| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Immunology |
RI (CD64) and Fc
RI (CD89)1
Departments of Cell Biology/Immunology and Surgical Oncology, Vrije Universiteit, Amsterdam, the Netherlands [M. v. E.]; Department of Immunology [A. B. v. S., H. V., G. H., J. G. J. v. d. W.], Medarex Europe [A. B. v. S.], and Genmab [J. G. J. v. d. W.], University Medical Center Utrecht, Utrecht, the Netherlands; and Department of Pathology, Faculty of Veterinary Medicine, Utrecht, the Netherlands [E. v. G.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
RI, CD64) and IgA (Fc
RI, CD89), which are potent cytotoxic trigger molecules. Both receptors, however, require the FcR chain for signaling. In this study, we show that FcRI and FcRI can trigger function independently of one another and do not cross-compete for the FcR chain. FcRI proved more efficient in initiating early signaling events and effector functions, such as redirected tumor cell killing and generation of superoxide. In addition, simultaneous engagement of FcRI and FcRI resulted in enhanced tumor cell lysis. These data support the development of concepts in which both FcRI and FcRI on PMN cells are targeted for tumor therapy. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Both the class I receptors for IgG (FcRI, CD64) and IgA (FcRI, CD89) have been identified as candidate therapeutic targets (9, 10, 11)
. These receptors exhibit a myeloid-restricted cell distribution and potently trigger effector functions like phagocytosis and tumor cell lysis (12
, 13)
. PMN cells constitutively express FcRI and can be induced to express FcRI upon treatment with IFN- or G-CSF (2
, 14)
. We thus posed the question whether it would be feasible to use both receptors simultaneously as trigger molecules for immunotherapy.
Both FcR classes, however, associate with the promiscuous FcR chain signaling subunit and are dependent on this FcR chain for stable surface expression (15, 16, 17, 18, 19)
. Consequently, it is conceivable that FcRI and FcRI "cross-compete" for the FcR chain, which would hinder the possibility of using both receptors in immunotherapy. The aim of this study was, therefore, to determine whether both receptors can function independently, irrespective of (limiting amounts of) the FcR chain. Furthermore, we analyzed whether simultaneous engagement of FcRI and FcRI on PMN cells facilitates destruction of malignant cells.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
RI was detected with FITC-conjugated F(ab')2 fragments of CD89 mAb A77 (Medarex, Annandale, NJ) or PE-labeled CD89 mAb A59 (PharMingen, San Diego, CA). FITC-conjugated CD64 mAb 22 (Medarex) was used to determine FcRI expression. Mouse PMN cells were defined with PE-conjugated Gr-1 (PharMingen).
Fully human IgA1 antibodies targeting Ep-CAM were obtained by using phage display and engineering as described previously (20)
. BsAb FcRIxHER-2/neu (22x520C9; MDXH210), FcRIxHER-2/neu (A77x520C9), FcRIxHLA-II (22xF3.3), and FcRIxCD20 (A77x1F-5) were prepared as described in Ref. 21
. mAb 520C9 (Medarex) recognizes HER-2/neu, a proto-oncogene product overexpressed on human carcinoma cells. mAb 1F5 and mAb F3.3 are directed against CD20, and MHC class II antigens, respectively, and were a kind gift from Dr. M. Glennie (Tenovus Research Laboratory, Southampton, United Kingdom).
Flow Cytometry.
Whole blood of mice was incubated with mAb (10 µg/ml) for 15 min at room temperature and subjected to fluorescence-activated cell sorting lysing solution (Becton Dickinson, San Jose, CA). Human PMN cells (2 x 105), either freshly isolated or cultured overnight, were incubated with 22-FITC and A59-PE for 30 min at 4°C. Cells were analyzed on a FACScan (Becton Dickinson).
Tg Mice.
Generation of FcRI (22)
and FcRI (19)
Tg mice was described earlier. Briefly, FcRI Tg mice were generated by injection of an 18-kb human genomic DNA fragment into FVB/N oocytes. A 41-kb cosmid clone served as a Tg construct to create FcRI Tg mice. Both Tg mice expressed the human receptor solely on myeloid cells, which parallels the human situation. FcRI Tg males were crossed with FcRI Tg females to generate (FcRI x FcRI) double Tg (dTg) mice. Expression of transgenes was determined by flow cytometry of peripheral blood cells using anti-FcRI mAb 22-FITC and anti-FcRI mAb A77-FITC.
To induce FcRI expression on PMN cells and to increase PMN cell counts in blood, mice were injected s.c. with 1.6 µg/mouse/day murine G-CSF for 4 days (23)
.
Cell Culture.
Peripheral blood (heparin anticoagulated) from healthy volunteers was collected and PMN cells were isolated by Ficoll-Histopaque discontinuous gradient centrifugation. PMN cells were collected at the interface between Ficoll and Histopaque and the remaining erythrocytes were removed by hypotonic shock. Both purity of PMN cells and viability checked with trypan blue exceeded 95%.
The breast carcinoma cell line SK-BR-3, overexpressing HER-2/neu and the malignant B-cell line ARH-77 were obtained from the American Type Culture Collection (Manassas, VA). Cells were cultured in RPMI 1640 medium (Life Technologies, Inc., Grand Island, NY) supplemented with 10% FCS and antibiotics. SK-BR-3 cells were harvested using trypsin-EDTA (Life Technologies, Inc., Paisley, United Kingdom).
In culture experiments, human or mouse cells were cultured with human or mouse cytokines, respectively. Human PMN cells were cultured overnight at 37°C with IFN- (300 units/ml; Boehringer Mannheim, Mannheim, Germany) to induce FcRI expression. Mouse bone marrow cells were cultured in DMEM medium, supplemented with 4.5 g/liter glucose, 10% FCS, and antibiotics, with or without granulocyte macrophage colony-stimulating factor (GM-CSF, 50 ng/ml) and tumor necrosis factor (TNF-, 50 ng/ml), or IFN- (250 units/ml; Amgen, Thousand Oaks, CA). After 24 h, nonadherent cells were harvested and stained with A77-FITC or 22-FITC. Gr-1-PE was used to define mouse PMN. Dr. J. Andresen (Amgen) generously provided GM-CSF and G-CSF. TNF- was kindly donated by Dr. W. Buurman (University Maastricht, the Netherlands).
Cytotoxicity Experiments.
51Cr release assays were used to evaluate the capacity of effector cells to lyse tumor cells (24)
. Either 1 x 106 SK-BR-3 or 1 x 106 ARH-77 tumor cells were incubated with 150 µCi of 51Cr (Amersham, Little Chalfont, United Kingdom) for 2 h at 37°C and washed three times.
In "cold target inhibition experiments," 2.5 x 103 51Cr-labeled SK-BR-3 cells were plated with 2.5 x 103 unlabeled ARH-77 cells (or vice versa) in 96-well round-bottomed microtiter plates. Fifty microliters of whole blood of G-CSF-treated dTg mice were added (E:T ratio, 120:1). Alternatively, 50 µl of RPMI 1640 medium containing 3 x 105 (E:T ratio, 60:1), 6 x 105 (E:T ratio, 120:1), or 9 x 105 (E:T ratio,180:1) IFN--treated human PMN cells were added. BsAb-mediated tumor cell lysis of 51Cr-labeled targets was compared with lysis of the same cells in the presence of a BsAb directed against competing unlabeled cells.
In an additional set of experiments, 51Cr-labeled SK-BR-3 or 51Cr-labeled ARH-77 cells (5 x 103/well) were incubated with effector cells and increasing amounts of anti-FcRI BsAb, anti-FcRI BsAb, or both types of BsAb. Cells were incubated at 37°C for 6 h, after which 51Cr release in supernatants was measured.
Respiratory Burst Experiments.
Polystyrene tubes were coated with 100 µg/ml human serum IgA (Cappel, Aurora, OH), 100 µg/ml human IgG (CLB, Amsterdam, the Netherlands), or PBS for 3 h at 37°C. After washing three times with PBS, all tubes were blocked with HEPES complete [20 mM HEPES (pH 7.4), 132 mM NaCl, 6 mM KCl, 1 mM MgSO4, 1.2 mM NaH2PO4, 1 mM CaCl2, 5.5 mM glucose, 0.5% BSA, and 1.5 mM MgCl2] for 1 h at 37°C. The luminol-enhanced chemiluminescence method was used for determination of real-time respiratory burst activity (25)
. Human PMN cells (2 x 105/0.2 ml HEPES) were gently centrifuged (400 rpm, 5 min, 4°C) and placed in a 953 LB Biolumat (Berthold, Wildbad, Germany). Luminol (150 mM) was injected in all tubes, and light emission was recorded continuously for 30 min at 37°C.
Statistics.
Results were analyzed by means of the unpaired two-tailed Student’s t test (comparison experiments described in Fig. 6
) or ANOVA tests (combination experiments; Fig. 5
). Differences in competition experiments were analyzed by Wilcoxon rank sum tests (Fig. 4)
. Results are expressed as mean ± SE, and significance was accepted at P < 0.05.
|
|
|
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
RI and FcRI crucially depend on the FcR signaling chain for stable surface expression, we investigated whether these receptors "cross-compete" for the FcR chain. We first checked expression of FcRI and FcRI under various conditions. Freshly isolated human PMN expressed FcRI, but not FcRI (Fig. 1A
, left panel). To induce surface FcRI, PMN cells were incubated with IFN-. FcRI expression was up-regulated after 24 h (Fig. 1A
, right panel), whereas FcRI levels were unaffected (Fig. 1B)
. Because FcRI expression on human PMN cells is difficult to manipulate experimentally, we created mice Tg for human FcRI or human FcRI. It was previously shown that human FcRI and FcRI physically interact with the murine FcR chain (17
, 19)
and these Tg models enabled us to modulate receptor expression separately and in vivo. As described before (19
, 22)
, cell distribution patterns in Tg mice closely parallels the human situation; FcRI is constitutively expressed on monocytes and macrophages and induced on PMN cells by G-CSF or IFN- treatment (22)
. FcRI Tg mice constitutively express FcRI on PMN, whereas expression can be induced on macrophages by culture with GM-CSF and TNF- (19
, 26)
.
|
RI x FcRI) dTg mice with GM-CSF and TNF- enhanced FcRI expression levels (Fig. 2A
, top panels), whereas IFN- selectively induced FcRI expression (Fig. 2A
, bottom panels). Up-regulation of either receptor class, however, did not influence expression levels of the other class. No difference in FcRI expression was found between FcRI sTg and dTg PMN cells upon culture with GM-CSF/TNF-, although the latter PMN cells expressed increased levels of FcRI (Fig. 2B
, top right panel). Similarly, increased levels of FcRI after culture with IFN- did not affect FcRI expression levels (Fig. 2B
, bottom left panel).
|
RI was up-regulated on dTg PMN, whereas expression of FcRI was unaltered (Fig. 3A)
. Again, enhanced FcRI expression levels did not affect levels of FcRI (Fig. 3B
, left panel). In addition, PMN cells from dTg and FcRI sTg mice showed identical FcRI expression levels, indicating that FcRI does not affect expression of FcRI either (Fig. 3B
, right panel). In summary, FcRI and FcRI expression levels on resting and cytokine-stimulated PMN cells are comparable between sTg and dTg mice.
|
RI and FcRI require the FcR chain for proper function (15, 16, 17, 18, 19)
, we investigated whether the FcR chain preferentially interacts with either one of these receptors. For this purpose, we set up a cold target inhibition assay. Effector cells were incubated with a mixture of 51Cr-labeled target cells X and unlabeled target cells Y (Fig. 4A)
. Lysis of 51Cr(X), either in the absence (Fig. 4, B–D
, open columns) or presence (Fig. 4, B–D
, filled columns) of a BsAb targeting the competing unlabeled cell line Y, was measured after incubation for 6 h. IFN--treated human PMN cells (Fig. 4, B and C)
or whole blood of G-CSF-treated dTg animals (Fig. 4D)
were used as effector cells. When 51Cr-labeled ARH-77 was used as target cell line X and the unlabeled SK-BR-3 as Y, neither lysis via FcRI nor that via FcRI was influenced when BsAb directed against SK-BR-3 and the competing receptor were present (Fig. 4B)
. In the alternate case, with 51Cr-labeled SK-BR-3 as X and ARH-77 as Y, no differences in FcRI-mediated tumor cell lysis were observed, either in the absence or presence of BsAb targeting FcRI and ARH-77 (Fig. 4C
, left panel). In addition, at E:T ratios 120:1 or 180:1 FcRI-mediated lysis of 51Cr-labeled SK-BR-3 cell was unaffected in the presence of a BsAb targeting FcRI (Fig. 4C
, right panel). However, at E:T ratios of 60:1 tumor cell lysis was somewhat reduced. No differences in FcRI- or FcRI-mediated lysis of either cell lines were observed when whole blood of dTg mice was used as effector population (Fig. 4D)
. In an additional set of experiments in which 51Cr release was measured after 2 or 4 h of incubation, similar results were found (data not shown, n = 2).
Next, tumor cell kill upon simultaneous engagement of FcRI and FcRI was assessed. Maximal lysis of ARH-77 cell was observed with either 1 µg/ml BsAb FcRIxHLAII or FcRIxCD20, which was not increased in the presence of higher BsAb concentrations. Tumor cell lysis was, however, enhanced upon incubation with two targeting BsAb, relative to either one of them separately (Fig. 5A)
. Comparable data were obtained with whole blood of G-CSF-treated dTg mice (data not shown, n = 3). We, furthermore, investigated whether the observed reduction in FcRI-mediated tumor cell lysis upon engagement of FcRI at E:T ratios of 60:1 would abrogate this enhancement in tumor cell lysis. Since BsAb FcRIxCD20 did not induce tumor cell lysis at the E:T ratio 60:1 (data not shown), SK-BR-3 cells expressing both HER-2/neu and Ep-CAM were used. Because an IgA Ab targeting Ep-CAM was available (20)
, BsAb FcRIxHER-2/neu and IgA anti-Ep-CAM Ab were used in these experiments. Maximal lysis of SK-BR-3 tumor cells was observed in the presence of 0.4 µg/ml FcRIxHER-2/neu or 2.0 µg/ml IgA anti-Ep-CAM, and again enhanced tumor cell lysis was observed upon addition of two (bispecific) Abs, relative to addition of only one (Fig. 5B)
.
Notably, FcRI proved more efficient in triggering tumor cell kill than FcRI (Fig. 6, A and B)
. Therefore, the capacity of FcRI and FcRI to initiate PMN cell signaling was investigated. Cross-linking of FcRI resulted in a more rapid induction of rises in intracellular free calcium levels than cross-linking of FcRI (Fig. 6C)
. Initiation of respiratory burst activity was tested as a more distal signaling event using a sensitive chemiluminescence method. No PMN oxygen radical production was evoked when PBS/HEPES-coated tubes were used. Tubes coated with either IgA or IgG activated the PMN NADPH-oxidase complex, but respiratory burst activity was consistently higher with IgA-coated tubes (Fig. 6D)
. This was observed with a range of IgA and IgG concentrations (data not shown, n = 2).
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
RI and FcRI, because both are selectively expressed on myeloid effector cells which can easily be mobilized in vivo and potently trigger tumor cell lysis in vitro
(2
, 9
, 10
, 27) . Moreover, treatment with a combination of G-CSF and BsAb, targeting FcRI and idiotype, led to effective antitumor responses in lymphoma-bearing FcRI Tg mice, which were not observed in control mice (including treated nontransgenic litter mates) (28)
. Similarly, treatment of FcRI Tg mice with an anti-FcRI BsAb resulted in prolonged survival, compared with control mice (29)
.
A possible drawback of therapies engaging both FcRI and FcRI, however, may be the (limiting) amount of FcR chain in effector cells restricting simultaneous triggering via two FcR chain-dependent receptors (15, 16, 17, 18, 19)
. In the present work, however, no evidence was found that the FcR chain limits expression of FcRI or FcRI, neither in vitro nor in vivo. Up-regulation of FcRI did not result in decreased expression of FcRI and vice versa (Figs. 1
2
3
). Furthermore, cold target inhibition experiments showed that in most circumstances both receptors function independently of each other without any cross-competition for the FcR chain. Since BsAb targeting either HLA class II or HER-2/neu induced efficient tumor cell lysis, it is feasible that these BsAb induce maximal occupancy of receptors and associating FcR chain. In one situation, where FcRIxHER-2/neu and FcRIxHLAII BsAb were used at an E:T ratio 60:1, FcRI-mediated tumor cell lysis was somewhat reduced upon engagement of FcRI, suggesting competition for the FcR chain. No FcR chain competition was observed when FcRIxHER-2/neu and FcRIxCD20 BsAb were added, which is likely attributable to less efficient tumor cell lysis via BsAb targeting CD20 than HLA class II. This indicates that FcR chain cross-competition may occur in situations where both classes of receptors are maximally engaged, while numbers of effector cells are limited. However, at E:T ratios of 60:1 simultaneous triggering of both receptor classes still enhanced tumor cell killing (Fig. 5B)
, suggesting that even under these conditions only minimal FcR chain competition occurs.
Notably, earlier data in mast cells supported strong competition between Fc
RI and FcRIIIa for the FcR chain (30
, 31)
. It may, thus, be possible that differences exist between FcR chain levels in PMN cells versus mast cells or that expression of FcRI and FcRIIIa is more strictly regulated than expression of FcRI and FcRI. Additionally, in mast cells, FcRIIIa and FcRI exist as multisubunit complexes consisting of FcR ß chain and FcR signaling units (32)
. Rather than FcR chain, the FcR ß chain might, therefore, be limiting.
Since FcRI was capable of triggering early and late signaling events more potently than FcRI (Fig. 6
; Refs. 33
and 34
), it is conceivable that different signaling pathways are initiated upon either FcRI or FcRI cross-linking. Simultaneous engagement of both pathways may, therefore, amplify effector functions. The higher capacity of FcRI to initiate PMN cell activation might well be attributable to the presence of the positively charged amino acid (Arg209) in the transmembrane region of FcRI (18)
. Because the FcR signaling chain bears a negatively charged amino acid in its transmembrane region, we hypothesize that this results in a stronger association of the FcR chain with FcRI than with FcRI (which lacks such a positively charged amino acid) (15)
. Alternatively, it is possible that the increased number of tumor antigens bound by effector cells resulted in enhanced tumor cell lysis.
Whereas BsAb targeting FcRI and CD20 were reported unable to initiate Ab-dependent cellular cytotoxicity, tumor cells were lysed in the presence of BsAb targeting FcRI and CD20 (35)
. Also, in our experiments, FcRI proved more efficient in initiating tumor cell killing. An attractive feature of FcRI as target molecule, however, is the ability of this receptor to induce a "vaccine" effect. FcRI was shown to initiate efficient antigen presentation in vitro and in vivo
(22
, 36)
, and recently a unique motif for antigen presentation has been identified in its cytoplasmic tail (37)
. We, therefore, speculate that targeting to FcRI might induce a memory response to recirculating tumor cells. Indeed, FcRI Tg mice with lymphoproliferative disease injected with BsAb (targeting FcRI) were not only cured, but also protected against tumor rechallenge (28)
.
In conclusion, this study documents the FcR chain not to be limiting for either expression or function of FcRI or FcRI on PMN cells. Because of this, FcRI and FcRI can be simultaneously engaged for induction of cell lysis, resulting in improved tumor cell killing. Importantly, it was shown that IgA1 and IgG1 anti-Ep-CAM Abs do not synergize (20)
. This has been attributed to binding of IgG1 anti-Ep-CAM Abs to inhibitory FcRIIb (CD32) receptors on PMN cells, which would inhibit rather than enhance FcRI-mediated killing. The usage of BsAb, selectively targeting to activatory PMN FcR, would overcome this problem and may thus be a prerequisite for combined treatment. Moreover, whereas FcRI was shown to be more active in killing malignant cells, FcRI might more potently induce a vaccine response. Immunotherapy, involving combined engagement of FcRI and FcRI, may, therefore, constitute an attractive option for the treatment of malignant disorders.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by National Organization for Scientific Research Grant 901-12-214. 
2 To whom requests for reprints should be addressed, at Department of Immunology, University Medical Center Utrecht, KC.02-085.2, Lundlaan 6, 3584 EA Utrecht, the Netherlands. E-mail: j.vandewinkel{at}lab.azu.nl
3 The abbreviations used are: PMN, polymorphonuclear; G-CSF, granulocyte colony-stimulating factor; Ab, antibody; mAb, monoclonal Ab; BsAb, bispecific Ab; Tg, transgenic; dTg, double Tg; FcR, Fc receptor; GM-CSF, granulocyte macrophage colony-stimulating factor; sTg, single Tg; TNF-, tumor necrosis factor ; PE, phycoerythrin.
Received 2/24/00. Accepted 3/14/01.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
RI, CD64) in enhanced tumor cell cytotoxicity of neutrophils during G-CSF therapy. Blood, 82: 931-939, 1993.RI (CD89) as a novel trigger molecule for bispecific antibodies. Blood, 90: 4485-4492, 1997.RI (CD64) or FcRI (CD89) on neutrophils. J. Infect. Dis., 179: 661-669, 1999.[Medline]
R). Crit. Rev. Immunol., 16: 423-440, 1996.[Medline]
RI) with the subunit of the IgE receptor. Proc. Natl. Acad. Sci. USA, 90: 6023-6027, 1993.R) with FcRI2 subunits in U937 cells. J. Immunol., 153: 3228-3236, 1994.[Abstract]
chain is essential for both surface expression and function of human FcRI (CD64) in vivo. Blood, 87: 3593-3599, 1997. chain. J. Biol. Chem., 270: 29781-29787, 1995.RI, CD89) function in transgenic mice requires both FcR chain and CR3 (CD11b/CD18). Blood, 93: 4387-4394, 1999.RI/CD64 triggers enhanced antibody responses in transgenic mice. J. Clin. Investig., 97: 331-338, 1996.[Medline]
receptor I bispecific antibodies. J. Immunol., 159: 5629-5639, 1997.[Abstract]
R bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer. Cancer Res., 57: 696-701, 1997.RI, CD89) on transgenic peritoneal macrophages triggers phagocytosis and tumor cell lysis. Immunol. Lett., 68: 83-87, 1999.[Medline]
RI, CD89) and tumor antigens efficiently promote cell-mediated cytotoxicity of tumor targets in whole blood. J. Immunol., 160: 1677-1686, 1998.RI/CD64-directed bispecific antibodies in B-cell lymphoma. Blood, 96: 3544-3552, 2000. chain deletion results in pleiotrophic effector cell defects. Cell, 76: 519-529, 1994.[Medline]
RI chain results in upregulation of FcRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between FcRI and FcRIII for limiting amounts of FcR ß and chains. J. Clin. Investig., 99: 915-925, 1997.[Medline]
RI): from physiology to pathology. Annu. Rev. Immunol., 17: 931-972, 1999.[Medline]
R) determined by measurement of chemiluminescence induced by serum or secretory IgA1 or IgA2. Immunology, 17: 328-334, 1990.
R but not FcRIII trigger a respiratory burst in neutrophils, although both trigger an increase in intracellular calcium levels and degranulation. Biochem. J., 306: 519-523, 1995.
receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J. Immunol., 165: 5954-5961, 2000.RI-targeted fusion proteins result in efficient presentation by human monocytes of antigenic and antagonist T cell epitopes. J. Clin. Investig., 98: 2001-2007, 1996.[Medline]
RIa (CD64) ligand binding chain triggers major histocompatibility complex class II antigen presentation independently of its associated FcR chain. Blood, 15: 808-817, 1999.
This article has been cited by other articles:
|
|
 |
|
  M. A. Otten, J. H. W. Leusen, E. Rudolph, J. A. van der Linden, R. H. J. Beelen, J. G. J. van de Winkel, and M. van Egmond FcR {gamma}-Chain Dependent Signaling in Immature Neutrophils Is Mediated by Fc{alpha}RI, but Not by Fc{gamma}RI J. Immunol., September 1, 2007; 179(5): 2918 - 2924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Jafarshad, M. H. Dziegiel, R. Lundquist, L. K. Nielsen, S. Singh, and P. L. Druilhe A Novel Antibody-Dependent Cellular Cytotoxicity Mechanism Involved in Defense against Malaria Requires Costimulation of Monocytes Fc{gamma}RII and Fc{gamma}RIII J. Immunol., March 1, 2007; 178(5): 3099 - 3106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Bakema, S. de Haij, C. F. den Hartog-Jager, J. Bakker, G. Vidarsson, M. van Egmond, J. G. J. van de Winkel, and J. H. W. Leusen Signaling through Mutants of the IgA Receptor CD89 and Consequences for Fc Receptor {gamma}-Chain Interaction J. Immunol., March 15, 2006; 176(6): 3603 - 3610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Martin, R. Wallich, J. Pardo, A. Mullbacher, M. Munder, M. Modolell, and M. M. Simon Quiescent and activated mouse granulocytes do not express granzyme A and B or perforin: similarities or differences with human polymorphonuclear leukocytes? Blood, October 15, 2005; 106(8): 2871 - 2878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Otten, E. Rudolph, M. Dechant, C. W. Tuk, R. M. Reijmers, R. H. J. Beelen, J. G. J. van de Winkel, and M. van Egmond Immature Neutrophils Mediate Tumor Cell Killing via IgA but Not IgG Fc Receptors J. Immunol., May 1, 2005; 174(9): 5472 - 5480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schettini, G. Salamone, A. Trevani, S. Raiden, R. Gamberale, M. Vermeulen, M. Giordano, and J. R. Geffner Stimulation of neutrophil apoptosis by immobilized IgA J. Leukoc. Biol., October 1, 2002; 72(4): 685 - 691. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
) or Fc
), IgG (
). B, lysis of SK-BR-3 tumor cells by IFN-
). D, whole blood of G-CSF-treated dTg mice was used as effector population. Lysis of 51Cr(SK-BR-3) or 51Cr(ARH-77) tumor cells is shown in the left and right panel, respectively. 51Cr release from triplicate (human PMN) or duplicate (mouse blood) samples was measured after 6 h of incubation at 37°C. Data represent mean ± SE of three separate experiments. *, P < 0.05.
