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) Is Important in T Lymphocyte Recruitment and Host Defense Following Viral Infection of the Central Nervous System1
*
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; and
Department of Immunology, The Lerner Research Institute, Cleveland, OH 44195
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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) in contributing to a Th1 response against
mouse hepatitis virus infection of the CNS. Analysis of the kinetics of
Mig expression revealed mRNA transcripts present at days 7 and 12
postinfection (p.i.) but not early (day 2) or late (day 35) in the
infection. To determine functional significance, mouse hepatitis
virus-infected mice were treated with anti-Mig antisera, and the
severity of disease was evaluated. Such treatment resulted in a marked
increase in mortality that correlated with a >3 log increase in viral
burden within the brains as compared with control mice treated with
normal rabbit serum. Anti-Mig-treated mice displayed a significant
decrease (p < 0.005) in CD4+ and
CD8+ T cell recruitment into the CNS as compared with
normal rabbit serum-treated mice. In addition, anti-Mig treatment
resulted in a significant decrease (p < 0.05) in
levels of IFN- and IFN-
that coincided with increased
(p < 0.02) expression of the anti-inflammatory
Th2 cytokine IL-10 within the CNS. Collectively, these data indicate
that Mig is important in contributing to host defense by promoting a
protective Th1 response against viral infection of the
CNS. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1, 2, 3, 4, 5, 6). Therefore, the collective
evidence indicates that a Th1-mediated response against MHV infection
of the CNS is critical in host defense and viral clearance.
Chemokines represent an ever-growing family of chemotactic cytokines
that have been shown to target specific populations of leukocytes
during periods of inflammation (7, 8). A recent study has
demonstrated that an orchestrated expression of chemokine genes occurs
following MHV infection of the CNS, suggesting that these molecules
function to attract leukocytes into the CNS in response to viral
infection (9). In support of this is a recent study
demonstrating that expression of the non-ELR (glutamic
acid-leucine-arginine) CXC chemokine IP-10 (IFN--inducible protein
10 kDa) is important in initiating a Th1 response characterized by T
lymphocyte infiltration and production of the IFN- in response to
MHV infection of the CNS (4). Mig (monokine induced by
IFN-) is another non-ELR CXC chemokine that shares similarities with
IP-10 (10). However, although IP-10 expression is
inducible by both IFN-
and IFN-, Mig expression in strictly
dependent on IFN- (10, 11, 12, 13, 14). Both Mig and IP-10 exert a
potent chemotactic effect on T lymphocytes by binding to the shared
receptor CXC chemokine receptor 3 (CXCR3) (10, 15, 16, 17).
Expression of IP-10 and Mig is thought to contribute to a variety of
inflammatory pathologies by attracting leukocytes to sites of infection
or injury (18, 19, 20, 21, 22). Moreover, both IP-10 and Mig have been
shown to exhibit antitumor properties as well as being important
contributors to antiviral defense (4, 23, 24, 25, 26).
Given the similarities as well as the differences between IP-10 and Mig
with regard to biochemical and functional properties, studies were
performed to investigate the contributions of Mig in host defense
following MHV infection of the CNS. The results presented indicate
that, unlike IP-10, which is expressed during acute and chronic
disease, Mig expression is limited to the acute stage of disease.
Neutralization of Mig activity through administration of
rabbit-specific antisera resulted in a marked increase in mortality and
delayed viral clearance that correlated with a significant decrease in
T lymphocyte infiltration into the brain. In addition, anti-Mig
treatment resulted in a significant decrease in mRNA transcripts and
protein for IFN- and IFN- that coincided with a significant
increase in the anti-inflammatory Th2 cytokine IL-10. Together,
these results indicate Mig is an important component in CNS host
defense following viral infection of the CNS by contributing to the
development of a protective Th1 response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The MHV strain V5A13.1 (referred to henceforth as MHV) was provided by M. Buchmeier (Scripps Research Institute, La Jolla, CA) (27). Age-matched (5–7 wk), male C57BL/6 mice (H-2b background) used for the studies described were purchased from Sprague-Dawley (San Diego, CA). Following anesthetization by inhalation of methoxyflurane (Pitman-Moore, Washington Crossing, NJ), mice were injected intracranially with 10 PFU of MHV suspended in 30 µl of sterile saline (9). Control (sham) animals were injected with sterile saline alone. Animals were sacrificed at days 3, 7, 9, and 10 postinfection (p.i.), at which point brains and spinal cords were removed. One-half of each brain was used for plaque assay on the DBT astrocytoma cell line to determine viral burden (1, 28). The remaining halves were either fixed for histologic analysis, stored at -80°C for RNA isolation, or used for FACS analysis.
Ab preparation and treatment of mice
Rabbit antisera to Mig were produced by Biosynthesis (Lewisville, TX) using a synthetic peptide (CISTSRGTIHYKSLK, coupled to carrier protein keyhole limpet hemocyanin) selected from the Mig protein sequence (24). This reagent has previously been shown to be specific for Mig and does not cross-react with IP-10, RANTES, or other known chemokines (24). MHV-infected mice were divided into two groups and treated with either normal rabbit serum (NRS) or anti-Mig. Mice were injected i.p. with 0.5 ml of Ab (0.5 mg/ml) on days 0, 2, 5, 7, and 9 p.i.
Combined in situ hybridization and immunohistochemistry
For studies designed to colocalize cellular Ags with in situ signal for Mig mRNA transcripts, immunohistochemical analysis preceded in situ hybridization using a previously described protocol (9). Staining for glial fibrillary acidic protein (GFAP) (rabbit polyclonal anti-bovine GFAP; Dakopatts, Carpinteria, CA) was performed on brain sections fixed in 10% normal buffered formalin and embedded in paraffin (9). PBS used for dilution of anti-GFAP (1:1000) as well as in washing steps was diethyl pyrocarbonate treated to reduce RNase contamination and loss of in situ signal. Following application of the chromagen diaminobenzidine, slides were washed twice in PBS and then prehybridized for 1 h at 42°C. Following this incubation, the linearized 35S-labeled riboprobe was added to the sections, and the standard in situ hybridization procedure was followed (9). Upon development, the slides were counterstained in hematoxylin only, dehydrated, and mounted.
T cell isolation and flow cytometry
Cells were obtained from brains of mice treated with either anti-Mig or NRS at days 3, 7, and 9 p.i. A single-cell suspension was obtained by a previously described method (1), and FITC-conjugated rat anti-mouse CD4 and CD8 were used to detect infiltrating CD4+ and CD8+ T cells. As a control, an isotype-matched FITC-conjugated Ab was used. Cells were incubated with Abs for 30 min at 4°C, washed, fixed in 1% paraformaldehyde, and analyzed on a FACStar (Becton Dickinson, Mountain View, CA) (1, 4).
Immunohistochemistry
Primary Abs (diluted in PBS containing 2% normal goat serum) used for immunohistochemical detection of cellular Ags were as follows: rat anti-mouse CD4 (PharMingen, San Diego, CA) at 1:200 and rat anti-mouse CD8a (PharMingen) at 1:100. Staining for CD4 and CD8 was performed on 8-µm frozen brain sections fixed in 95% ethanol for 10 min at -20°C. These reagents are capable of recognizing either mouse CD4 or CD8 (manufacturer’s specifications). A biotinylated secondary Ab was used (1:300; Vector Laboratories, Burlingame, CA) and the ABC Elite (Vector Laboratories) staining system was used according to manufacturer’s instructions. Diaminobenzidine was used as a chromagen. All slides were counterstained with hematoxylin, dehydrated, and mounted. Staining controls were omission of primary Abs from the staining sequence (original magnification x40).
RT-PCR
Total RNA was extracted using Trizol reagent (Life Technologies, Grand Island, NY) and reverse transcribed using the avian myeloblastoma virus reverse transcriptase system (Promega, Madison, WI). PCR amplification was performed on resulting cDNA for 30 cycles with specific primers for either CXCR3(forward, 5'-GCGGCCGCAACTCTTCCATTGTGG; reverse, 5'-GAATTCAAGGCCCCTGCATAGAAGTT), L32 (forward, 5'-AACGCTCAGCTCCTTGACAT; reverse, 5'-AACCCAGAGGCATTGACAAC), or Mig (forward, 5'-CGT CGT CGT TCA AGG AAG; reverse, 5'-TCG AAA GCT TGG GAG GTT). Sequence analysis of CXCR3, L32, and Mig amplicons confirmed primer specificity. Amplification was performed on an automated Perkin-Elmer/Cetus (Norwalk, CT) model 480 DNA thermocycler using the following profile: step 1, initial denaturation at 94°C for 45 s; step 2, annealing at 60°C for 45 s; and step 3, extension at 72°C for 2 min. Steps 1–3 were repeated 29 times for a total of 30 cycles and were followed by a 7-min incubation at 72°C. The Mig fragment was cloned into the pCR Script SK+ vector (Stratagene, San Diego, CA) and used for RNase protection assay (RPA) analysis as described.
RNase protection assay
Total RNA was extracted from brains and spinal cords of MHV-infected animals treated with either anti-Mig or NRS at days 2, 7, 12, and 35 p.i. (9). The antisense riboprobe used to detect Mig mRNA was derived by RT-PCR amplification of cDNA generated from total RNA isolated from the brain of an MHV-infected mouse at day 7 p.i. For analysis of Mig and MHV gene expression, the Mig riboprobe was used in combination with a previously described riboprobe specific for the MHV spike gene and IP-10 (5, 9). L32 was added as an internal control to verify consistency in RNA loading and assay performance (1, 9). Cytokine transcripts were analyzed using the mCK-3 multitemplate probe sets (PharMingen). RPA analysis was performed with 15 µg of total RNA using a previously described protocol (1, 9). For quantification of signal intensity, autoradiographs were scanned and individual chemokine bands were normalized as the ratio of band intensity to the L32 control (1, 4, 9). Analysis was performed using NIH Image 1.61 software.
ELISA
IFN-, IL-4, and IL-10 protein levels within experimental
groups were determined using the Quantikine M mouse immunoassay kits
(R&D Systems, Minneapolis, MN) (1, 4). Tissue samples were
homogenized in 1 ml of sterile PBS and spun at 400 x g
for 5 min at 4°C. Duplicate supernatant samples were used to
determine respective protein levels present within the tissues
according to the manufacturer’s instructions. Following the enzymatic
color reaction, samples were read at 450 nm and respective protein
levels were quantified in comparison to a standard curve (supplied by
the manufacturer). The limit of sensitivity of protein detection was
8.0 pg/ml. The reagents used for these experiments do not
cross-react with other mouse cytokines (manufacturer’s
specifications).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Following MHV infection of the CNS, viral titers peaked at day
7 p.i., yet virus could not be isolated by 10 days p.i. as
determined by plaque assay (limit of detection 100 PFU/g tissue),
which is similar with the kinetics of viral clearance determined in
previous studies (Table I
)
(4). During the acute stage of disease (
day 7), virus
replicates within neurons as well as glial cells (29, 30).
Animals that survive acute disease often develop a chronic
demyelinating disease characterized by viral persistence within
astrocytes and oligodendrocytes accompanied by mononuclear cell
infiltration and myelin destruction (29, 31). Total RNA
was isolated from brains at days 2, 7, 12, and 35 days p.i., and the
kinetics of Mig, IP-10, and viral gene expression was determined by
RPA. The results presented in Fig. 1
demonstrate that MHV spike gene and IP-10 expression is detected as
early as day 2 p.i., yet Mig is not detected at this time point.
However, Mig, IP-10 and the MHV spike gene are prominently expressed at
days 7 and 12 p.i. By day 35 p.i., a time in which the
animals exhibit extensive myelin loss (data not shown), Mig transcripts
are undetectable, whereas spike gene and IP-10 transcripts are still
present. Double-labeling using an antisense riboprobe specific for Mig
mRNA and a polyclonal Ab to GFAP indicate that astrocytes express Mig
following MHV infection (Fig. 2). Greater
than 95% of cells expressing Mig transcripts were found to be
astrocytes as determined by counting double-positive cells within the
brains of infected mice. Although double-labeling was not performed, it
is likely that macrophages are the additional cellular sources of Mig
expression within the CNS of infected mice (10).
Collectively, these data suggest that Mig expression is important
during acute disease but does not contribute to chronic demyelination
within persistently infected mice.
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MHV-infected mice were treated with anti-Mig antisera in an
attempt to evaluate the functional significance of Mig expression
following viral infection of the CNS. Such treatment resulted in a
marked increase in mortality as compared with control mice treated with
NRS (Fig. 3). By day 12 p.i., <10%
of anti-Mig-treated mice survived the infection in contrast to an
approximate 50% survival rate in infected mice treated with NRS (Fig. 3). Surviving mice treated with anti-Mig displayed significantly
higher (p < 0.001) titers of virus (5.4
± 0.4, n = 4) as compared with titers present in
NRS-treated mice (2.0 ± 0.2, n = 10) (Table I
).
These data indicate that neutralization of Mig during acute disease
results in increased mortality that correlates with an increase in
viral burden within the CNS.
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We have previously shown that CD4+ and
CD8+ T lymphocytes present within the CNS of
MHV-infected mice express CXCR3, the shared receptor for Mig and IP-10
(4). These data suggest that Mig is able to attract T
cells into the CNS in response to viral infection. To determine T
lymphocyte infiltration into the CNS, FACS analysis was performed at 3,
7, and 9 days p.i. At 3 days p.i. no appreciable difference in T
lymphocyte infiltration was observed between anti-Mig- and
NRS-treated mice (Table II). This
observation is not unexpected as Mig expression is not detected at this
point (Fig. 1). In contrast, at 7 and 9 days p.i., MHV-infected mice
treated with anti-Mig displayed significantly lower levels of both
CD4+ (45 and 53% decrease at 7 and 9 days p.i.,
respectively) and CD8+ (60 and 40% decrease at 7
and 9 days p.i., respectively) T lymphocyte infiltration into the CNS
when compared with levels present within NRS-treated mice (Table II).
This decrease in infiltration was further confirmed using
immunohistochemical staining for either CD4 or CD8 Ag within brains of
mice treated with either anti-Mig or NRS (Fig. 4). Consistent with the FACS data,
increased numbers of CD4+ and
CD8+ T lymphocytes were detected within
perivascular cuffs present within the brains of NRS-treated mice as
compared with anti-Mig-treated mice. T lymphocytes that are present
within the CNS of anti-Mig-treated mice migrate to similar anatomic
areas of the brain as control mice, e.g., areas where viral Ag is
detected, indicating tissue distribution of infiltrating T cells is not
affected (data not shown).
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, CXCR3 mRNA
transcript levels within the CNS of mice treated with anti-Mig are
markedly lower than levels present in the brains of mice treated with
NRS. Similar to Mig, IP-10 has been shown to be chemotactic for
CD4+ and CD8+ T lymphocytes
through interaction with the receptor CXCR3. Determination of the
levels of IP-10 at 7 days p.i. by RPA analysis revealed a decrease
(18%) in IP-10 mRNA transcripts in the CNS of mice treated with
anti-Mig antisera when compared with NRS control mice (data not
shown).
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One mechanism by which T cells contribute to host defense against
MHV infection of the CNS is through the release of the cytokine IFN-
(2, 5, 6). To determine whether IFN- levels were
altered in MHV-infected mice treated with anti-Mig, cytokine mRNA
transcript levels within the CNS of anti-Mig- or NRS-treated mice
were evaluated by RPA at days 3 and 7 p.i. Quantification of
signal intensities indicated that at 3 days p.i. there were no
appreciable differences in cytokine mRNA expression between mice
treated with anti-Mig and NRS. In contrast, anti-Mig-treated
mice displayed an 85% decrease in IFN- transcripts
(p < 0.05) as well as a 65.1% decrease in
IFN- transcript levels (p < 0.02) as
compared with mice treated with NRS at 7 days p.i. (Table III). Consistent with the RPA results,
IFN- protein levels were reduced by 91% (p
< 0.05) within the CNS of anti-Mig-treated mice as compared with
NRS-treated mice as determined by ELISA (Table IV). Coinciding with decreased IFN-
levels within anti-Mig-treated mice was a 4-fold increase
(p < 0.02) in levels of the
anti-inflammatory Th2 cytokine IL-10, whereas another
Th2-associated cytokine, IL-4, was not detected in either group of mice
at this time point (Table IV). Treatment of mice with other
anti-chemokine antisera such as anti-RANTES does not result in
altered IL-10 levels, suggesting that the effect observed is specific
for Mig neutralization (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study has evaluated the role of Mig in contributing to host
defense following MHV infection of the CNS. The results presented
demonstrate similarities as well as differences between Mig and IP-10
as they relate to MHV-induced CNS disease. Unlike IP-10, which is
expressed during acute and chronic disease, expression of Mig was
limited to the acute stage of infection (9). The highest
levels of Mig mRNA transcripts were detected at day 7 p.i.
followed by a 60% decrease by day 12 p.i. During this time,
astrocytes were determined to be a cellular source of Mig; this is
consistent with previous studies (33, 34). In contrast to
IP-10, Mig transcripts are not detected at day 2 p.i., which
represents a time in which very little IFN- is present within the
CNS (Table III). Therefore, given the dependence of Mig on IFN- as a
triggering signal, this may explain why Mig is not seen at this stage
of infection. The presence of IP-10 transcripts at day 2 is consistent
with a previous study and can now be explained by data indicating
IFN- is present at this time (9). In addition, Mig
transcripts were undetectable at day 35 p.i. at which point
surviving animals were persistently infected with virus and undergoing
chronic demyelination. Together, these results suggest that expression
of Mig is important during the acute stage of disease but does not
contribute to the pathology of chronic demyelination. In support of
this is the demonstration that Ab-mediated neutralization of Mig
activity resulted in a shift from a protective Th1 to a Th2 response
characterized by 1) a significant reduction (p
< 0.005) in CD4+ and CD8+
T cell infiltration into the CNS; 2) decreased IFN- expression
(p 0.05); and 3) increased levels
(p 0.02) of the anti-inflammatory Th2
cytokine IL-10 as compared with levels found in NRS-treated mice. This,
in turn, correlated with a marked increase in mortality accompanied by
a significant increase (p 0.001) in viral
titers within the CNS of anti-Mig-treated mice vs NRS-treated
mice.
The results presented support and extend an earlier study from our
laboratory that determined that IP-10 expression is important in host
defense against MHV infection of the CNS by contributing to mononuclear
cell infiltration into the CNS and viral clearance (4).
Collectively, these results indicate that both Mig and IP-10 are
important contributors in host defense from MHV infection of the CNS by
promoting a protective Th1 response. Due to the fact that Mig and IP-10
share receptor use and functional properties, it is interesting that
neutralization of Mig did not result in an IP-10-mediated compensatory
effect in host defense. However, this may be explained by the
demonstration that anti-Mig-treated mice displayed decreased CNS
transcript levels of IFN- and IFN-, both of which are potent
inducers of IP-10 expression (11, 12, 13). Therefore, it is
possible that the decrease in stimulatory signals for IP-10 expression
resulted in a diminished ability of IP-10 to compensate for the
inhibition of Mig activity. Indeed, there was an 18% decrease in
IP-10 transcript levels in mice treated with anti-Mig when compared
with NRS-treated mice, which may help explain this observation.
The dramatic increase in CNS IL-10 levels within mice treated with
anti-Mig is most likely a reflection of the reduced levels of
IFN- present within these mice. Treatment of mice with
anti-RANTES does not result in increased IL-10 levels, suggesting
that the increase in IL-10 expression following anti-Mig treatment
is not due to altered macrophage function (T.E.L. and M.T.L.,
unpublished observations). Furthermore, IL-10 expression has been shown
to be dependent on the presence or absence of IFN-. Studies by
Donnelly et al. (35) demonstrate that IFN- is capable
of suppressing IL-10 expression in monocytes in a dose-dependent
manner. In addition, in vitro infection of PBMC with human herpes virus
type 6 results in increased expression of IL-10 that is inhibited
following IFN- treatment. Neutralization of IFN- activity
restored IL-10 expression by human herpes virus type 6-infected cells
(36). Therefore, the increased levels of IL-10 may further
diminish an effective host response to MHV by contributing to the
inhibition of CNS inflammation as well as inhibiting cellular function
as has been suggested to occur in experimental autoimmune
encephalomyelitis and other models of CNS inflammation
(37, 38, 39, 40, 41).
Although the reduction in IFN- levels was not surprising given the
dramatic decrease in T cell infiltration, the lowered transcript levels
of IFN- was interesting. Neutralization of IP-10 does not affect
IFN- transcript levels within the CNS of MHV-infected mice,
indicating that Mig may directly influence IFN- expression (M.T.L.
and T.E.L., unpublished observations). In addition, it is also possible
that the reduction in IFN- transcript levels in the CNS of
anti-Mig-treated mice is a reflection of reduced cellular
infiltration as has been suggested by Mahalingam et al.
(23) in studies with a recombinant vaccinia virus
expressing Mig. The increased viral burden within the CNS of mice
treated with anti-Mig antisera is most likely the result of
decreased levels of IFN- and IFN- as both cytokines are
considered to contribute to host defense against MHV infection
(5, 6, 42).
In conclusion, the data presented in this study provide further evidence that chemokine expression is important in host defense against viral infection of the CNS by helping to promote a protective Th1 response (4). Moreover, these studies provide additional support for the concept that selected Ab-mediated targeting of chemokines is a powerful method of modulating the severity of neuroinflammation following viral infection (1, 4, 43, 44). Therefore, the use of Ab-mediated neutralization of chemokine activity may also provide attractive strategies for ameliorating the severity of human neuroinflammatory diseases such as multiple sclerosis in which chemokines have been postulated to have an important role in the pathology of disease (45, 46).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas E. Lane, Department of Molecular Biology and Biochemistry, University of California, Irvine, 3205 Biological Sciences II, Irvine, CA 92697-3900.
3 Abbreviations used in this paper: MHV, mouse hepatitis virus; Mig, monokine induced by IFN-; IP-10, IFN--inducible protein 10; NRS, normal rabbit serum; RPA, RNase protection assay; p.i., postinfection; CXCR3, CXC chemokine receptor 3; GFAP, glial fibrillary acidic protein.
Received for publication July 24, 2000. Accepted for publication November 2, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is required for viral clearance from central nervous system oligodendroglia. J. Immunol. 162:1641. and chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. J. Immunol. 160:970.-interferon transcriptionally regulates an early response gene containing homology to platelet proteins. Nature 315:672.[Medline]
-interferon encodes a member of the platelet factor 4 family of cytokines. Proc. Natl. Acad. Sci. USA 87:5238., MCP-1, IP-10 and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am. J. Pathol. 153:1849. and chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am. J. Pathol. 150:617.[Abstract]
-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J. Immunol. 163:5686., promotes tumor necrosis in vivo. Blood 89:2635.-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol. Appl. Neurobiol. 26:133.[Medline]
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 G. VALBUENA and D. H. WALKER EFFECT OF BLOCKING THE CXCL9/10-CXCR3 CHEMOKINE SYSTEM IN THE OUTCOME OF ENDOTHELIAL-TARGET RICKETTSIAL INFECTIONS Am J Trop Med Hyg, October 1, 2004; 71(4): 393 - 399. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9 J. Immunol., July 1, 2004; 173(1): 615 - 623. [Abstract] [Full Text] [PDF]
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W. G. Glass, M. J. Hickey, J. L. Hardison, M. T. Liu, J. E. Manning, and T. E. Lane Antibody Targeting of the CC Chemokine Ligand 5 Results in Diminished Leukocyte Infiltration into the Central Nervous System and Reduced Neurologic Disease in a Viral Model of Multiple Sclerosis J. Immunol., April 1, 2004; 172(7): 4018 - 4025. [Abstract] [Full Text] [PDF]
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K. Abel, L. La Franco-Scheuch, T. Rourke, Z.-M. Ma, V. de Silva, B. Fallert, L. Beckett, T. A. Reinhart, and C. J. Miller Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques J. Virol., January 15, 2004; 78(2): 841 - 854. [Abstract] [Full Text] [PDF]
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U. Christen, D. B. McGavern, A. D. Luster, M. G. von Herrath, and M. B. A. Oldstone Among CXCR3 Chemokines, IFN-{gamma}-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN-{gamma} (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease J. Immunol., December 15, 2003; 171(12): 6838 - 6845. [Abstract] [Full Text] [PDF]
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 G. Valbuena, W. Bradford, and D. H. Walker Expression Analysis of the T-Cell-Targeting Chemokines CXCL9 and CXCL10 in Mice and Humans with Endothelial Infections Caused by Rickettsiae of the Spotted Fever Group Am. J. Pathol., October 1, 2003; 163(4): 1357 - 1369. [Abstract] [Full Text] [PDF]
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J. Melchjorsen, L. N. Sorensen, and S. R. Paludan Expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function J. Leukoc. Biol., September 1, 2003; 74(3): 331 - 343. [Abstract] [Full Text] [PDF]
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M. J. Trifilo, C. C. Bergmann, W. A. Kuziel, and T. E. Lane CC Chemokine Ligand 3 (CCL3) Regulates CD8+-T-Cell Effector Function and Migration following Viral Infection J. Virol., April 1, 2003; 77(7): 4004 - 4014. [Abstract] [Full Text] [PDF]
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W. G. Glass and T. E. Lane Functional Expression of Chemokine Receptor CCR5 on CD4+ T Cells during Virus-Induced Central Nervous System Disease J. Virol., December 6, 2002; 77(1): 191 - 198. [Abstract] [Full Text] [PDF]
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J. J. Yun, M. P. Fischbein, D. Whiting, Y. Irie, M. C. Fishbein, M. D. Burdick, J. Belperio, R. M. Strieter, H. Laks, J. A. Berliner, et al. The Role of MIG/CXCL9 in Cardiac Allograft Vasculopathy Am. J. Pathol., October 1, 2002; 161(4): 1307 - 1313. [Abstract] [Full Text] [PDF]
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K. Boztug, M. J. Carson, N. Pham-Mitchell, V. C. Asensio, J. DeMartino, and I. L. Campbell Leukocyte Infiltration, But Not Neurodegeneration, in the CNS of Transgenic Mice with Astrocyte Production of the CXC Chemokine Ligand 10 J. Immunol., August 1, 2002; 169(3): 1505 - 1515. [Abstract] [Full Text] [PDF]
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J. S. Haring, L. L. Pewe, and S. Perlman Bystander CD8 T Cell-Mediated Demyelination After Viral Infection of the Central Nervous System J. Immunol., August 1, 2002; 169(3): 1550 - 1555. [Abstract] [Full Text] [PDF]
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J. Melchjorsen, F. S. Pedersen, S. C. Mogensen, and S. R. Paludan Herpes Simplex Virus Selectively Induces Expression of the CC Chemokine RANTES/CCL5 in Macrophages through a Mechanism Dependent on PKR and ICP0 J. Virol., February 22, 2002; 76(6): 2780 - 2788. [Abstract] [Full Text] [PDF]
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 K. Kakimi, T. E. Lane, S. Wieland, V. C. Asensio, I. L. Campbell, F. V. Chisari, and L. G. Guidotti Blocking Chemokine Responsive to {gamma}-2/Interferon (IFN)-{gamma} Inducible Protein and Monokine Induced by IFN-{gamma} Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus-specific Cytotoxic T Lymphocytes J. Exp. Med., December 17, 2001; 194(12): 1755 - 1766. [Abstract] [Full Text] [PDF]
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K. Kakimi, T. E. Lane, F. V. Chisari, and L. G. Guidotti Cutting Edge: Inhibition of Hepatitis B Virus Replication by Activated NK T Cells Does Not Require Inflammatory Cell Recruitment to the Liver J. Immunol., December 15, 2001; 167(12): 6701 - 6705. [Abstract] [Full Text] [PDF]
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B. P. Chen, W. A. Kuziel, and T. E. Lane Lack of CCR2 Results in Increased Mortality and Impaired Leukocyte Activation and Trafficking Following Infection of the Central Nervous System with a Neurotropic Coronavirus J. Immunol., October 15, 2001; 167(8): 4585 - 4592. [Abstract] [Full Text] [PDF]
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M. T. Liu, H. S. Keirstead, and T. E. Lane Neutralization of the Chemokine CXCL10 Reduces Inflammatory Cell Invasion and Demyelination and Improves Neurological Function in a Viral Model of Multiple Sclerosis J. Immunol., October 1, 2001; 167(7): 4091 - 4097. [Abstract] [Full Text] [PDF]
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