Rat and Human Natural Killers Exhibit Contrasting Immunoglobulin G Subclass Specificities in Antibody-Dependent Cellular Cytotoxicity Reflecting Differences in Their Fc Receptors (FcγR)

Song, Elizabeth S.; Young, Katie; Sears, Duane W.

doi:10.1002/jlb.48.6.524

Cited by 11 publications

(7 citation statements)

References 37 publications

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“…The IgG subclass specificities of mouse and rat phagocytic cells FcγR are likely to be more similar to each other (Song et al . ). FcγRII lack phagocytic activity (Takai et al .…”

Section: Discussionmentioning

confidence: 97%

Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia

Morkūnienė

Žvirblienė

Dalgėdienė

et al. 2013

Journal of Neurochemistry

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Beta amyloid (Ab) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease. However, clinical trials using Ab immunization were unsuccessful due to strong brain inflammation, the mechanisms of which are poorly understood. In this study we tested whether monoclonal antibodies to oligomeric Ab would prevent the neurotoxicity of Ab oligomers in primary neuronal-glial cultures. However, surprisingly, the antibodies dramatically increased the neurotoxicity of Ab. Antibodies bound to monomeric Ab fragments were non-toxic to cultured neurons, while antibodies to other oligomeric proteins: hamster polyomavirus major capsid protein, human metapneumovirus nucleocapsid protein, and measles virus nucleocapsid protein, strongly potentiated the neurotoxicity of their antigens. The neurotoxicity of antibodyoligomeric antigen complexes was abolished by removal of the Fc region from the antibodies or by removal of microglia from cultures, and was accompanied by inflammatory activation and proliferation of the microglia in culture. In conclusion, we find that immune complexes formed by Ab oligomers or other oligomeric/ multimeric antigens and their specific antibodies can cause death and loss of neurons in primary neuronal-glial cultures via Fc-dependent microglial activation. The results suggest that therapies resulting in antibodies to oligomeric Ab or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation.

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“…The IgG subclass specificities of mouse and rat phagocytic cells FcγR are likely to be more similar to each other (Song et al . ). FcγRII lack phagocytic activity (Takai et al .…”

Section: Discussionmentioning

confidence: 97%

Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia

Morkūnienė

Žvirblienė

Dalgėdienė

et al. 2013

Journal of Neurochemistry

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“…Even though 4A5 binds to ROR1 with nearly an order of magnitude higher affinity than D10, this mAb is less effective in inhibiting the growth of ROR1 × TCL1 leukemia cells in vivo. It appears unlikely that this is due to differences in antibody subclass, as the heavy chain constant region isotype of D10 or 4A5 is IgG2 a or IgG2 b , respectively, each of which could direct antibody-dependent cellular cytotoxicity (36)(37)(38). Instead we hypothesize that the activity of each mAb also may be influenced by how each mAb binds to ROR1, which The bars represent the mean number for each group ± SEM; n = 3; *P < 0.05, **P < 0.01, compared with the mIgG group, as calculated using the Student t test.…”

Section: Discussionmentioning

confidence: 99%

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

Widhopf¹,

Cui²,

Ghia³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell-restricted expression of ROR1 and could develop clonal expansions of ROR1 bright CD5 + B220 low B cells resembling human CLL at ≥15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eμ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5 + B220low B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1. Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell-cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of K i -67-positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL. mouse model | monoclonal antibody | AKT | immune therapy R eceptor tyrosine kinase-like orphan receptor 1 (ROR1) is a type 1 tyrosine kinase surface protein expressed on chronic lymphocytic leukemia (CLL) B cells, but not on nonmalignant postpartum tissues (1). Expression of ROR1 ordinarily is confined to early embryogenesis, where it contributes to organogenesis (2-4). However, ROR1 is not detected on postpartum tissues, including hematopoietic stem cells, except on a small subset of B-cell precursors, called hematogones (5). We and others have found ROR1 expressed on the neoplastic cells of patients with CLL (1, 6, 7), other B-cell lymphomas (8), acute leukemias (5, 9), and on any one of a variety of solid tumors (10-13). However, it still is uncertain whether ROR1 plays a role in cancer development and/or disease progression.ROR1 has an extracellular domain that is essential for ligand binding and potentially for intracellular signaling (14). Although it has a putative kinase domain, ROR1 might function as a pseudokinase, serving instead as a cofactor for other signaling proteins (13). We found that ROR1 could serve as a receptor for Wnt5a, which could provide a survival/growth signal to CLL cells from the microenvironment (1). Also, ROR1 could enh...

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“…However, these data could also represent antibody-dependent cellular cytotoxicity of tumor cells by host antigen-presenting cells. 29,30 Tumors consist of a heterogeneous population of cells, including tumor cells, endothelial cells, fibroblasts and immune cells, such as PMNs and macrophages. Recent evidence suggests that immune cell infiltration can either antagonize tumor growth via immune surveillance or promote tumor growth and metastasis via immune enhancement.…”

Section: Discussionmentioning

confidence: 99%

Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts

Roland

Dineen

Toombs

et al. 2010

Exp Biol Med (Maywood)

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Tumor infiltration of immune cells (polymorphonuclear cells [PMNs] and macrophages) was initially thought to be an attempt by the host organism to combat malignancy. It appears, however, that certain subsets of chronically activated immune cells likely promote tumor growth, facilitate tumor cell survival and aid in metastasis. The association between tumor cells and tumor-associated PMNs has been demonstrated in several types of cancer, but the presence of tumor-associated PMNs in pancreatic cancer has not been well studied in vivo. Intercellular adhesion molecule-1 (ICAM-1) functions in cell-cell and cell-extracellular matrix adhesion and has a physiological role in PMN tight adhesion of leukocytes via interaction with the ligands LFA-1 and Mac-1. Increased ICAM-1 expression correlates with poor prognosis in pancreatic cancer. Therefore, the aim of this study was to investigate the function of ICAM-1 and tumor-associated PMNs in pancreatic cancer progression using ICAM-1-null (ICAM-1(-/-)) mice. We hypothesize that ICAM-1 null mice have decreased pancreatic cancer progression. Surprisingly, there is no significant difference in pancreatic cancer progression in wild-type versus ICAM-1 null mice. Interestingly, we found that tumor-derived ICAM-1 co-localizes with host PMNs at the leading edge of the tumor in ICAM-1 null mice. These results suggest that tumor-derived ICAM-1 is a sufficient ligand for tumor-associated PMNs and may play a role in subsequent tumor growth and metastasis.

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Rat and Human Natural Killers Exhibit Contrasting Immunoglobulin G Subclass Specificities in Antibody-Dependent Cellular Cytotoxicity Reflecting Differences in Their Fc Receptors (FcγR)

Cited by 11 publications

References 37 publications

Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia

Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts

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