Department of Cell Biology and Molecular Genetics, University of Maryland, College Park
Correspondence: David M. Mosser, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742. E-mail: dm268{at}umail.umd.edu
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. However, when antigen was targeted to Fc receptors on these macrophages, their phenotype changed, and they now induced a T cell response that was predominated by IL-4. The initial biasing by activated macrophages toward a Th1-like response was a result of activation of the innate immune response, as macrophages from MyD88-/- mice failed to produce Th1-inducing cytokines. The reversal of the Th1 biasing was a result of FcR ligation, as macrophages lacking the FcR common chain failed to reverse this biasing. To show that this biasing could occur in vivo, mice were injected with activated macrophages or activated macrophages whose FcR had been ligated with an irrelevant immune complex. Mice injected with FcR-ligated macrophages made more antibody than those receiving conventionally activated macrophages, and the antibody was predominantly of the IgG1 isotype. These studies demonstrate that FcR ligation on activated macrophages can change the phenotype of these APCs to cells that preferentially drive a Th2-like response. We have termed these cells type 2 activated macrophages.
Key Words: cytokines • T cells • Th-2 • IL-4 • IL-10 • immune deviation
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(IFN-) [4
]. Th2 cells, in contrast, are often associated with humoral immunity and are characterized by the production of IL-4, IL-5, and IL-13 [4
]. Numerous factors are known to influence CD4+ cell differentiation; however, the dominant influence may be the cytokine environment in which the activated T cell develops [5
]. IL-12 is a proinflammatory cytokine and is considered to be an important inducer of Th1 cells [3
]. This cytokine is produced primarily by macrophages, dendritic cells, and granulocytes and is essential for cell-mediated immune responses [6
]. The prototypic Th2-inducing cytokine is IL-4. Mice lacking IL-4 fail to induce Th2-like responses to infection [7
], and the induction of IL-4 correlates with Th2-like responses to antigen [5
].
The identification of Toll-like receptors (TLRs) and their ligands has provided insight into the host response to microbes and microbial products [8
, 9
]. Ligation of TLRs results in recruitment of IL-1 receptor-associated kinase and tumor necrosis factor receptor-associated factor 6 through interaction with the adaptor protein MyD88. The signaling pathway leads to translocation of nuclear factor-
B and activation of mitogen-activated protein kinases [10
, 11
]. This results in the transcription of several immune response genes. Recent studies have focused on the importance of these innate immune responses in determining the fate of an adaptive response [12
]. These studies demonstrated that TLR-dependent innate immunity can preferentially induce Th1-like responses. We have recently demonstrated that immune complexes can preferentially promote Th2-like responses [13
], and we implicated the Fc receptors in this process.
The receptors for the Fc portion of immunoglobulin G (IgG; FcR) are expressed on numerous cells of hemopoietic origin, allowing cells to respond to the products of an adaptive immune response. Three different classes of FcR exist on murine macrophages. The FcRI and FcRIII consist of 
chains associated with a signaling chain that contains a tyrosine-based activation motif. The low-affinity murine FcRII consists of an chain that contains an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic region (reviewed in ref [14
]). In a series of studies, we have demonstrated that the ligation of FcR on macrophages in conjunction with inflammatory stimuli can influence the kinetics, quantity, and character of cytokine production [15
16
17
]. Whereas microbial stimuli alone induced macrophages to produce high levels of IL-12 and only moderate levels of IL-10, the addition of immune complexes together with the inflammatory stimulus resulted in a reversal of the production of these two cytokines [16
17
18
]. These two cytokines are diametrically opposed in their action. Whereas IL-12 is an inducer of a Th1 response, IL-10 exerts immunosuppressive effects on macrophages, preventing macrophage activation and diminishing inflammatory cytokine production [19
, 20
, 21
].
In the present work, we examined the extent to which activated macrophages could influence T cell biasing. We show that activated macrophages produced IL-12 in response to innate activation and induced a Th1 response. However, when immune complexes were added to these cells, they produced IL-10 and shifted the T cell response to a Th2 response. This reversal of the Th1 response was dependent on signaling through the FcR chain, as macrophages from mice deficient in the chain failed to induce a shift toward a Th2 phenotype.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ß for ovalbumin (OVA)323–339, were purchased from the Jackson Laboratories (Bar Harbor, ME) and were used as a source of antigen specific CD4+ cells. Breeder pairs of mice deficient in the FcR chain [23
] on a BALB/c background were purchased from Taconic (Germantown, NY). Mice deficient in MyD88 [24
] were generated by Dr. Shizuo Akira (Osaka University, Japan), and generously provided by Dr. Douglas Golenbock (University of Massachusetts Medical School, Worcester).
Macrophage activation
Macrophages were prepared from the bone marrow progenitors as described previously [15
]. Briefly, bone marrow was flushed from the femurs of 6- to 8-week-old mice and plated in petri dishes with Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum (FCS), glutamine, Pen/Strep, and 20% conditioned medium from macrophage colony-stimulating factor-secreting L929 cells. Media was replaced at day 6. Ten- to 12-day-old macrophages were used for experiments. Bone marrow-derived macrophages were activated by priming with 100 U/ml recombinant IFN- (R&D Systems, Minneapolis, MN) overnight. Cells were then washed three times and activated with 10 ng/ml lipopolysaccharide (LPS; Escherichia coli, 0127:B8, Sigma Chemical Co., St. Louis, MO) and either 150 µg/ml OVA (Sigma Chemical Co.) or IgG-OVA immune complexes. Immune complexes were made by mixing a tenfold molar excess of rabbit anti-OVA IgG (Cappel, Durham, NC) to OVA for 30 min at room temperature. In some cases, IgG-opsonized erythrocytes were used for FcR ligation and were generated as described previously [17
]. Briefly, sheep erythrocytes (Lampire, Piperesville, PA) were incubated with rabbit anti-sheep erythrocyte IgG (Cappel) at nonagglutinating titers for 40 min, washed, and added to cultures at a red blood cell:macrophage ratio of 10:1.
T cell stimulation assays
CD4+ cells were prepared from the spleens of DO11.10 mice by immunomagnetic positive selection using anti-CD4 (L3T4) microbeads (Miltenyi Biotec, Auburn, CA). Cells were >95% CD4+CD45RBhi as determined by flow cytometry. In the secondary response, >95% of the cells were positive for CD4. For primary stimulation assays, 2 x 105 macrophages were plated per well in a 48-well plate and activated as described above. Three hours following stimulation of macrophages, 5 x 105 CD4+ T cells were added to each well in a total volume of 0.6 ml RPMI 1640 (Cellgro, Herndon, VA) supplemented with 10% FCS, HEPES, Na Pyruvate Pen/Strep, and 50 µM 2-mercaptoethanol. Four days following primary stimulation, fresh RPMI was added with 10 U/ml IL-2 to maintain cell viability. Seven days following the primary stimulation, cells were removed from culture, washed, counted, and added to 3 x 105 fresh macrophages or immobilized anti-CD3 (BD Pharmingen, San Diego, CA), which was prepared by adding 5 µg/ml anti-CD3 in phosphate-buffered saline overnight. After 24 h, cytokines were measured by either enzyme-linked immunosorbent assay (ELISA) or intracellular staining.
Cytokine measurement
Cytokines were measured by sandwich ELISA using antibody pairs provided by BD Pharmingen (San Jose, CA) (IL-12p70, 9A5, and C17.8; IL-10, JES-2A5, and JES-16E3; IFN-, R4-6A2, and XMG1.2; IL-4, 11B11, and BVD6-24G2) according to the manufacturer’s instructions. Intracellular staining was performed on secondarily stimulated T cells using Pharmingen Cytofix/Cytoperm kit (#2076KK). Cells were washed and stained with fluorochrome-conjugated antibodies to IL-4 (11B11) and IFN- (R4-6A2). Cells were analyzed on a Becton Dickinson FACSCalibur flow cytometer. Quadrants were set to an isotype control antibody for analysis.
Macrophage transfer experiments
For passive transfer studies, macrophages were primed for 6 h with IFN- and stimulated in vitro with 10 ng/ml LPS or LPS + erythrocytes opsonized with IgG (E-IgG) for 1 h. After washing, a total of 2 x 106 macrophages was injected intraperitoneally (i.p.) into mice, which were immunized with 50 µg OVA in the absence of adjuvant. Ten days later, this procedure was repeated. Mice were bled 9 days after the second immunization. For Ig determinations, plates were coated with 10 µg/mL OVA overnight and then incubated with serum followed by alkaline phosphatase-conjugated goat anti-mouse Ig (H+L), IgG1, or IgG2a (Southern Biotechnology Associates, Birmingham, AL). OVA-specific antibody titers were determined as the final dilution of sera that yielded an optical density (OD) value at 405 nm in excess of 0.1.
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and then stimulating with low levels of bacterial LPS. These activated wild-type (WT) macrophages made relatively high levels of biologically active IL-12 (Fig. 1A
, left) but only modest levels of IL-10. The second population of macrophages was activated in the same way but also given E-IgG to ligate their FcR at the time of LPS stimulation. The cytokine profile of these macrophages was altered dramatically (Fig. 1A
, left). Following FcR ligation, IL-12 levels decreased to near undetectable levels, and IL-10 levels were increased dramatically, as described previously with macrophages from BALB/c mice [13
, 17
]. To show that macrophage cytokine production depended on innate recognition mediated by TLRs, similar studies were performed with macrophages from mice lacking MyD88. Macrophages from these mice failed to produce IL-12 in response to LPS (Fig. 1A
, right) and made minimal IL-10. The amount of IL-10 that was produced was at the limit of detection of the assay, and it was not increased following FcR ligation. Therefore, IL-12 production and the induction of IL-10 following FcR ligation depend on innate activation through MyD88.
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Figure 1. Cytokine production by activated macrophages. (A) Bone marrow-derived macrophages from WT C57BL/6 (left) or MyD88-/- (right) mice were primed overnight with IFN- and activated with 10 ng/ml LPS in the presence or absence of E-IgG. IL-12 (solid bars, left axis) and IL-10 (open bars, right axis) were measured in supernatants by ELISA 24 h following stimulation. (B) Macrophages from BALB/c mice were primed overnight with IFN- and activated with LPS in the presence or absence of immune complexes consisting of E-IgG or IgG-OVA. Control cells were stimulated in the presence of OVA alone, unopsonized erythrocytes (E), or anti-OVA (IgG) alone. Cytokine production was measured by ELISA 24 h later. *, Statistically significant decrease in IL-12 production relative to IFN-/LPS stimulation (P<0.05); **, statistically significant increase in IL-10 production relative to IFN-/LPS stimulation (P<0.05).
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Activated macrophages as antigen presenting cells (APCs)
The dramatic shift in cytokine production by these two populations of activated macrophages suggested that they might behave differently when used as APCs. To study this, activated macrophages were cultivated with T cells from the OVA-TCR transgenic D011.10 mouse. Secondary T cell responses to antigen were analyzed, following a primary stimulation with activated macrophages and either OVA or IgG-OVA to ligate the FcR. Secondary stimulation was performed under nonbiasing conditions using resting macrophages and OVA alone. Activated macrophages exposed to OVA alone in the primary and secondary stimulation induced the production of T cells that exhibited a bias in cytokine production, producing primarily Th1-like cytokines. By ELISA, these T cells produced relatively high amounts of IFN-, but substantially less IL-4 (Fig. 2A
, open bars). By flow cytometry (Fig. 2B
, right profile), a high percentage of CD4+ lymphocytes in the population (23%) produced IFN-, whereas only 2% made IL-4. This Th1-like response did not occur when activated macrophages given OVA plus E-IgG were used as APCs. These macrophages induced a population of Th2-like T cells, making substantially more IL-4 than IFN- (Fig. 2A , hatched bars). The CD4+ T cells in the population producing IL-4 increased to 26%, whereas only 2% made IFN- (Fig. 2B
, left profile).
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Figure 2. Cytokine production from T cells exposed to different APC populations. (A) Macrophages from BALB/c mice were activated as described previously in the presence of OVA (open bars) or OVA + E-IgG (hatched bars) and used as APCs for CD4+ cells from DO11.10 mice. Seven days following the primary stimulation under biasing conditions, CD4+ cells were harvested, washed, and restimulated with fresh, unactivated macrophages with OVA (secondary stimulation, nonbiasing conditions). Cytokine production was measured 24 h later by ELISA. Data represent the mean ± SD of one triplicate experiment that is representative of at least three independent experiments (P<0.05). (B) Parallel populations of secondarily stimulated T cells were analyzed by intracellular staining for IFN- and IL-4 production using fluorescein isothiocyanate (FITC)-conjugated antibody to IFN- and phycoerythrin (PE)-conjugated antibody to IL-4, as described in Materials and Methods. Flow cytometry data are representative of three independent experiments.
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and low levels of IL-4 in the secondary response, regardless of whether they were restimulated with OVA alone (Fig. 3
, gray bars) or with IgG-OVA (Fig. 3
, gray hatched bars). The converse was also true: T cells stimulated with macrophages receiving IgG-OVA in the primary response made high levels of IL-4 and low levels of IFN-, irrespective of the secondary stimulation (Fig. 3
, open bars). Thus, the initial biasing of T cell cytokine production by activated macrophages was stable upon secondary stimulation.
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Figure 3. The stability of T cell biasing. Resting, naïve CD4+ cells were added to activated macrophages in the presence of OVA (gray bars) or IgG-OVA (open bars) in the primary stimulation, as described previously. Seven days following the primary stimulation, CD4+ cells were harvested, washed, and added to fresh macrophages that were unactivated (unhatched bars) or activated in the opposite manner that had been done in the primary stimulation (hatched bars). Twenty-four hours following secondary stimulation, T cell cytokine production was measured by ELISA. This figure is representative of three experiments.
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chainR ligation, we performed similar studies on macrophages lacking the common chain of the FcR. The chain signals through the FcRI and -III, and we have demonstrated previously that this signaling chain is required for the induction of IL-10 following FcR ligation [16
]. Similar to wild-type (WT) macrophages, activation of -/- macrophages induced the production of high levels of IL-12, and this IL-12 production was diminished substantially by the addition of IgG-OVA (Fig. 4A
, solid bars). Unlike WT macrophages, however, the addition of IgG-OVA to these cells failed to induce IL-10 production (Fig. 4A
, open bars). IL-10 production by parallel monolayers of WT macrophages stimulated in the same manner is shown in the inset of Figure 4
. Significant differences in IL-10 production between -/- macrophages and WT cells are designated by **.
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Figure 4. The biasing of antigen-specific CD4+ T cells using macrophages from -/- mice. (A) Activated macrophages from -/- mice (main graph) or WT BALB/c mice (inset) were activated in the presence of OVA or IgG-OVA. Twenty-four hours later, the production of IL-12 (solid bars) and IL-10 (open bars) was measured by ELISA. *, Statistically significant decreases in IL-12 production relative to IFN-/LPS; **, statistically significant decrease in IL-10 production relative to WT mice (P<0.05). (B) Seven days after primary stimulation under biasing conditions using OVA (unhatched bars) or IgG-OVA (hatched bars), CD4+ cells were harvested, washed, and restimulated under nonbiasing conditions using immobilized anti-CD3. T cell cytokine production was measured 24 h later by ELISA. Data represents the mean ± SD of triplicates of a representative experiment. *, Statistically significant decrease in IL-4 production relative to stimulation by WT macrophages (P<0.05). (C) Parallel samples were analyzed by intracellular staining for IFN- and IL-4 using FITC-conjugated antibody to IFN- and PE-conjugated antibody to IL-4, as described in Materials and Methods. The data are representative of three independent experiments.
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-/- mice exposed to OVA alone induced a Th1-like response that was similar in character to that induced by WT macrophages (Fig. 4B
, unhatched bars). By flow cytometry, macrophages from WT and -/- mice induced similar numbers of T cells producing IFN- (35 vs. 33), and only 2% of the cells in either population produced IL-4 (Fig. 4C)
. In response to IgG-OVA, however, the two populations were substantially different. Whereas WT macrophages induced the expected Th2-like response, with high IL-4 and lower IFN- (Fig. 4B
and 4C)
, macrophages from -/- mice failed to reverse the Th1-like response. There were lower amounts of IL-4 in the supernatants (Fig. 4B
, hatched bars), and by flow cytometry, only 4% of the cells made detectable amounts of IL-4 (Fig. 4C)
. Thus, targeting antigen to the macrophage FcR reverses innate Th1-like biasing and induces Th2-like responses, and this reversal is dependent on the chain of the FcR.
T cell biasing in animals
In vivo experiments were performed to determine the extent to which the biased cytokine production by macrophages could affect immune responses in whole animals. Macrophages were activated in vitro in the presence or absence of an irrelevant immune complex, E-IgG, as described above for Figure 1
. These activated macrophages were then transferred i.p. into naive mice, and the recipients were immunized with OVA in the absence of adjuvant. The use of activated macrophages as an adjuvant resulted in significant antibody production. Mice receiving traditionally activated macrophages (type 1) developed significant titres of OVA-specific antibody, comprised of both IgG1 and IgG2a. The transfer of macrophages that had been stimulated in vitro with E-IgG immune complexes, which we have termed type 2 M
, however, resulted in the production of higher total antibody levels, and this increase was largely due to an increase in the amount of the IgG1 isotype produced (Fig. 5
). Thus, the targeting of antigen to FcR on macrophages can influence the amount and quality of the ensuing humoral immune response, resulting in higher total levels of IgG of the IgG1 isotype.
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Figure 5. Antibody production following passive macrophage transfer. Macrophages from BALB/c mice were primed with IFN- and activated in vitro with LPS (type 1 M) or activated with LPS plus E-IgG (type 2 M). One hour later, macrophages were washed, and a total of 2 x 106 macrophages was transferred i.p. into mice along with 50 µg OVA in the absence of adjuvant. This procedure was repeated 10 days later. Nine days after the second treatment, mice were bled, and OVA-specific Ig, IgG1, and IgG2a were measured by ELISA. The titer is defined as the final dilution of serum at which the absorbance at 405 nm was equal to 0.1 OD units (*, p<0.1; **, P<0.05).
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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R on activated macrophages can result in the production of antigen-specific T cells, which preferentially produce Th2-like cytokines. This FcR-dependent Th2 biasing is stable and preserved when T cells are subsequently restimulated under nonbiasing conditions or reverse biasing conditions. These observations may have profound conceptual implications about the role of APCs in influencing an adaptive immune response.
For these studies, macrophages that had been activated with IFN- and LPS were used as the APCs. These cells produced relatively high levels of proinflammatory cytokines as a result of innate immune recognition of microbial products. Macrophages from mice deficient in the gene for MyD88 failed to produce these cytokines, demonstrating that the TLR pathway was involved in this process. The use of activated macrophages as APCs resulted in the preferential induction of a Th1 response characterized by T cells that produced high levels of IFN- in the secondary response. Our studies confirm a recent study showing that innate immune responses can preferentially drive Th1-like adaptive immune responses [12
]. These studies extend this analysis in an important way by showing that the ligation of FcR on activated macrophages can reverse the influence of an innate immune response and preferentially drive Th2-like responses. Thus, in some settings, IgG itself may be an important inducer of Th2-like responses. The mechanism by which IgG can influence immune deviation is by changing the phenotype of APCs and inducing them to produce IL-10 instead of IL-12.
Our observations with macrophages from -/- mice in this report illustrate the importance of IL-10 in the deviation from a Th1 to a Th2 phenotype. Although these -/- macrophages down-regulated IL-12 production following FcR ligation, they failed to produce high levels of IL-10 following FcR ligation, as demonstrated previously [17
]. Consistent with the lack of IL-10 production, these cells failed to induce Th2-like responses. At this time, it is not clear whether IL-10 plays a Th2 enhancing role, a Th1 inhibitory role, or both, in order to induce the development of Th2 cells. It is important to note that high IL-10 production by WT macrophages happens only when FcR ligation occurs in conjunction with inflammatory stimuli.
To show that the shift to a Th2 phenotype following FcR ligation was not the result of a more efficient mechanism for directing the antigen to the endocytic pathway, an irrelevant immune complex, E-IgG, was used. T cells exposed to the same amounts of OVA antigen in the presence of E-IgG produced comparably high levels of IL-4 and low levels of IFN-. Thus, the deviation that we observe is not a result of an antigen dosage effect.
To directly demonstrate that APCs can contribute to the alteration in antibody production observed in vivo, an adaptive macrophage transfer study was undertaken. Macrophages were stimulated in vitro with irrelevant immune complexes (E-IgG) and were transferred into naive mice, which were subsequently immunized with OVA. Mice receiving (type 2) stimulated APCs made higher levels of total IgG, and there was a significant increase in the levels of the IgG1 isotype. Thus, macrophages that are appropriately stimulated can exert a significant influence on the quantity and character of antibody that is produced in response to antigen.
In this work, we show that the phenotype of activated macrophages can be changed dramatically by ligating their FcR. Activated macrophages have been shown to be important APCs in a variety of autoimmune and inflammatory diseases where the Th1-inducing cytokine production of these cells may contribute to pathology [25
26
27
28
]. Thus, these observations may have conceptual and applied implications. The reciprocal reversal of cytokine production that we describe may be exploited to modulate pathologies associated with autoimmune diseases associated with Th1-like responses. Conversely, the induction of Th2-like responses following FcR ligation may be exploited to improve IgG responses to weakly immunogenic antigens.
Received February 13, 2002; revised March 22, 2002; accepted April 8, 2002.
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receptors on macrophages J. Immunol. 168,3697-3701RI J. Exp. Med. 188,217-222 receptors J. Immunol. 166,6861-6868 receptor ligation J. Immunol. 166,4498-4506This article has been cited by other articles:
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T R D J Radstake, P L E M van Lent, G J Pesman, A B Blom, F G J Sweep, J Ronnelid, G J Adema, P Barrera, and W B van den Berg High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc{gamma}R triggering Ann Rheum Dis, June 1, 2004; 63(6): 696 - 702. [Abstract] [Full Text]
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N. E. Rodriguez, H. K. Chang, and M. E. Wilson Novel Program of Macrophage Gene Expression Induced by Phagocytosis of Leishmania chagasi Infect. Immun., April 1, 2004; 72(4): 2111 - 2122. [Abstract] [Full Text] [PDF]
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A. W. M. Minto, L.-P. Erwig, and A. J. Rees Heterogeneity of Macrophage Activation in Anti-Thy-1.1 Nephritis Am. J. Pathol., November 1, 2003; 163(5): 2033 - 2041. [Abstract] [Full Text] [PDF]
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D. M. Mosser The many faces of macrophage activation J. Leukoc. Biol., February 1, 2003; 73(2): 209 - 212. [Full Text] [PDF]
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