
Stimulating Factor

Abstract [Introduction] Recent data suggest that monocytes are the dominant effector cells during immunotherapy using the anti-CD20 monoclonal antibody rituximab, depleting B cells through FcγR-dependent pathways. Because monocyte colony-stimulating factor (M-CSF) enhances the antibody-dependent cellular cytotoxicity (ADCC) of monocytes, the clinical efficacy of rituximab might be improved by the addition of M-CSF. We have studied the effect of M-CSF in the enhancement of rituximab-mediated ADCC against B-cell lymphoma. [Methods] Monocytes were isolated by negative selection of PBMCs from healthy individuals for the absence of T-cell, B-cell, and NK-cell markers. Cytotoxicity was determined by a flow cytometry using two fluorescent dyes, calcein-AM and ethidium homodimer to specifically stain living and dead cells respectively. Monocytes were cultured for 48 hours in the presence or absence of human recombinant M-CSF (66 ng/ml). The B-cell lymphoma cell line Daudi was used as target in the presence of rituximab (5 μg/ml) or human IgG1 as control for 30 min at room temperature. Effector cells and target cells were incubated at different ratios ranging from 1:1 to 15:1 for 4 hours at 37°C. The expression of FcγRl, FcγRII, and FcγRIII on monocytes was determined using a flow cytometry. [Results] Monocytes treated with M-CSF showed a significant increase in rituximab-mediated cytotoxicity against B lymphoma cells: specific lysis at an E:T ratio of 15:1 was 39% ± 7% (mean ± SD) vs. 21% ± 5%, M-CSF-treated monocytes vs. non-treated monocytes. Lysis of lymphoma cells treated with rituximab alone was 8% ± 4%. Treatment with M-CSF led to a 1.5- to 2.0-fold increase of FcγRI and FcγRIII expression in monocytes, while FcγRII expression remained unchanged. [Conclusion] Pretreatment of monocytes with M-CSF enhances their rituximab-mediated ADCC against B-cell lymphoma, which may partly result from increasing expression of FcγRI and FcγRIII on monocytes via M-CSF stimulation. These in vitro results may provide a new approach to improve the therapeutic activity of rituximab.

scholarly journals Cytotoxicity of interleukin 2-activated lymphocytes for leukemia and lymphoma cells

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 938-948
Author(s):  
K Oshimi ◽  
Y Oshimi ◽  
M Akutsu ◽  
Y Takei ◽  
H Saito ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Target Cells ◽  
Lymphoma Cells ◽  
Peripheral Blood Mononuclear ◽  
Primary Tumors ◽  
Effector Cells ◽  
Lak Activity

Studies were undertaken to determine whether leukemia and lymphoma cells would be lysed by autologous and allogeneic lymphokine-activated killer (LAK) cells. Peripheral blood mononuclear cells (PBMC) from patients and normal donors were cultured for five days, 2 weeks, and 4 weeks with medium containing 2,500 units of recombinant interleukin 2 (IL-2) per mL, and their cytotoxicity was assayed by a five-hour 51Cr- release test. Of primary tumors isolated from patients with acute nonlymphoblastic leukemia, acute lymphoblastic leukemia, and non- Hodgkin's lymphoma, tumors of 37 out of 40 patients tested were shown to be susceptible to normal donors' LAK, and tumors of 18 of 20 patients tested were shown to be susceptible to autologous LAK. LAK cultured for longer periods showed a tendency to have lower cytotoxicity. LAK had also low, but significant, levels of cytotoxicity for nonmalignant target cells. Because PBMC expanded in IL-2-containing medium consisted mainly of OKT3-positive pan T cells, OKT8-positive suppressor/cytotoxic cells, and Leu-11-positive natural killer (NK) cells, and treatment with OKT3 and Leu-11 monoclonal antibodies (mAb) reduced LAK activity for autologous and allogeneic tumor cells, both T and NK cells appeared to be effector cells for LAK activity. Mechanisms of target-cell recognition in the LAK system seem to be different from those in alloreactive cytotoxic T lymphocytes (CTL) based on the results that, while cytotoxicity of alloreactive CTL was inhibited by the treatment of effector cells with mAb, OKT3, and OKT8, and by the treatment of target cells with a mAb that reacts with HLA class I antigen, LAK activity was not inhibited by the above treatment. When chromosomes of IL-2-expanded PBMC in nine patients and two normal individuals were analyzed, PBMC from one patient showed chromosomes of clonal abnormalities, and PBMC from five donors showed those of nonclonal abnormalities.

scholarly journals Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages

1980 ◽  
Vol 152 (1) ◽  
pp. 198-208 ◽  
Author(s):  
C Nathan ◽  
Z Cohn
Keyword(s):  
Hydrogen Peroxide ◽  
Cytochalasin B ◽  
Starch Granules ◽  
Activated Macrophages ◽  
Myristate Acetate ◽  
Lymphoma Cells ◽  
Bacille Calmette Guerin ◽  
Effector Cells ◽  
Hydrogen Peroxide Release

The alloantiserum-dependent lysis of TLX9 lymphoma cells by peritoneal cells from Bacille Calmette-Guerin (BCG)-treated mice was inhibited 62 percent by depletion of oxygen. This effect did not appear to be a result of interference with mitochondrial respiration because cyanide, azide, and dinitrophenol did not inhibit cytotoxicity. Preincubating the effector cells for 2 h without glucose, which markedly reduces their ability to release hydrogen peroxide, likewise suppressed antibody-dependent cytolysis by 62 percent. Lysis of sensitized lymphoma cells was virtually abolished by 6 mg/ml of thioglycollate broth, a concentration that also abrogated the detectable release of hydrogen peroxide and the lysis of lymphoma cells by BCG-activated macrophages in response to phorbol myristate acetate (PMA). This concentration of thioglycollate broth was not toxic to the effector cells, as judged by adherence to plastic, binding of opsonized erythrocytes, and phagocytosis of radiolabeled starch granules. Catalase, superoxide dismutase, horseradish peroxidase, mannitol, ethanol, benzoate, and diazabicyclooctane were without consistent effects. Cytochalasin B and dihydrocytochalasin B both markedly suppressed cytolysis, whether induced by antibody or by PMA (ID(50), 0.5 μg/ml). Cytoehalasin B was an equally potent suppressor of glucose uptake and PMA-induced hydrogen peroxide release by BCG-activated macrophages (ID(50), 0.5 μg/ml). However, dihydrocytochalasin B lacked these latter effects, which suggests that cytotoxicity required intact contractile elements. The extracellular lysis of antibody-coated lymphoma cells by BCG-activated macrophages appears to have a predominantly oxidative basis.

Cytotoxicity of interleukin 2-activated lymphocytes for leukemia and lymphoma cells

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 938-948 ◽  
Author(s):  
K Oshimi ◽  
Y Oshimi ◽  
M Akutsu ◽  
Y Takei ◽  
H Saito ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Target Cells ◽  
Lymphoma Cells ◽  
Peripheral Blood Mononuclear ◽  
Primary Tumors ◽  
Effector Cells ◽  
Lak Activity

Abstract Studies were undertaken to determine whether leukemia and lymphoma cells would be lysed by autologous and allogeneic lymphokine-activated killer (LAK) cells. Peripheral blood mononuclear cells (PBMC) from patients and normal donors were cultured for five days, 2 weeks, and 4 weeks with medium containing 2,500 units of recombinant interleukin 2 (IL-2) per mL, and their cytotoxicity was assayed by a five-hour 51Cr- release test. Of primary tumors isolated from patients with acute nonlymphoblastic leukemia, acute lymphoblastic leukemia, and non- Hodgkin's lymphoma, tumors of 37 out of 40 patients tested were shown to be susceptible to normal donors' LAK, and tumors of 18 of 20 patients tested were shown to be susceptible to autologous LAK. LAK cultured for longer periods showed a tendency to have lower cytotoxicity. LAK had also low, but significant, levels of cytotoxicity for nonmalignant target cells. Because PBMC expanded in IL-2-containing medium consisted mainly of OKT3-positive pan T cells, OKT8-positive suppressor/cytotoxic cells, and Leu-11-positive natural killer (NK) cells, and treatment with OKT3 and Leu-11 monoclonal antibodies (mAb) reduced LAK activity for autologous and allogeneic tumor cells, both T and NK cells appeared to be effector cells for LAK activity. Mechanisms of target-cell recognition in the LAK system seem to be different from those in alloreactive cytotoxic T lymphocytes (CTL) based on the results that, while cytotoxicity of alloreactive CTL was inhibited by the treatment of effector cells with mAb, OKT3, and OKT8, and by the treatment of target cells with a mAb that reacts with HLA class I antigen, LAK activity was not inhibited by the above treatment. When chromosomes of IL-2-expanded PBMC in nine patients and two normal individuals were analyzed, PBMC from one patient showed chromosomes of clonal abnormalities, and PBMC from five donors showed those of nonclonal abnormalities.

scholarly journals Mechanistic Characterization of Tafasitamab-Mediated Antibody-Dependent Cellular Phagocytosis Alone or in Combination with Lenalidomide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4064-4064
Author(s):  
Dimitrios Mougiakakos ◽  
Simon Voelkl ◽  
Christian Bach ◽  
Andrej Stoll ◽  
Katrin Bitterer ◽  
...  
Keyword(s):  
B Cell ◽  
B Cell Lymphoma ◽  
Receptor Expression ◽  
Target Cells ◽  
B Cell Malignancies ◽  
Lymphoma Cells ◽  
Tumoricidal Activity ◽  
Effector Cells ◽  
Immunomodulatory Agent ◽  
Significant Difference

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Approximately 60% of DLBCL patients can be cured using standard chemotherapy, including an anti-CD20 antibody (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). However, 40% of DLBCL patients have refractory disease or experience relapse. This highlights the need for more effective therapies for this subset of relapsing or refractory patients. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal anti-CD19 antibody, currently in clinical development in patients with relapsed or refractory (r/r) DLBCL in combination with either the immunomodulatory drug lenalidomide (LEN) (L-MIND study) or the chemotherapeutic agent bendamustine (B-MIND study). The B-lymphocyte antigen CD19 is broadly and homogeneously expressed throughout B-cell development and across different B-cell malignancies, including DLBCL. CD19 has been reported to enhance B-cell receptor signaling, which is assumed important for B-cell survival. This makes CD19 a promising therapeutic target in B-cell malignancies. Macrophages are abundant in the bone marrow stroma and lymph nodes of lymphoma patients. These lymphoma-associated macrophages (LAMs) support proliferation, survival, and drug resistance of lymphoma cells; therefore, serving a tumor-promoting function (Farinha et al, Blood, 2005). However, macrophages can also act as immune effector cells for antitumor effects exerted by therapeutic monoclonal antibodies, like tafasitamab. Given their abundance in DLBCL, an attractive therapeutic approach would be to stimulate their tumoricidal activity in order to promote antitumor immunity. Consequently, the immunomodulatory agent LEN has the potential to synergize with tafasitamab by enhancing antibody dependent cellular phagocytosis (ADCP). Here, we demonstrate that monocyte-derived macrophages and isolated LAMs from DLBCL patients can kill lymphoma cell lines and autologous lymphoma cells by tafasitamab-mediated phagocytosis. Tafasitamab-mediated ADCP activity was correlated with FcγRIII/FcγRI levels and inversely correlated with SIRPα expression on macrophage/effector cells (Spearman r between 0.51 and 0.62). Analyzing immune checkpoint receptor expression on LAMs of DLBCL patients, we found increased expression of VISTA, SLAMF7 and SIRPα compared with normal macrophages from healthy volunteers (VISTA: 2.8-fold, p=0.0006; SLAMF7: 2.9-fold, p=0.03; SIRPα: 1.8-fold, p=0.04). In contrast, we found no significant difference in FcγR expression (CD16: 1.4-fold, p=0.12; CD32: 1.3-fold, p=0.32; CD64: 1.2-fold, p=0.12). Moreover, pretreatment with lenalidomide showed a 3 to 5-fold enhanced tafasitamab-mediated cytotoxicity by macrophages and isolated LAMs (Figure 1A). Of note, the increased cytotoxicity was tafasitamab-specific and neither attributable to direct cytotoxic effects of LEN, nor increased CD19 expression on target cells. In addition, LEN treatment decreased the expression of SIRPα on macrophages (control vs. LEN: 3,117±652 MFI [mean fluorescent intensity] vs 2,327±610 MFI) (Figure 1B). This suggests that the CD47-SIRPα pathway may be suppressed by downregulation of SIRPα by LEN, contributing to the observed ADCP enhancement. These results suggest that tafasitamab leverages the presence of tumor-promoting LAMs as effector cells. The inherent ADCP activity of tafasitamab can be further improved by the immunomodulatory agent LEN, potentially via reduction of SIRPα levels on macrophages. Finally, our results provide a rationale for targeting the CD47-SIRPα axis that should be further explored in preclinical and clinical studies. Figure 1 Disclosures Endell: MorphoSys AG: Employment, Patents & Royalties. Boxhammer:MorphoSys AG: Employment, Patents & Royalties. Bruns:Morphosys AG: Research Funding.

scholarly journals NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1420
Author(s):  
Jagoda Siemaszko ◽  
Aleksandra Marzec-Przyszlak ◽  
Katarzyna Bogunia-Kubik
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Bacterial Infections ◽  
Killer Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Effector Cells ◽  
Stressed Cells ◽  
The Right ◽  
Nkg2d Receptor

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

scholarly journals Cell-mediated lympholysis to H-2-matched target cells modified with a series of nitrophenyl compounds.

1976 ◽  
Vol 144 (4) ◽  
pp. 1134-1140 ◽  
Author(s):  
T G Rehn ◽  
J K Inman ◽  
G M Shearer
Keyword(s):  
T Cell ◽  
Target Cells ◽  
Cell Recognition ◽  
Receptor Model ◽  
Spleen Cells ◽  
Effector Cells ◽  
T Cell Recognition ◽  
Cytotoxic Effector

The specificity of C57BL/10 cytotoxic effector cells generated by in vitro sensitization with autologous spleen cells modified with a series of related nitrophenyl compounds was investigated. The failure of trinitrophenyl (TNP)-sensitized effector cells to lyse TNP-beta-alanylglycylglycyl(AGG)-modified target cells is presented as evidence contradicting the intimacy or dual receptor model or T-cell recognition in its simplest form. Data are also shown indicating that sensitization with N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-AGG-modified stimulating cells generates noncross-reacting clones of cytotoxic effector cells.

scholarly journals Modulation of phagosome-lysosome fusion in mouse macrophages.

1981 ◽  
Vol 153 (4) ◽  
pp. 1015-1020 ◽  
Author(s):  
M C Kielian ◽  
Z A Cohn
Keyword(s):  
Concanavalin A ◽  
Immune Serum ◽  
Cross Linking ◽  
Activated Macrophages ◽  
Enzymatic Modification ◽  
Inflammatory Agent ◽  
Proteose Peptone ◽  
Mouse Macrophages ◽  
Control Fusion ◽  
Rate Limiting

A previously described fluorescence assay has been used to characterize factors that modulate phagosome-lysosome (P-L) fusion in mouse macrophages. Fusion was not affected by enzymatic modification or by concanavalin A cross-linking of the plasma membrane or by coating the phagocytic particle with concanavalin A or immune serum. Pretreatment of cells with 10-5-10-4 M colchicine, or treatment immediately after ingestion with 1-10 microgram/ml cytochalasin did not alter P-L fusion; implying that the cytoskeleton does not control fusion in a rate-limiting way. Fusion was strikingly elevated in 5-h cultures of activated macrophages from immune-boosted mice. A lower enhancement was seen in cells activated by proteose-peptone, a nonspecific inflammatory agent.

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