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*
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208; and
Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/-
mice. Absence of the FcR -chain did not affect the expression
of IFN- and IL-10 in the lungs and spleens after intranasal
immunization with an influenza subunit vaccine. Titers of serum and
respiratory Abs of the IgM, IgG1, IgG2a, and IgA isotypes in FcR
-/- mice were similar to levels seen in FcR
+/+ mice. Nevertheless, FcR -/- mice
were highly susceptible to influenza infection, even in the presence of
anti-influenza Abs from immune FcR +/+ mice. NK
cells were not necessary for the observed Ab-mediated viral clearance,
but macrophages were found to be capable of actively ingesting
opsonized virus particles. We conclude that Fc receptor-mediated
phagocytosis plays a pivotal role in clearance of respiratory virus
infections. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The development of mice with genetic disruptions in Fc receptor
expression has allowed detailed study of the importance of these
receptors in the clearance of infections (25). One Fc
receptor knockout mouse that has been developed lacks the common
-chain signaling molecule (26) shared by two Fc
receptors that interact with IgG (FcRI and FcRIII), as well as
the high affinity Fc receptor for IgE (Fc
RI) (27).
Previous studies have shown that FCR -/- mice lack
opsonophagocytosis and Ab-dependent cell-mediated cytotoxicity (ADCC)
(26), and have increased susceptibility to fungal (28) and
bacterial (25) infections. However, the role of Fc
receptors in the clearance of viral infections has not yet been
characterized.
In this study, we describe a novel role for Fc receptors in protection
against influenza virus challenge. Upon i.n. immunization with
influenza vaccine, FcR -/- and FcR
+/+ mice produced equivalent levels of
cytokines and specific Abs, yet FcR -/- mice
were significantly more susceptible to influenza infection than FcR
+/+ mice. The role of FcR-bearing cells in
protection was investigated using mice that are transgenic for human
CD3 and thus lack functional NK cells (29), and by
using an in vitro opsonophagocytosis assay with Ab-coated influenza
virus and the J774A.1 macrophage cell line. The results are discussed
in relation to the role of Fc receptors and macrophages in mucosal
immunity to influenza virus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult (4–8 wk old) BALB/c mice with a genetic disruption in
expression of the FcR -chain (26) were obtained from
Taconic Farms (Germantown, NY). Age-matched FcR
+/+ BALB/c controls were purchased from
Charles River Breeding Laboratories (Raleigh, NC) through the National
Cancer Institute (Bethesda, MD). Adult (C57BL/6J x
CBA/J)F1 mice transgenic for the human CD3
signaling subunit (29) and nontransgenic controls were
obtained from The Jackson Laboratory (Bar Harbor, ME). All experiments
were performed in accordance with guidelines established by the
Institutional Animal Care and Use Committee at Albany Medical College
(Albany, NY).
i.n. immunization
Immunizations were performed as described previously (12). Briefly, mice were anesthetized by i.p. injection of 80 mg kg-1 Ketamine HCl (Fort Dodge Laboratories, Fort Dodge, IA) and 16 mg kg-1 Xylazine (Phoenix Pharmaceuticals, St. Joseph, MO) diluted in PBS to a final volume of 200 µl per mouse. The anesthetized mice were inoculated i.n. with 5 µg of an influenza A/PR/8/34 protein preparation containing hemagglutinin subtype 1 (H1) and neuraminidase subtype 1 (N1). In addition, mice were inoculated i.n. with 1 µg recombinant murine IL-12 using 1% (v/v) normal mouse serum in PBS (1% NMS-PBS) as a vehicle. The total volume used for i.n. immunization was 50 µl per mouse. Recombinant murine IL-12 was provided by V. H. Van Cleave (Genetics Institute, Cambridge, MA).
Cytokine measurements
Mice were sacrificed by Halothane (Halocarbon Laboratories,
River Edge, NJ) inhalation 24 h after immunization, and RNA
from spleens and lungs was prepared using the Ambion Total RNA
Isolation Kit (Ambion, Austin, TX). Two microliters cDNA prepared using
the Life Technologies (Grand Island, NY) reverse transcription kit were
analyzed for IFN- and IL-10 by real-time PCR with a Perkin-Elmer
(Branchburg, NJ) ABI Prism 7700 Sequence Detection System and the
TaqMan PCR Reagent Kit. Amplification was performed using the primers,
probes, and conditions described previously (30). Primer
(300 nM) and 200 nM probe were used. Primers and probes were mixed with
3.5 mM MgCl2, 200 µM dATP, 200 µM dCTP, 200
µM dGTP, 400 µM dUTP, 0.025 U µl-1
AmpliTaq Gold Taq polymerase, and 0.01 U
µl-1 AmpErase Uracil N-glycosylase
in buffer to a final volume of 25 µl. Before amplification, samples
were heated to 50°C for 2 min followed by 95°C for 10 min. The
samples were then subjected to 45 cycles at 95°C for 15 s and
60°C for 1 min. The samples were quantitated using known
concentrations of plasmid DNA encoding murine IFN- and IL-10
(provided by R. M. Locksley, University of California at San Francisco)
(31). Differences in cytokine expression between groups of
mice were analyzed using Student’s t test with statistical
significance reported as p < 0.05.
Bronchoalveolar lavage (BAL) fluid Ab analysis
Anesthetized mice were inoculated i.n. with 5 µg of H1N1 on day 0 and with either 1 µg recombinant murine IL-12 in 1% NMS-PBS or 1% NMS-PBS alone on days 0, 1, 2, and 3. The total volume used for each daily i.n. inoculation was 50 µl per mouse. Mice were then boosted i.n. with 3 µg H1N1 on days 14 and 28. Mice initially receiving IL-12 were given another 1-µg dose of IL-12 i.n. on day 28. On day 35, mice were sacrificed by inhalation of Halothane, and their lungs were immediately washed with 2 ml PBS containing 5 mM EDTA. Blood contamination was tested in the BAL fluid using Albustix (sensitivity of 150 µg ml-1) (Bayer, Elkhart, IN), and those BAL fluid samples with measurable levels of albumin were discarded. BAL fluid was stored at -80°C after centrifugation at 12,000 x g for 5 min to remove cellular debris.
Anti-H1N1 Abs were analyzed using isotype-specific ELISAs (12). Briefly, 96-well microtiter plates (Nalge Nunc, Rochester, NY) were coated by incubation with 1 µg ml-1 A/PR/8/34 virus (Charles River, North Frankin, CT) in PBS overnight at 4°C. The plates were washed with PBS containing 0.3% (v/v) Brij-35 (Sigma, St. Louis, MO) and then blocked with PBS containing 5% (v/v) FBS (HyClone, Logan, UT) and 0.3% (v/v) Brij-35 for 1 h at room temperature. Two-fold serial dilutions of BAL fluids were added to the plates and incubated overnight at 4°C. After washing, alkaline phosphatase-conjugated goat anti-mouse isotype-specific Abs (Southern Biotechnology Associates, Birmingham, AL) were added to the plates and incubated for 1 h at room temperature. p-nitrophenyl phosphate substrate (Sigma) was added to the plates, and OD at 405 nm was measured using a Bio-Tek Microplate Autoreader (Bio-Tek Instruments, Winooski, VT). The reciprocal BAL dilution corresponding to 50% maximal binding was reported as the titer. Titer values for each group were compared for statistical significance using Student’s t test. Significant differences are reported as p < 0.05.
Serum Ab analysis
Mice were immunized i.n. with H1N1 and boosted on days 14 and 28 as described above. On day 35, serum obtained by bleeding mice from the orbital plexus was analyzed by the same ELISA used to measure BAL Ab levels. Titer values were compared for statistical significance using Student’s t test, with significant differences reported as p < 0.05.
Influenza virus challenge
Anesthetized mice were immunized i.n. with 5 µg H1N1 on day 0 and treated with either 1 µg IL-12 in 1% NMS-PBS or 1% NMS-PBS alone on days 0, 1, 2, and 3. Approximately 30 days later, these mice were challenged i.n. with 1 x 103 PFU A/PR/8/34 influenza virus in a volume of 40 µl. Mice were then monitored daily for survival and weight loss. A loss of 33% of initial body weight was considered lethal, and mice that reached this point were sacrificed by i.p. injection of 100 mg kg-1 Pentobarbital.
Passive transfer of serum
Sera obtained from mice 35 days after immunization were pooled and adjusted to a standard total Ab titer of 7.4 x 104 ml-1 in PBS. This serum pool was then injected i.p. in a 200-µl volume into naive mice. Four hours later, the mice were anesthetized and challenged i.n. with 2.7 x 102 PFU A/PR/8/34 virus as described above. Mice were monitored daily for survival and weight loss.
Cell culture conditions
The BALB/c macrophage cell line J774A.1 was obtained from the American Type Culture Collection (Manassas, VA). Cells were propagated in DMEM with 4500 mg L-1 glucose, 110 mg L-1 sodium pyruvate HCl, and NaHCO3 (Sigma). In addition, the medium was supplemented with 10% (v/v) FBS, 4 mM L-glutamine (Life Technologies), 1 mM sodium pyruvate (Life Technologies), and 10 µg ml-1 gentamicin (Sigma).
Opsonophagocytosis assay
A/PR/8/34 influenza virus was labeled with FITC (Sigma) as
described previously (32). Briefly, 1 ml of concentrated
virus (
1 x 109 PFU) was mixed with 100
µl of a 1 mg ml-1 solution of FITC in 1 M
sodium carbonate (pH 9.6) for 1 h at 37°C. This mixture was then
dialyzed against PBS for 18 h at 4°C. Opsonophagocytosis of
FITC-labeled influenza was analyzed by a modification of a previously
described technique (33). Serum samples containing an Ab
titer of 1.4 x 103 in 20 µl were mixed
with 10 µl FITC-labeled virus at 37°C for 30 min. J774A.1 cells
(1 x 106) were then incubated with the
opsonized A/PR/8/34 virus for 30 min at 37°C. Extracellular
fluorescence was quenched with 20 µl of a 0.2 mg
ml-1 solution of trypan blue, and fluorescence
was measured using a BD Biosciences (San Diego, CA) FACSCalibur flow
cytometer. In some instances, cells were photographed using an Olympus
(Melville, NY) fluorescence microscope with an Optronics (Goleta, CA)
digital camera and software.
Depletion of total Ig was performed using Sepharose beads (Sigma) coated with goat anti-mouse total Ig (Southern Biotechnology Associates). Goat anti-mouse Ig was bound to Sepharose beads as described (34). Briefly, 1 mg goat anti-mouse total Ig was mixed with cyanogen bromide-activated Sepharose beads at pH 3. After blocking unbound sites with 1 M ethanolamine (Sigma), serum samples were mixed with the coated beads overnight at 4°C and supernatants were collected. Depletion of total and specific Ig from serum was confirmed by ELISA.
Confocal microscopy
Following incubation with FITC-labeled virus particles and quenching of extracellular fluorescence with trypan blue as described above, J774A.1 cells were washed with PBS and placed onto a poly-L-lysine-coated coverslip. Images of optical sections, taken at 0.3-µm intervals in the z-direction, were collected on a Nikon Diaphot inverted microscope (Melville, NY) attached to a Noran-Oz laser scanning confocal microscope system (Noran Instruments, Middleton, WI). Maximum intensity projection fluorescence images, fluorescence images of a single optical slice, and transmitted light images were generated using the Noran Intervision 3D and 2D software packages, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- and FcR +/+ mice
Cytokine mRNA levels were quantitated in the lungs and spleens of
mice 24 h after i.n. immunization with H1N1, either alone or with
IL-12 as an adjuvant. After immunization with the vaccine alone, low
levels of IFN- and IL-10 were detected in the lungs and the spleens
(Table I
), with no significant
differences between FcR -/- and FcR
+/+ mice. As previously described
(12), IL-12 codelivery with the vaccine led to significant
increases (p < 0.05) in both IFN- and IL-10
levels in the lungs and the spleens of FcR +/+
mice. Similar increases in cytokine expression were observed in FcR
-/- mice after vaccine and IL-12
coadministration.
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-/- and FcR +/+ mice
After immunization with the H1N1 vaccine in the presence or
absence of IL-12, sera, and BAL fluids were analyzed for IgM, IgG1,
IgG2a, IgA, and total influenza-specific Ab. After i.n. inoculation of
vaccine only, mice showed dominant expression of IgA in the BAL fluid
(Fig. 1), whereas IgM, IgG1, and IgA
dominated in the serum (Fig. 2). After
codelivery of IL-12, IgM, and IgG2a expression was increased in mucosal
secretions, whereas IgG2a was the only Ab isotype showing increased
expression in serum. With the exception of serum IgM levels, no
significant differences between FcR -/- and
FcR +/+ mice were observed. Influenza-specific
IgG2b and IgG3 levels were also measured, and no significant
differences were seen between the two groups (data not shown).
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-/- and FcR
+/+ mice to influenza infection
FcR -/- and FcR
+/+ mice were infected with 1 x
103 PFU A/PR/8/34 influenza virus either after no
pretreatment or 30 days after exposure to a single dose of the
influenza subunit vaccine ± IL-12. In the group of mice that
received no vaccine, FcR -/- mice were
somewhat more susceptible to infection than FcR
+/+ mice (9.9 ± 1.5 days mean survival
for FcR -/- mice compared with 11.6 ±
0.5 days mean survival for FcR +/+ mice) (Fig. 3A). However, the difference
in susceptibility was significantly greater after i.n. immunization
with the H1N1 vaccine, with 13.3 ± 5.0 days and 25% survival
among FcR -/- mice compared with 17.0
± 5.6 days with 63% survival among FcR +/+
mice (Fig. 3B). Codelivery of IL-12 with vaccine enhanced
protection in FcR +/+ mice (19.9 ± 3.2
days with 88% survival), as seen previously (12), but
failed to have any effect in FcR -/- mice
(12.4 ± 5.7 days with 25% survival) (Fig. 3C). Weight
loss, expressed as a percentage of the initial body weight, was
measured as a sign of morbidity (Fig. 4).
In all instances, mice lost weight until approximately day 10, at which
point the mice that survived recovered to preinfection levels.
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-/- and FcR +/+ mice
Sera obtained from FcR -/- and FcR
+/+ BALB/c mice after immunization with H1N1
and IL-12 were pooled, adjusted to a total Ab titer of 7.4 x
104 ml-1, and transferred
i.p. into naive mice. Four hours later, the recipients were challenged
i.n. with 2.7 x 102 PFU A/PR/8/34 virus.
The dose of virus chosen for infection was an amount that allowed
differences in protective efficacy to be optimally detectable (63%
survival among naive FcR +/+ BALB/c mice after
delivery of immune serum). As expected, normal serum from unimmunized
mice failed to protect FcR +/+ mice regardless
of whether the serum was derived from FcR +/+
mice (9.1 ± 1.1 days with 0% survival) (Fig. 5A) or FcR
-/- mice (9.1 ± 0.8 days with 0%
survival) (Fig. 5B). Immune serum from FcR
+/+ mice protected FcR
+/+ mice to the expected level (16.9 ±
6.0 days with 63% survival), but had significantly reduced
efficacy in FcR -/- mice (11.6 ± 4.0
days with 13% survival) (Fig. 5C). Similarly, immune serum
from FcR -/- mice protected FcR
+/+ mice (18.0 ± 4.2 days with 63%
survival), but not FcR -/- mice (11.0
± 1.5 days with 0% survival) (Fig. 5D). Again, weight loss
was monitored (Fig. 6), and mice lost
weight until approximately day 11, at which time the mice that survived
the infection began to regain weight. These results show that FcR
-/- mice are fully capable of producing
protective Abs, yet are significantly more susceptible to influenza,
likely due to a failure to effectively clear the infection through the
action of Fc receptor-bearing cells.
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-transgenic mice
To determine the potential role of ADCC mediated by NK cells in
the observed protective effects, passive transfer experiments were
performed with CD3 mice, which lack both NK and T cells
(29). Serum was obtained from FcR
+/+ BALB/c mice after immunization with H1N1
and IL-12, and passively transferred into naive CD3 mice that were
subsequently challenged as described above. As expected, normal serum
from unimmunized mice failed to protect either wild-type or CD3 mice
(11.3 ± 0.5 days with 0% survival for wild-type mice and
11.3 ± 0.8 with 0% survival for CD3 mice) (Fig. 7A). In addition, transfer of
immune serum protected both wild-type and CD3 mice and resulted in
100% survival of each strain through day 17 of the influenza infection
(Fig. 7B). The ability of CD3 mice to survive an
influenza infection after passive transfer of serum demonstrates that
neither NK nor T cells play an important role in Ab-mediated recovery
from infection.
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An opsonophagocytosis assay was next used to measure the ability
of macrophages to ingest opsonized influenza virus particles.
Ab-coated, FITC-labeled A/PR/8/34 virus particles were mixed with
1 x 106 J774A.1 BALB/c cells, and the cells
were analyzed by flow cytometry. Use of serum from H1N1 +
IL-12-immunized mice resulted in an approximate 10-fold shift in the
mean fluorescence intensity compared with normal mouse serum (Fig. 8A). Visualization of the
cells by fluorescence microscopy (Fig. 8B) showed more viral
uptake by cells after incubation of virus with serum from H1N1 +
IL-12-immunized mice.
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C), and that the inclusion of IL-12
in the immunization regimen noticeably increased the resulting efficacy
of macrophage opsonophagocytosis. Depletion of total mouse Ig from
immune serum reduced the ability of the preparation to mediate
opsonophagocytosis to the level observed with normal mouse serum,
showing that Abs were responsible for the observed uptake of influenza
virus. Blocking of FcRII and FcRIII on the J774A.1 cells with
2.4G2 mAb before exposure to the opsonized virus did not reduce
opsonophagocytic activity (data not shown), suggesting the importance
of FcRI in the observed phagocytosis of virus. Confocal microscopy
(Fig. 9) was used to confirm that
Ab-coated viral particles were internalized by the cells. Additional
experiments showed that peritoneal macrophages from FcR
-/- mice were not able to phagocytose virus
as efficiently as FcR +/+ macrophages, as
expected (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- and FcR +/+
mice showed similar cytokine and Ab responses, but FcR
-/- mice were significantly more susceptible
to influenza infection than FcR +/+ mice.
IL-12 codelivery with the vaccine enhanced protection in FcR
+/+ mice, but did not affect survival of FcR
-/- mice. Passive transfer of immune serum
into naive FcR -/- and FcR
+/+ mice directly demonstrated the crucial
role for host Fc receptors in protection of mice from influenza
infection. Furthermore, passive transfer of serum into mice lacking T
and NK cells demonstrated a lack of involvement of NK cell-mediated
ADCC reactions in the observed viral clearance. A viral
opsonophagocytosis assay revealed that macrophages ingest opsonized
influenza virus. These findings implicate a pivotal role for
phagocytosis in the clearance of influenza virus.
Although there was variability in IFN- expression in the spleens of
FcR +/+ mice and the lungs of FcR
-/- mice after i.n. vaccination and IL-12
treatment, there were no statistically significant differences between
the groups. There was also no significant difference in IL-10
expression between FcR -/- and FcR
+/+ mice regardless of whether they received
the vaccine alone or the vaccine with IL-12. The increase in IL-10 copy
number observed after IL-12 treatment has been previously seen in our
laboratory (12, 35) and others (36, 37, 38), and
is believed to be important for down-regulating IFN- levels, thus
reducing potential toxicity (39).
A study by Vora et al. (40) demonstrated that FcR
-/- mice respond the same as FcR
+/+ mice with regard to
anti-(4-hydroxy-3-nitrophenyl)acetyl serum Ab production. In
general, anti-influenza Ab expression in both serum and BAL of FcR
-/- and FcR +/+
mice in our experiments was similar, although FcR
-/- mice had significantly higher serum IgM
expression and noticeably higher levels of serum IgG1 and total Ab
after vaccination. Significant increases in IgG1 expression in the
absence of the FcR -chain have been reported by Kleinau et al.
(41), but the reason for this increase is unknown. The
mechanism behind the significant increase in serum IgM reported here is
also unknown. Two of four FcR +/+ mice
receiving H1N1 in the absence of IL-12 displayed IgG2a Ab titers in
their mucosal secretions. However, the IgG2a seen in these FcR
+/+ mice did not appear to mediate the
difference in survival rates between FcR -/-
and FcR +/+ mice because both types of mice
given exogenous IL-12 together with the vaccine demonstrated equivalent
IgG2a expression.
Although their cytokine and Ab responses were similar, challenge of
immunized mice showed that FcR -/- mice were
more susceptible to influenza infection than FcR
+/+ mice. Codelivery of IL-12 with vaccine
enhanced protection in FcR +/+mice, consistent
with previous results (12), but not in FcR
-/- mice. Furthermore, passive transfer of
immune sera into naive mice revealed that both FcR
-/- and FcR +/+
mice produced Abs that protected FcR +/+, but
not FcR -/-, mice from influenza infection.
The enhanced susceptibility of FcR -/- mice
demonstrates a critical role for Fc receptors in protection from
influenza. In all instances, mice infected with influenza began losing
weight shortly after infection. This weight loss continued for 10
days, at which time the mice that survived infection regained weight.
This suggests that all mice were initially infected with virus, and
those animals with functional Fc receptor-bearing cells were able to
efficiently clear the virus and survive the infection. It should be
noted that the FcR -/- mice used in this
study still express the neonatal FcR, which uses
2-microglobulin to transport IgG across
epithelial cells (42). Thus, an inability to neutralize
virus within epithelial cells cannot be an explanation for the observed
susceptibility of FcR -/- mice to viral
infection.
The use of CD3-transgenic mice revealed that the observed protection
was independent of T and NK cells. Although CD3 mice receiving
immune serum survived much longer than CD3 mice receiving normal
mouse serum, two of the seven CD3 mice in the experimental group
that received immune serum eventually died between days 18 and 21 of
the experiment (our unpublished observations). These mice had
measurable levels of influenza virus present in their lungs at death as
determined by a hemagglutination assay. Thus, NK and/or T cells may be
important for complete removal of virus. Nevertheless, it appears that
opsonophagocytosis mediated by lung macrophages plays the major role in
Ab-directed clearance of influenza virus.
Although Fc receptors and macrophages are known to be important for the clearance of bacterial and fungal infections (25, 28), there has been no direct evidence for their role in the clearance of viral infections. The data presented here demonstrate for the first time the need for Fc receptor-mediated clearance in antiviral immunity, and imply that macrophages are the crucial Fc receptor-bearing cells involved in this process. Because a large portion (up to 85%) of the cells present in BAL fluid can be alveolar macrophages (43), it is likely that these cells play a critical role in the clearance of viral infections at these sites.
Although it has been thought that CD8 cytotoxic T cells are primarily responsible for clearance of virus in infected hosts through lysis of infected cells (44), cytokines released by these cells are also likely to be responsible for their protective functions (45, 46, 47, 48, 49). Such cytokines may in turn cause activation of Fc receptor-bearing macrophages, which then mediate virus clearance (50, 51). In addition to their ability to ingest Ab-coated particles by opsonophagocytosis, macrophages also could potentially destroy infected cells by ADCC (52). Interestingly, B cells but not cytotoxic lymphocytes were recently found to be required for heterosubtypic immunity to influenza virus infection (53). Our findings have important implications for antiviral vaccination strategies and stress the need for the targeting of Ab responses at mucosal sites that preferentially stimulate Fc receptor-mediated host mechanisms.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dennis W. Metzger, Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. E-mail address: metzged{at}mail.amc.edu
3 Abbreviations used in this paper: i.n., intranasal; ADCC, Ab-dependent cell-mediated cytotoxicity; H1, hemagglutinin subtype 1; N1, neuraminidase subtype 1; 1% NMS-PBS, 1% (v/v) normal mouse serum in PBS; BAL, bronchoalveolar lavage.
Received for publication January 23, 2001. Accepted for publication April 10, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 M. D. Wareing, A. B. Lyon, B. Lu, C. Gerard, and S. R. Sarawar Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice J. Leukoc. Biol., October 1, 2004; 76(4): 886 - 895. [Abstract] [Full Text] [PDF]
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A. Jegerlehner, N. Schmitz, T. Storni, and M. F. Bachmann Influenza A Vaccine Based on the Extracellular Domain of M2: Weak Protection Mediated via Antibody-Dependent NK Cell Activity J. Immunol., May 1, 2004; 172(9): 5598 - 5605. [Abstract] [Full Text] [PDF]
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 Y. Harada, M. Muramatsu, T. Shibata, T. Honjo, and K. Kuroda Unmutated Immunoglobulin M Can Protect Mice from Death by Influenza Virus Infection J. Exp. Med., June 16, 2003; 197(12): 1779 - 1785. [Abstract] [Full Text] [PDF]
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P.-Y. Berclaz, Z. Zsengeller, Y. Shibata, K. Otake, S. Strasbaugh, J. A. Whitsett, and B. C. Trapnell Endocytic Internalization of Adenovirus, Nonspecific Phagocytosis, and Cytoskeletal Organization Are Coordinately Regulated in Alveolar Macrophages by GM-CSF and PU.1 J. Immunol., December 1, 2002; 169(11): 6332 - 6342. [Abstract] [Full Text] [PDF]
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J. S.-y. Li, F. Chu, A. Reilly, and G. M. Winslow Antibodies Highly Effective in SCID Mice During Infection by the Intracellular Bacterium Ehrlichia chaffeensis Are of Picomolar Affinity and Exhibit Preferential Epitope and Isotype Utilization J. Immunol., August 1, 2002; 169(3): 1419 - 1425. [Abstract] [Full Text] [PDF]
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C. Mold, B. Rodic-Polic, and T. W. Du Clos2 Protection from Streptococcus pneumoniae Infection by C-Reactive Protein and Natural Antibody Requires Complement But Not Fc{gamma} Receptors J. Immunol., June 15, 2002; 168(12): 6375 - 6381. [Abstract] [Full Text] [PDF]
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