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Departments of
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Immunology and
Pathology, University of Manitoba, Winnipeg, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells in Th2 generation. Here, we
examine the impact of in vivo NK cell depletion on the development of
exogenous Ag-specific cytokine and Ab responses using a murine model of
human immediate hypersensitivity. OVA-specific immune responses were
induced in 1) C57Bl/6 bg/bg and bg/+ mice, 2)
BALB/c mice pretreated with anti-asialoGM1 or control Ab, and 3)
C57Bl/6 mice depleted of NK1.1-expressing cells by in vivo
administration of anti-NK1.1 mAb PK136. Depletion efficacy was
assessed by functional assays and flow cytometric analysis. Each of
these approaches indicated that depletion of NK cells and
NK1.1+CD4+ T cells fails to alter the Th1:Th2
balance of Ag-driven cytokine synthesis, as indicated by OVA-stimulated
cytokine synthesis in primary bulk culture. Similarly, the kinetics and
intensity of effector responses such as OVA-specific IgG2a and IgE
synthesis were neither increased nor decreased in any of the three
models examined. The results argue that NK cells and peripheral
NK1.1+ T cells do not play an essential role in shaping the
induction of Ag-specific immune responses to soluble exogenous Ags, the
most common class of inhalant allergen. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, both
directly (5, 6) and secondary to IL-12 (7, 8), and likely IL-18,
production (9, 10), plays a critical role in promoting Th1-like
dominance. Recently, much attention has been devoted to determining the
sources of this early cytokine synthesis.
One intriguing hypothesis is that effector cells of the innate immune
response play a pivotal role in shaping initial T cell activation
(11, 12, 13, 14). Activated NK cells exhibit rapid secretion of several
cytokines, notably IFN- (15). There is compelling evidence that NK
cells play a central role in early IFN- synthesis in response to
infection with a number of protozoal, bacterial, and viral pathogens
(16, 17, 18, 19, 20, 21, 22). Some superantigens (staphylococcus endotoxin B) have also
been demonstrated to directly activate IFN- production by NK
cells (23).
Collectively, these data have led to a broadly based consensus that
early NK cell responses have a profound effect on the characteristics
of the ensuing Ag-specific adaptive immune response and are generally
required for optimal Th1-like T cell activation (11, 12, 13, 14, 20, 24, 25).
It should be noted that most of these experimental systems used Ags
that tend to be very effective macrophage activators, frequently
intracellular pathogens. Several have been shown to be excellent
inducers of IL-12 synthesis that stimulate NK cells to promptly produce
IFN- (7, 8, 26).
At the same time, independent studies implicate NK1.1-expressing T
cells, both CD4+CD8- and
CD4-CD8-, in providing the initial source of
IL-4 for Th2 priming (27, 28, 29, 30, 31, 32). These cells express CD3 and an almost
invariant ß TCR specific for the MHC class I-like molecule CD1.
They produce high levels of IL-4 and IFN- very rapidly upon
activation. However, virtually all studies to date have evaluated
IL-4/IFN- production in vivo or in vitro in response to polyclonal
(anti-CD3-, anti-IgD-, or superantigen-mediated) stimulation,
rather than physiologic activation by nominal Ag following conventional
Ag processing. Indeed, IgE responses were recently reported to be
equivalent in CD1-KO and wild-type littermates despite the absence of
IL-4-secreting CD1-dependent cells (33). However, Ab and cytokine
responses were also exclusively evaluated using anti-IgD and
anti-CD3.
Immediate hypersensitivity is the most widespread immunologic disorder
in humans. In some countries, allergies represent the most prevalent
(and rapidly increasing) chronic health problem among individuals over
15 yr of age (34). The factors responsible for initial induction of
Th2-like responses in vivo, and ultimately immediate hypersensitivity,
remain incompletely understood. Given that the most widely distributed
and clinically prominent class of allergens is the soluble protein Ags,
and that the role played by NK cells in steering initial activation of
exogenous Ag-specific responses is not known, we investigated the role
of NK cells and NK1.1 T cells in the initial induction of such immune
responses in vivo using three independent approaches. In each, this
deficiency was found not to influence the kinetics, intensity, or
balance of cytokine (IFN- vs IL-4/IL-10 production in primary bulk
culture) or Ab (specific IgG2a vs IgE in vivo) responses that
developed. The results argue that NK cells and NK1.1+ T
cells do not play an essential role in shaping the induction of immune
responses to soluble exogenous Ags, the most common class of inhalant
allergen.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c, C57Bl/6 mice, and Sprague-Dawley rats were bred at the University of Manitoba. C57Bl/6J-bg/bg and C57Bl/6J-bg/+ mice were purchased from The Jackson Laboratory (Bar Harbor, ME). All animals were maintained and used in strict accordance with the guidelines issued by the Canadian Council on Animal Care. Mice were seronegative to mycoplasma, Sendai virus, and rodent coronaviruses, including murine hepatitis virus, by ELISA (murine ImmunoComb, Charles River, Lexington, MA).
Treatment of mice and culture conditions
BALB/c were injected i.p. with 40 µl of anti-ASGM1 (Wako
Chemicals, Inc., Neuss, Germany) diluted in 0.5 ml of saline, an
equivalent amount of normal rabbit IgG, or nothing on days -2 and 0
and every 5 days thereafter until sacrifice. C57Bl/6 were treated with
anti-NK1.1 (PK136 ascites at 300 µg mAb/injection) on the same
schedule. The optimal amount of Abs for in vivo depletion was
determined in preliminary assays of NK activity and flow cytometry
(data not shown). For full depletion using anti-NK1.1 this
represents approximately sixfold that commonly employed (i.e., 50
µg), a concentration that was recently observed to yield only partial
depletion (35). All mice were immunized i.p. with OVA (2 µg in 2 mg
of Al(OH)3 adjuvant) or OVA (100 µg) in saline (see
Results), then bled for determination of specific Ab
production and/or killed for analysis of Ag-driven cytokine production
in short term culture. Sera were collected on days 10 and 14, then
stored at -20 C until analyzed for OVA-specific IgG1 and IgG2a levels
by ELISA and for IgE levels by passive cutaneous anaphylaxis as
previously described (36). For culture, mice were killed 5 days
following OVA (alum) immunization or, in experiments conducted in the
absence of adjuvants, 8 days after OVA (saline) immunization, times
previously found to produce maximal cytokine responses. In time-course
experiments, mice were killed between 1 and 8 days postimmunization.
Spleen cell suspensions were cultured at 7.5 x 106/ml
(2 ml/well) in 24-well plates (Corning Science Products, Rochester, NY)
at 37°C in complete medium (37) alone and in the presence of OVA as
previously reported. In some experiments, mice were killed at earlier
time points (see Results). Mice within each group
were bled and cultured individually, with duplicate cultures
established for each condition tested. Supernatants were harvested for
analysis of IL-4 at 24 h, of IFN- at 48 h, and of IL-10 at
96 h. In most experiments, NK cells were assessed functionally
and/or phenotypically at the time of sacrifice.
Analysis of NK cell depletion
NK cell levels were assessed via functional assays and flow cytometry. Briefly, in functional assays YAC-1 and BW1100 target cells were labeled with Na251CrO4 (Amersham, Oakville, Ontario, Canada) at a dose of 50 µCi/1 x 106 cells for 60 min, washed three times in supplemented RPMI 1640, and resuspended to a final concentration of 1 x 105 cells/ml. Ten thousand target cells suspended in 100 µl of medium and various numbers of splenic effector cells, also suspended in 100 µl of medium, were plated into the wells of a plastic 96-well microtiter plate. For each assay performed, four E:T ratios (100 to 12.5:1) were plated in triplicate. The plates were then incubated at 37°C for 4 h in humidified air containing 5% CO2. Following centrifugation at 350 x g, 100 µl of supernatant was harvested from each well and counted for 2 min in a LKB gamma counter (Rockville, MD). The average value (counts per minute) was then determined for each supernatant. The percent lysis was calculated as follows: %lysis = {[CPM(experimental) - CPM(spontaneous)]/[CPM(maximum) - CPM(spontaneous)]} x 100.
The mean percent lysis and the SE were determined for each triplicate. Dose-response curves were then generated from these values at the specific E:T ratios used in the assay, and lytic units per 107 effector cells were calculated using exponential fit as previously described (38). One lytic unit was defined as the number of effector cells required to achieve 10% cytotoxicity.
As a complementary approach to evaluating the effectiveness of NK cell depletion, flow cytometric analysis was conducted using a Coulter Electronics EPICS 753 cell sorter with argon ion laser excitation set at 488 nm (500 mW; Coulter Electronics, Hialeah, FL). Forward vs side light scatter histograms were collected to identify and set a bit map gate for single intact lymphocytes; fluorescence histograms were based on 10,000 cells that satisfied this gate. Spleen cells from PK136 (in vivo)-treated and control Ab-treated C57Bl/6 mice were B cell depleted via adherence to anti-Ig-coated plates. CD4+-enriched T cells were obtained by passage of nonadherent cells through a CD4 T cell negative selection column (Biotex Laboratories, Inc., Edmonton, Alberta, Canada). The resulting population was typically >92% CD4 positive, with <0.7% contamination with B cells or CD8+ T cells as assessed by flow cytometry. Both B-depleted and CD4-enriched cell populations (which also contain CD4-CD8- cells) were stained at 4 C with purified PK136 (IgG2a) or an irrelevant mouse IgG2a mAb (MK.D6) followed by biotinylated goat anti-mouse IgG2a (Southern Biotechnology Associates, Birmingham, AL) and streptavidin-phycoerythrin (Pierce, Rockford, IL). The fluorescence signals derived from each cell were split with a 550-nm dichroic longpass filter, with FITC and phycoerythrin signals detected through 525- and 575-nm bandpass filters, respectively. Color compensations were based on test samples stained with the two fluorochromes separately. Data were collected in histogram format and subsequently analyzed using Coulter Elite workstation software, version 4.01.
Cytokine determinations
IL-4. IL-4 levels were determined using an MTS colorimetric assay employing CT.4S (cells provided by Dr. W. Paul, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD) as previously described (39). The specificity of this assay was assured by analysis of representative sample aliquots with anti-IL-4 mAb (11B11), with values inhibited by >85% attributed to IL-4. The presence of rIL-2 did not significantly alter the standard curve obtained with rIL-4. As used here, this assay detects IL-4 at 0.1 to 0.25 U/ml and readily quantitates IL-4 levels above 0.5 U/ml while being unresponsive to IL-2 levels <200 U/ml.
IL-10. A dual mAb-based ELISA employing purified SXC1 and biotinylated, similarly purified SXC2 was used (40). Hybridomas and rIL-10 standard were initially provided by Dr. T. Mosmann (University of Alberta, Edmonton, Alberta, Canada). As described here, this assay detects 0.2 U/ml, with quantitation at >0.5 U/ml.
IFN-.
An ELISA using purified anti-IFN- mAbs XMG 1.2 and purified,
biotinylated R4–6A2 (American Type Culture Collection, Rockville, MD)
was performed (40). Serial dilutions of IFN--containing, Con
A-stimulated spleen cell supernatants, calibrated against World Health
Organization-National Institute of Allergy and Infectious Diseases
International Reference Reagent Gg02-901-533 (provided by Dr. C.
Laughlin, National Institute of Allergy and Infectious Diseases,
National Institutes of Health) were included. The lower limit of
detection is 0.2 U/ml, with quantitative measurement of IFN-
>0.5 U/ml.
Statistical analysis
Arithmetic mean cytokine, IgG1, and IgG2a production (of two to
six experiments, see Results) is shown ± SEM.
IgE responses are expressed as geometric means. Statistical
significance was determined using unpaired two-tailed Student’s
t tests. Statistical significance of differences in mean
IFN-:IL-4 ratios was determined via a paired Wilcoxon rank sum
test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first examined OVA-specific T cell activation in normal B6, B6
bg/bg, and B6 bg/+ mice. Mice were immunized with
OVA and killed 8 days later, the time of peak IFN-, IL-4, and IL-10
responses. Examination of these cytokine responses in bulk culture
revealed that normal, Beige, and heterozygous control mice exhibited no
difference in the intensity of the IFN- response, or in the balance
between Th1 vs Th2-like activation as indicated by OVA-stimulated IL-4
or IL-10 synthesis in primary culture. The mean ratio of IFN-:IL-4
synthesis was virtually identical in these three strains (1.60, 1.46,
and 1.48 in groups I, II, and III, respectively; p >
0.05; data calculated from Table I
),
indicating development of a Th1-like dominance that is of virtually
identical intensity in OVA-primed normal B6, B6 bg/bg, and
B6 bg/+ mice. Similar ratios were obtained for comparisons
of OVA-stimulated IFN- and IL-10 synthesis.
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, primary and secondary
Ag-specific IgE, IgG1, and IgG2a responses did not differ among the
three groups. Anti-ASGM1 treatment does not detectably alter Th1-like vs Th2-like induction in BALB/c mice
Mice homozygous for the bg gene are genetically
deficient in most classic NK cell functions, and as such have provided
a model previously used to support the hypothesis that NK cells play a
pivotal role in the initial induction of the Th1-like response. At the
same time, the bg/bg defect is not the optimal means of
characterizing NK cell function, as it does not abolish all NK cell
functions (i.e., IFN- synthesis). Consequently, we employed an
alternative model of NK depletion: chronic administration of polyclonal
anti-asialoGM1 Ab to BALB/c mice. Virtually all murine NK cells
express this marker (41), and as widely demonstrated, this approach
effectively depletes functional and phenotypic NK cell activity in
vivo. Following administration of these Abs, even mice treated with the
potent NK cell activator poly(I:C) failed to exhibit demonstrable NK
cells. NK cell depletion was effective within 18 h (Table II) and persisted for a minimum of 7
days. Therefore, to ensure NK cell depletion, Ab treatment was given at
5-day intervals, beginning 2 days before OVA immunization and
continuing until sacrifice. In some experiments, randomly selected mice
within each cohort were killed at various times over the course of the
experiments (5–42 days) to confirm that NK cells remained at
undetectable levels.
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vs IL-4 and IL-10). As shown in Figure 1, neither OVA-stimulated IFN- nor
IL-4/IL-10 responses were detectably influenced by anti-ASGM1
treatment, arguing that development of OVA-specific responses is
independent of such cells.
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). Collectively, these data argue
that, in contrast to a number of infectious disease models in which
IFN- produced by NK cells is involved in immune defense against
certain pathogens (18, 20, 21), anti-ASGM1-mediated NK cell
depletion does not impact on development of the specific immune
response to soluble exogenous Ag.
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As ASGM1 is expressed on rare peripheral T cells and monocytes as
well as NK cells (41), an in vivo NK cell depletion model developed by
Koo and colleagues (42) was employed as a third approach. We took
advantage of the fact that B6 mice constitutively exhibit NK cell
activity that is higher than that of BALB/c and that can be selectively
abolished by chronic administration of anti-NK 1.1 mAb.
Anti-NK1.1-treated C57Bl/6 mice exhibited no detectable NK cell lytic
function, even in groups administered poly(I:C) 18 h before
sacrifice, indicating the effectiveness of this approach (Table III). Phenotypic analysis further
confirmed its efficacy in depleting NK1.1-expressing cells among whole
spleen and CD4+-enriched populations to levels below
the limits of detection (Fig. 3 and Table III). Finally, while anti-NK1.1 has been shown to be capable of
activating IFN- synthesis in vitro in the absence of other stimuli
(43), spleen cells from mice treated with PK136 and their controls
consistently demonstrated IFN-, IL-4, and IL-10 responses that were
below the levels of detection (0.1–0.3 U/ml) when cultured without OVA
restimulation (data not shown). Collectively, the data demonstrate that
chronic, high dose, in vivo administration of PK136 reduces classical
NK and NK1.1 T cell activities to below detectable levels.
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). Development and maintenance of
primary and secondary IgG1 and IgG2a responses were similarly
unaffected by anti-NK1.1 treatment. Direct analysis of cytokine
synthesis in bulk culture also failed to support the contention that
depletion of NK1.1-expressing populations impacts on primary cytokine
responses in this system in terms of either the strength or the
relative Th1/Th2 balance of the OVA-specific response (Fig. 5).
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or IL-4/IL-10 responses might be influenced
by NK cell depletion, OVA-stimulated bulk cultures were established at
1, 2, 3.5, 5, and 8 days postimmunization (Fig. 6). IL-4, IL-10, and IFN- responses in
OVA-immunized mice are very low (0.5–4 U/ml) or undetectable on day 1
(not shown) and day 2 postimmunization. Ag-driven cytokine responses
increase by day 3.5, reaching their maximum on day 5. Neither the speed
with which responses developed in vivo nor the intensity at any of the
time points examined differed among the groups. In the absence of OVA
restimulation in vitro, each of the cytokines examined was at
undetectable levels (data not shown). Taken as a whole, the data argue
that NK cells and NK1.1 T cells do not play an essential role in
shaping the establishment or maintenance of the Th1/Th2 balance or the
expression of in vivo effector responses, such as serum Ab, to
soluble Ag.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-4/IFN- production, respectively, even when these cells are in a
resting, nonpreactivated state, suggests a potential role for these
cells as important early sources of cytokine driving commitment to Th1-
and Th2-dominated responses. Using three independent experimental
methods, we demonstrate that the absence of detectable NK or NK1.1 T
cells does not discernibly influence the development of murine cytokine
(IFN- vs IL-4 and IL-10) or serum Ab (IgG2a vs IgE) responses
elicited by soluble protein Ag.
In vivo studies indicating that NK cells secrete IFN- early during
the course of bacterial infection without a requirement for T cell help
(18), in vitro studies demonstrating a capability of activated NK cells
to increase IgG2a synthesis (44, 45), and findings that superantigens
can act directly on NK cells to activate IFN- synthesis (23) are
consistent with hypotheses linking innate and acquired immunity in the
development of T cell-dependent responses (11, 12, 13, 14, 31). Compelling
evidence of a role for NK cells in shaping the initial induction of
Th1-like responses in vivo has been obtained for several bacterial,
protozoal, and viral pathogens, suggesting a potent mechanism by which
the innate immune response could limit the development of potentially
hazardous Th2-like cytokine production. Conversely, the capacity of
NK1.1+ T cells to promptly produce IL-4 following
polyclonal activation (27, 28, 29, 30, 31, 32) is frequently suggested as the source of
the initial burst of IL-4 that is needed to steer commitment of
conventional CD4 T cells to Th2-dominated patterns. Studies indicating
that transgenic mice with marked overexpression of NK1.1 T cells
exhibited 10- to 100-fold increases in IL-4 production (following
mitogen-driven activation) in vitro or in vivo and that baseline levels
of IgE and IgG1 were selectively elevated in vivo were consistent with
this hypothesis (29).
The novelty of our approach lies in its focus on the role of NK cells and NK1.1+ T cells in the development of soluble Ag-driven responses; the class of Ag that is of primary relevance to immediate hypersensitivity. We initially hypothesized that depletion of classical NK cells before immunization would lead to less Th1-like and more Th2-like cytokine and Ab responses. Specifically, we reasoned that if NK cells play an essential role in shaping the developing OVA-specific response, their depletion immediately before Ag exposure should markedly influence both cytokine synthesis in short term culture and the balance of OVA-specific IgE vs IgG2a synthesis in vivo. Unseparated spleen cell populations were used for culture to avoid excluding, a priori, contributions to cytokine synthesis by non-CD4 cell populations.
The first approach to test this hypothesis, using normal and bg/bg C57Bl/6 mice, demonstrated strong, qualitatively identical (with respect to Th1-like vs Th2-like activation) cytokine and Ab responses following OVA immunization. Administration of anti-ASGM1 or normal rabbit IgG to BALB/c mice yielded similar conclusions. The third, most specific, approach used anti-NK1.1 treatment to evaluate the impact of NK cells and NK1.1-expressing cells on initial development of soluble Ag-driven responses. Again, OVA-specific IgE, IgG1, and IgG2a production (intensity or kinetics) revealed no differences between treated and control mice. Each of the experimental models used has recognized limitations. The concerns associated with bg/bg mice are well recognized. Anti-ASGM1 treatment may deplete low frequency subpopulations of activated T cells that also express these markers. Treatment with lower concentrations of anti-NK1.1 (i.e., one dose of 50 µg, i.p.) yields virtually complete elimination of classical NK cells but only partial removal of NK1.1 T cells (35). Notwithstanding these reservations, we note that each of the models used above has been used in support of a role for NK cells in directing initial development of the acquired immune response. Alternative approaches to NK cell inactivation, such as chronic administration of anti-IL-2R ß-chain mAb (46), were not evaluated in this study due to our concern that they would have additional, less specific, effects on the immune response (37).
Others have shown that NK cell depletion via anti-ASGM1 or
anti-NK1.1 treatment before immunization or infection led to
markedly decreased IFN- production and/or increased IL-4 synthesis
following short term Ag-driven restimulation in vitro (13, 19, 20, 21).
These qualitative changes in the dominant pattern of cytokine
responsiveness were frequently accompanied by substantial changes in
effector functions, such as serum Ab responses or host survival in
response to pathogen challenge, providing support for the hypothesis
that NK cells act as an essential link between innate and adaptive
immunity to these pathogens. We speculate that the difference between
these studies and our own may be in the nature of the inducing Ags and,
consequently, the APC populations used to initiate the CD4 responses
measured.
The role of NK cells in shaping responsiveness to soluble protein Ags
was initially considered by Bogen et al. (12). Immunohistochemical
evidence was taken to suggest the presence of IFN--producing NK-like
cells at 3 and 7 days postimmunization of mice injected in the footpads
with Ag in CFA or, to a lesser extent, aluminum hydroxide.
Anti-ASGM1-mediated NK cell depletion reduced KLH-specific IgG2a
responses by two- to threefold, unlike the data reported here or that
reported by Wilder et al. (45) for anti-NK1.1-treated B6 mice.
Bogen speculated that this NK-like response regulates the phenotype of
the subsequent phosphorylcholine specific T cell response by promoting
the development of Th1 cells. Subsequent efforts to evaluate the impact
of anti-NK1.1 treatment on cytokine and Ab responsiveness in B6
mice were unsuccessful in obtaining NK cell depletion (25).
Although most attention has centered on the hypothesis that NK cells
produce IFN- early, thereby promoting a default Th0/Th1-like
response in preference to a potentially hazardous Th2 response, several
groups have (27, 28, 29, 30, 31, 32) recently published evidence demonstrating that
high levels of IL-4 (and IFN-) are readily derived from low
frequency NK1.1+CD4+/-CD3+
peripheral cells. In at least one in vivo model, NKT cells were shown
to be essential for generation of a Th2 response (27). These data have
been taken by some groups to conclude that class I-selected
CD4-CD8- and
CD4+CD8- ß T cells are important sources
of IL-4 in the development of specific Th2 immune responses in mice
(28, 31) and, perhaps, humans (47). The mechanism by which these class
I-restricted T cell populations with highly restricted TCR repertoires
are activated in vivo (i.e., other than by experimentally used
anti-CD3 mAb or CD1 expressed on APC) remains speculative.
It remains possible that residual, undetectable levels of NK cells or NK1.1+ cells are responsible for shaping the cytokine and Ab responses observed above. However, recent observations in human (48, 49) and murine (50, 51) systems provide persuasive evidence that at least in vitro, naive T cells can themselves provide the IL-4 required for Th2 development independent of a need for NK1.1+ T cells or mast cell/basophil-derived IL-4. Following submission of this manuscript, Brown et al. (52) and Zhang et al. (53) took a genetic approach to NK1.1 T cell depletion, finding that these cells are not essential for Th2 development and IgE responses to exogenous Ag immunization.
In summary, while numerous investigators have used in vivo depletion models of NK cell activity to argue for a critical role for NK cells as a link between innate and acquired resistance, the data above argue that depletion of classical NK cells or of T cell populations expressing NK1-associated markers neither inhibits nor selectively promotes Th1- or Th2-like activation in the OVA- specific response. While there is strong evidence of an important role for this arm of the innate immune response in shaping host resistance to many pathogens or T-independent Ags (54, 55), the role of NK cells in influencing effector responses to exogenous protein Ags appears minor.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kent HayGlass, Department of Immunology, University of Manitoba, 730 William Ave., Winnipeg, Canada R3E 0W3.
Received for publication November 11, 1996. Accepted for publication October 10, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 D. Yuan, R. Bibi, and T. Dang The role of adjuvant on the regulatory effects of NK cells on B cell responses as revealed by a new model of NK cell deficiency Int. Immunol., May 1, 2004; 16(5): 707 - 716. [Abstract] [Full Text] [PDF]
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W. Tao and E. R. Sherwood {beta}2-Microglobulin knockout mice treated with anti-asialoGM1 exhibit improved hemodynamics and cardiac contractile function during acute intra-abdominal sepsis Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2004; 286(3): R569 - R575. [Abstract] [Full Text] [PDF]
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A. Teige, I. Teige, S. Lavasani, R. Bockermann, E. Mondoc, R. Holmdahl, and S. Issazadeh-Navikas CD1-Dependent Regulation of Chronic Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2004; 172(1): 186 - 194. [Abstract] [Full Text] [PDF]
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S. P. Chapoval, K. Iijima, E. V. Marietta, M. K. Smart, A. I. Chapoval, A. G. Andrews, and C. S. David Allergic Inflammatory Response to Short Ragweed Allergenic Extract in HLA-DQ Transgenic Mice Lacking CD4 Gene J. Immunol., January 15, 2002; 168(2): 890 - 899. [Abstract] [Full Text] [PDF]
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N. Gao, T. Dang, and D. Yuan IFN-{gamma}-Dependent and -Independent Initiation of Switch Recombination by NK Cells J. Immunol., August 15, 2001; 167(4): 2011 - 2018. [Abstract] [Full Text] [PDF]
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