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Neutrophil FcRI as Target for Immunotherapy of Invasive Candidiasis

Annemiek B. van Spriel^*,, Ingrid E. van den Herik-Oudijk^* and Jan G. J. van de Winkel^1,*,

^* Immunotherapy Laboratory, Medarex Europe, and Genmab, University Medical Center, Utrecht, The Netherlands

	Abstract

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Invasive candidiasis represents a life-threatening disease for immunocompromised patients. This study focused on new immunotherapeutic approaches for systemic Candida albicans infections in a human FcRI-transgenic mouse model. FcRI (CD64) is a potent immunoactivating receptor on phagocytic and dendritic cells. In vivo targeting of C. albicans toward neutrophil-FcRI by bispecific Abs and G-CSF effectively protected FcRI-transgenic mice from lethal candidiasis. Nontransgenic mice were not protected, and treatment with bispecific Ab or G-CSF alone did not reduce mortality. Furthermore, infected FcRI-transgenic mice developed high titers of anti-C. albicans IgG, and survival was extended on secondary infection without further treatment. These findings document the capacity of FcRI to initiate potent anti-C. albicans immunity and support the development of FcRI-directed immunotherapy of invasive fungal disease.

	Introduction

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Candida albicans is responsible for the majority of severe systemic fungal diseases occurring in immunocompromised patients (1, 2). High mortality (60%) is observed among these patients, despite treatment with antifungal drugs (3, 4). Neutropenia represents a crucial risk factor, because neutrophils (polymorphonuclear leukocytes (PMNL²)) are indispensable for antifungal immunity (5). G-CSF increases circulating PMNL numbers, stimulates differentiation, and modulates PMNL activity (6, 7). G-CSF has documented therapeutic efficacy in fungal infection models and is well established for the treatment of neutropenic and nonneutropenic patients (5, 8). Covalent attachment of polyethylene glycol (peg) to G-CSF increases its circulating half-life and may further optimize G-CSF treatment (9). Recently, peg-G-CSF has been documented to prolong survival of mice with disseminated C. albicans infection (10).

PMNL express different receptors capable of phagocytosis of microorganisms, including FcR, complement receptors, and a number of carbohydrate-binding molecules. Opsonins (i.e., Ab or complement components) engaging these receptors are essential for elimination of C. albicans by PMNL (11). PMNL express three classes of FcR, FcRIIa (CD32), FcRIIIb (CD16), and FcRI (CD64), on activation with IFN- or G-CSF (12). Both FcRIIa and FcRI are, in contrast to FcRIIIb, potent immunoactivating receptors capable of mediating phagocytosis, Ab-dependent cellular cytotoxicity, and initiation of inflammatory cytokine release. FcRI is exclusively expressed on phagocytic and dendritic cells, in contrast to the widely distributed FcRII (13, 14). Moreover, FcRI represents the only FcR with a well-documented capacity to facilitate immunological memory in vivo (15, 16, 17).

Targeting C. albicans toward PMNL FcRI results in potent PMNL fungicidal activity in vitro (18). Because FcRI is a high affinity IgG receptor, which is saturated with serum IgG in vivo, conventional Ab are ineffective in targeting FcRI. Bispecific Abs (BsAb), which contain dual specificity for both target (C. albicans) and effector (PMNL FcRI), will by binding outside the Ab-binding site of FcRI overcome this problem (18). BsAb may furthermore improve the selectivity and efficacy of Ab-based therapeutics (19). The increasing need for novel therapeutic approaches for fungal disease prompted us to investigate the therapeutic efficacy of FcRI-targeting during invasive candidiasis in a transgenic (Tg) mouse model. This study demonstrates FcRI-directed BsAb and G-CSF to effectively protect mice against lethal candidiasis, supporting FcRI as candidate target for immunotherapy.

	Materials and Methods

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Experiments were approved by the ethical committee of University Medical Center Utrecht.

Antibodies

BsAb (FcRI x Can) was produced as described previously (18). FITC-conjugated mAb 22 (Medarex, Annandale, NJ) was used to detect FcRI expression. FITC-conjugated goat F(ab')₂ anti-mouse IgG (Jackson ImmunoResearch Laboratories, West Grove, PA) detected mouse anti-C. albicans IgG in mouse sera.

G-CSF

Pegylated G-CSF (peg-G-CSF), kindly provided by Dr. J. Andresen (Amgen, Thousand Oaks, CA), was synthesized by coupling recombinant human G-CSF N-terminally to 20-kDa peg as described (9). Previous work indicated a single s.c. injection of 15 µg to elevate circulating neutrophil numbers in mice for 3–4 days (10).

C. albicans

C. albicans strain UC820 is described as a clinical isolate (11). After overnight culture at 37°C in Sabouraud maltose broth (Difco, Detroit, MI), yeasts were centrifuged, washed three times in sterile 0.9% NaCl (saline), and counted. For phagocytosis assays, yeast particles were FITC labeled as described previously (18).

Mice

Because Ab to mouse FcRI are not available, human FcRI Tg mice have been developed that exhibit similar FcRI cell distribution and expression patterns as in humans (15). Female Tg FVB/N x C57BL/6 F₁ mice 9–12 wk old were used. Nontransgenic (NTg) FVB/N x C57BL/6 littermates served as controls. Mice were screened for FcRI expression by incubating blood (25 µl) with FITC-labeled mAb 22, followed by analysis on a FACScan (Becton Dickinson, San Jose, CA). Human FcRI is constitutively expressed by monocytes and macrophages, whereas expression on PMNL of FcRI Tg mice is induced by IFN- or G-CSF, similar to the situation in humans (15).

Isolation of mouse PMNL

Mice were injected s.c. with 15 µg peg-G-CSF (in 150 µl saline), or with saline alone (control). On day 3, mice were injected i.p. with 1 ml thioglycolate (Difco). The mice were killed after 4 h, and 5 ml ice-cold RPMI 1640 (Life Technologies, Gaithersburg, MD) were injected into the abdominal cavity to harvest peritoneal cells. The cells were washed in RPMI 1640 and counted, and viability tested by trypan blue exclusion was always >90%.

Phagocytosis assays

Isolated mouse PMNL (1 x 10⁵) were incubated with FITC-labeled C. albicans particles (4 x 10⁵) in RPMI 1640 alone (control) or in medium containing 10 µg/ml BsAb (FcRI x Can) for 30 min at 37°C. C. albicans phagocytosis was quantified by measuring FITC fluorescence intensities of PMNL by flow cytometry. PE-conjugated GR-1 (PharMingen, San Diego, CA) was used to identify mouse PMNL. The percentage of PMNL that phagocytosed one or more C. albicans yeast particles was determined. In addition, phagocytosis was analyzed in cytospin preparations by light microscopy.

Infection protocol

On day 0, mice (Tg and NTg) were injected i.v. with 5 x 10⁵ viable C. albicans (in 100 µl saline). Groups of at least five mice received either no treatment (controls) or peg-G-CSF (two s.c. injections on days -3 and 0) combined with BsAb (FcRI x Can) treatment (three i.v. injections on days 0, 1, and 2), as outlined in the underlying treatment scheme. Other groups were given peg-G-CSF or BsAb (FcRI x Can) alone. Survival of mice was assessed twice daily.

In some experiments, surviving FcRI Tg mice received a secondary infection (5 x 10⁵ C. albicans) at day 70 without any further treatment (rechallenge).

Detection of anti-C. albicans IgG

Sera of infected FcRI Tg mice were collected at day 60 after primary infection. Serum of uninfected Tg mice served as controls. Anti-C. albicans IgG titers were determined by immunofluorescence. Serial serum dilutions were incubated with freshly grown C. albicans (5 x 10⁵) for 60 min at 4°C. After two washings in saline, C. albicans were incubated with FITC-conjugated goat F(ab')₂ anti-mouse IgG for 30 min at 20°C, washed again, and analyzed by flow cytometry.

Statistical analysis

Kaplan-Meyer log rank tests were performed on survival data using SPSS 10.0 for Windows (SPSS, Chicago, IL). Significance was accepted at p < 0.05.

	Results

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Peg-G-CSF enhances FcRI-mediated PMNL phagocytosis

The effect of peg-G-CSF treatment of Tg and NTg mice on PMNL function was first analyzed in vitro. Three days after a single injection of peg-G-CSF, membrane FcRI expression was strongly up-regulated on Tg, but not on NTg PMNL (Fig. 1A). Furthermore, circulating PMNL numbers increased from 12% (±2%, n = 6) before treatment to 50% (±4%, n = 4) of total leukocytes at day 3 in both Tg and NTg mice. Next, the effect of peg-G-CSF on C. albicans phagocytosis by Tg and NTg PMNL was analyzed by different detection methods. NTg PMNL did not mediate phagocytosis in the presence of FcRI-directed Ab, irrespective of peg-G-CSF treatment (Fig. 1B, top). Tg PMNL, on the contrary, potently internalized C. albicans via FcRI after peg-G-CSF treatment (Fig. 1B, bottom). No phagocytosis was observed by PMNL in the absence of Ab, and preabsorption of Ab with C. albicans removed the capacity of Ab to induce phagocytosis (data not shown).

View larger version (53K): [in this window] [in a new window]   FIGURE 1. In vivo peg-G-CSF stimulation triggers PMNL FcRI expression and function. A, Peg-G-CSF induces FcRI expression on Tg PMNL. A single administration of peg-G-CSF increases FcRI expression on PMNL of Tg mice, but not on NTg PMNL. Thick lines, FcRI expression on peg-G-CSF-primed PMNL; thin lines, expression on unprimed PMNL. B, FcRI-mediated C. albicans phagocytosis by NTg (top) and Tg (bottom) PMNL was analyzed with (right) or without (left) peg-G-CSF priming by both light microscopy and flow cytometry (insets). The relative PMNL number (GR-1-positive cells) was plotted against the FITC fluorescence (arbitrary U). Tg PMNL mediate effective C. albicans phagocytosis only after peg-G-CSF priming (lower right). Experiments were repeated four times, yielding similar results.

FcRI targeting of C. albicans protects mice from invasive candidiasis

Next, we investigated the therapeutic efficacy of in vivo FcRI-targeting in a murine candidiasis model. FcRI Tg and NTg mice received an invasive C. albicans infection, which was lethal within 1 mo. Mice were untreated, treated with FcRI-BsAb or peg-G-CSF alone, or treated with both (see Materials and Methods for details). Untreated mice (Tg/NTg) showed 100% mortality within 34 days, and treatment with BsAb alone did not prolong survival (Fig. 2). Mice (Tg/NTg) that received peg-G-CSF alone and NTg mice receiving both peg-G-CSF and BsAb all showed 100% mortality within 50 days (data shown for NTg mice treated with peg-G-CSF and BsAb). However, combined treatment with peg-G-CSF and BsAb was highly therapeutic in Tg mice, decreasing mortality to 20%. Mice were monitored for >150 days and remained healthy.

View larger version (16K): [in this window] [in a new window]   FIGURE 2. Tg mice are protected from lethal candidiasis by combined FcRI-BsAb and peg-G-CSF treatment. Mice (NTg/Tg) were infected with C. albicans at day 0 and received no treatment (), FcRI-BsAb (*), or FcRI-BsAb combined with peg-G-CSF (NTg, •; Tg, ), after which survival was assessed. Survival curves of NTg and Tg mice treated with peg-G-CSF alone were similar to those of NTg mice receiving peg-G-CSF and BsAb. Experiments were repeated three times with at least five mice per group, yielding essentially identical results.

Prolonged survival of FcRI Tg mice on secondary infection (rechallenge)

Because combined therapy of peg-G-CSF and FcRI-directed Ab resulted in 80% survival of Tg mice, we investigated anti-C. albicans immunity of surviving mice. Mouse sera were tested for the presence of specific anti-C. albicans IgG at day 60 after infection. All surviving mice contained anti-C. albicans IgG with titers ranging from 1/20 to 1/2000 (Fig. 3A), in contrast to uninfected Tg mice. Next, groups of surviving Tg mice were rechallenged with a lethal C. albicans dose without any further treatment. Significant prolonged survival and decreased mortality was observed at this secondary infection, compared with survival of Tg mice dealing with primary disease (Fig. 3B).

View larger version (11K): [in this window] [in a new window]   FIGURE 3. Prolonged survival of Tg mice on secondary C. albicans infection. A, Sera were collected from Tg mice that survived lethal candidiasis after combination treatment (see Fig. 2) at day 60. Specific anti-C. albicans IgG levels were determined in sera of surviving mice (•) and in sera of uninfected Tg mice () by flow cytometry. Ab titers were determined in serial dilutions of sera and are presented for individual mice of two experiments; nd, not detectable. B, Treated FcRI Tg mice that survived lethal candidiasis were rechallenged with a similar C. albicans dose at day 70, in the absence of any further treatment. Survival of these mice was assessed () and compared with survival of Tg mice () that received a primary C. albicans infection. x-axis, number of days after primary infection () or after secondary infection on day 70 (). Survival of pretreated Tg mice was significantly prolonged (p = 0.0087) compared with Tg mice receiving a primary infection. Data are representative of two experiments with five mice per group.

	Discussion

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To develop effective antifungal immunity in vivo, there is a requirement for 1) sufficient fungicidal effector cells, i.e., PMNL, and 2) opsonins engaging phagocytic receptors. The significance of elevated PMNL numbers and PMNL activation is emphasized by the well-established effects of G-CSF during experimental candidiasis. With respect to the importance of phagocyte receptor engagement, we selected human FcRI as the target for immunotherapy of invasive fungal disease based on the following grounds. Targeting C. albicans toward PMNL FcRI results in potent fungicidal activity by both human and FcRI Tg mouse PMNL in vitro (18). Moreover, FcRI represents the only activating FcR, which is exclusively expressed by phagocytes and APC. Recent studies support evidence for induction of "vaccine effects" on in vivo Ag targeting toward FcRI (15, 16, 17). FcRI, being a high affinity IgG receptor, however, is likely to be saturated with serum IgG in vivo. We therefore focused on targeting an epitope located outside the ligand-binding region of FcRI by using BsAb. Such BsAb are not hindered by serum IgG and furthermore interact more efficiently with FcR than conventional Ab (19).

First, we showed peg-G-CSF to be crucial for effective C. albicans phagocytosis by PMNL FcRI, which was linked to increased FcRI expression levels. Consistent with this, protection against lethal candidiasis in Tg mice was achieved only when FcRI-BsAb therapy was combined with peg-G-CSF treatment. This indicates that mononuclear cells, which constitutively express FcRI (13), are not effective in clearing C. albicans in our in vivo model. The requirement for G-CSF corresponds well with recently observed antitumor activity induced by FcRI-BsAb and G-CSF (16). It is currently unknown whether G-CSF is needed for induction of increased levels of FcRI only, or whether the growth factor is also important for PMNL activation. The observation that mortality of treated NTg mice was not decreased (Fig. 2) proved protection to be mediated by human FcRI. Moreover, we observed in vivo phagocytosis of C. albicans by blood PMNL of infected Tg mice treated with peg-G-CSF and BsAb, and a reduced fungal outgrowth in kidneys, in contrast to controls (data not shown). This indicates PMNL phagocytosis via FcRI to represent the underlying mechanism of BsAb-mediated protection to invasive candidiasis.

Excitingly, survival of Tg mice was significantly prolonged on C. albicans rechallenge without further treatment. This suggests that FcRI targeting, combined with peg-G-CSF treatment, induces anti-C. albicans immunity. Indeed, treated Tg mice developed specific anti-C. albicans IgG in serum, which may have contributed to the prolonged survival. Because the cell wall of C. albicans is composed largely of carbohydrates, anti-Candida Ab are typically of the IgM isotype (20, 21, 22). Most anti-Candida Ab available are directed against intracellular Ags, further emphasizing the difficulty of developing protective IgG responses.

Elevated Ab responses on in vivo Ag targeting toward FcRI have been documented before using a number of Ags (15, 17). Moreover, induction of antitumor activity by FcRI-directed Ab triggers resistance to tumor rechallenge (16). APC effectively internalize Ags via FcRI and are proposed to initiate immunological memory by enhancing Ag presentation (23, 24). A unique intracellular trafficking motif in the cytoplasmic tail of FcRI proved crucial for its capacity to facilitate Ag presentation (25). Not only is MHC class II-restricted Ag presentation enhanced on FcRI targeting but also MHC class I presentation (Refs. 25 and 26 ; L. Bevaart, H. H. van Ojik, P. M. Guyre, J. G. J. van de Winkel, and M. J. van Vugt, unpublished observations). This suggests that Ag targeting toward FcRI primes both CD4⁺ and CD8⁺ T cell responses.

Although survival of Tg mice was prolonged after infection rechallenge, mortality was still 80%. This implies that endogenous anti-C. albicans IgG, by itself, is not sufficient to cure mice from invasive candidiasis. The in vivo role of Ab in immunity to C. albicans is controversial (27, 28), mainly because candidiasis patients often contain anti-C. albicans Ab. Ab protection is dependent on many variables, including Ab quantity, isotype, affinity, and Ag specificity. Saturation of FcR with IgG or engagement of inhibitory FcR may also contribute to lack of protection. This again underlines the value of using BsAb for immunotherapy of fungal disease.

In summary, this study demonstrates FcRI-directed Ab combined with peg-G-CSF to protect mice from lethal candidiasis and to prolong survival upon fungal rechallenge. These data support FcRI to represent a candidate therapeutic target for the development of immunotherapies for invasive fungal disease.

	Acknowledgments

 
We thank Toon Hesp, Agnes Goderie, Gerard Geelen, and Ingrid van den Brink for excellent animal care.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Jan G. J. van de Winkel, Immunotherapy Laboratory, University Medical Center Utrecht, Room KC02.085.2, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. E-mail address: J.vandewinkel{at}lab.azu.nl

² Abbreviations used in this paper: PMNL, polymorphonuclear leukocyte; peg, polyethylene glycol; peg-G-CSF, pegylated G-CSF; BsAb, bispecific Ab; NTg, nontransgenic; Tg, FcRI-transgenic.

Received for publication January 16, 2001. Accepted for publication April 27, 2001.

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