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Departments of
*
Microbiology-Immunology and
Pathology and the Interdepartmental Immunobiology Center, Northwestern University Medical School and the Northwestern University Institute for Neuroscience, Chicago, IL 60611;
Ben May Institute for Cancer Research and the Committee for Immunology, University of Chicago, Chicago, IL 60637; and
§
Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
TNF-
in response to the immunogen, proteolipid protein 56–70. In
fact, IFN- and TNF- production by Ag-specific T cells was
enhanced in both the B7-1 and B7-2-deficient NOD mice. In contrast,
peptide-specific delayed-type hypersensitivity responses in these
animals were significantly decreased, suggesting a critical role for
CD28 costimulation in in vivo trafficking and systemic immunity.
Collectively, these results support a critical role for CD28
costimulation in EAE induction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For this reason, we and others have explored the role of this costimulatory system in the induction and progression of murine experimental autoimmune encephalomyelitis (EAE),4 a CD4+ Th1-mediated inflammatory demyelinating disease of the CNS and a well-established animal model for the human disease, multiple sclerosis (13, 14). Studies employing CTLA-4Ig, a soluble CD28 antagonist that binds to both B7-1 and B7-2, in a proteolipid protein (PLP139–151)-induced relapsing-remitting EAE model in SJL mice have shown a predominant role for CD28-mediated costimulation in EAE induction (15). Additionally, blockade of CD28 signaling with CD28 F(ab) ameliorates myelin basic protein-induced EAE (16), demonstrating the critical role for CD28-mediated costimulation in EAE induction and progression. However, the individual effects of anti-B7-1 and anti-B7-2 mAb therapies on disease induction were less clear. Kuchroo et al. reported that anti-B7-1 mAbs inhibited the disease while anti-B7-2 led to disease exacerbation. However, the effectiveness of the mAb required continuous therapy for 30 days postimmunization overlapping the first acute and relapse phases (17). In contrast, studies from our laboratory showed that treatment of SJL mice with anti-B7-2 during disease remission had no effect on further disease progression, while blockade of B7-1 with anti-B7-1 F(ab) suppressed clinical relapses (18, 19). These results demonstrate potential separate functional roles for B7-1 and B7-2 during EAE induction and progression. However, the interpretation of these data are complicated by the fact that the efficacy of mAb therapy will depend on the effectiveness of the blockade based on the type or the dose of mAb used but, more importantly, may be influenced by the potential signaling capacity of the mAbs. This is perhaps best exemplified by the observation that treatment of SJL mice with intact anti-B7-1 mAbs during disease remission EAE results in accelerated relapses pathology and epitope spreading (19).
To more directly discern the potential roles of B7-1, B7-2, and CD28 in
EAE induction, we compared disease induced in mice deficient for
expression of CD28 (CD28-/-) or B7
costimulatory molecules (B7-1-/- and
B7-2-/-) to the effects of mAb therapy for 10
days following the primary induction of EAE in wild-type mice. We
describe the development of a new model of acute EAE in nonobese
diabetic (NOD) mice using a proteolipid peptide,
PLP56–70, previously shown to be
encephalitogenic in Biozzi AB/H (I-Ag7) mice
(20). Disease severity was most significantly reduced in
B7-2-/- NOD mice and absent in
CD28-/- NOD mice as compared with wild-type NOD
animals, despite the ability of these animals to produce normal or
enhanced levels of IFN- and TNF- to the immunizing Ag.
Furthermore, disease induction was significantly delayed in mice
treated for 10 days postimmunization with either CTLA-4Ig or with a
combination anti-B7-1 plus anti-B7-2 mAbs, indicating a
critical role for B7/CD28 signaling in EAE induction in the NOD
mouse.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NOD female mice, 4–5 wk old, and CD28-/- mice on the C57BL/6 background were purchased from The Jackson Laboratory (Bar Harbor, ME). B7-1-/- and B7-2-/- mice were generated on the 129/S4AvJae background by gene targeting (21, 22). These knockout mice were backcrossed onto the NOD strain for five or more generations. The backcrossed animals were intercrossed, and female mice were used in all experiments. All mice were housed in barrier conditions with the Center for Experimental Animal Research at Northwestern University and were maintained on standard laboratory food and water ad libitum. Paralyzed animals were afforded easier access to food and water.
Peptides
PLP56–70 (DYEYLINVIHAFQYV) and OVA323–339 (ISQAVHAAHAEINEAGR) were purchased from Peptides International (Louisville, Kentucky). Amino acid composition was verified by mass spectrometry, and purity (>98%) was assessed by HPLC.
Induction and clinical evaluation of PLP56–70-induced EAE
Five- to 7-wk-old female NOD mice were immunized s.c. with 200 µl of an emulsion containing 800 µg of Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI) and 200 µg PLP56–70 distributed over two spots on the flank. Each mouse additionally received 200 ng pertussis toxin (List Biological Laboratories, Campbell, CA) in 200 µl PBS i.v. on days 0 and 2 postimmunization. Individual animals were observed daily, and clinical scores were assessed on a 0–5 scale as follows: 0, no abnormality; 1, limp tail; 2, limp tail and hind limb weakness (legs slip through cage top); 3, partial hind limb paralysis; 4, complete hind limb paralysis; and 5, moribund. The data are reported as the mean daily clinical score for all animals in a particular group and/or as the mean peak clinical score, i.e., the mean clinical score for all animals at the peak of disease. Animals were also monitored for the development of diabetes by determining urinary glucose levels. No animals were found to develop overt diabetes, probably due to the fact that CFA administration prevents clinical disease in NOD mice (23).
Ab treatments
The following mAbs were employed: hamster control Ig (Parsi12), anti-CD80 (B7-1) mAb 16-10A1, and anti-CD86 (B7-2) mAb GL-1 (24). Murine CTLA4-Ig was obtained from the Genetics Institute (Boston, MA). Abs were produced in an Acusyst Jr. Bioreactor and purified as previously described (10). Mice were treated i.p. with 50 µg of Ab in 500 µl saline every other day from day -2 until day 10 postimmunization (7 doses total).
Elicitation of delayed-type hypersensitivity (DTH) responses
DTH responses were quantitated using a 24-h ear swelling assay. Prechallenge ear thickness was determined using a Mitutoyo model 7326 engineer’s micrometer (Schlesinger’s Tool, Brooklyn, NY). Immediately thereafter, DTH responses were elicited by injecting 10 µg of peptide (in 10 µl of saline) into the dorsal surface of the ear using a 100-µl syringe fitted with a 30-gauge needle. The increase in ear thickness was determined 24 h after ear challenge. Results are expressed in units of 10-4 inches ± SEM. Background swelling ranged between 3–10 x 10-4 inches.
In vitro proliferation and cytokine assays
On day 10 postimmunization, draining lymph node and splenic
cells were harvested and cultured in 96-well microtiter plates at a
density of 5 x 105 cells/well in a total
volume of 200 µl DMEM containing 10% FBS, 1 mM glutamine, 1%
penicillin-streptavidin, 1 mM nonessential amino acids, and 5 x
10-5 M 2-ME (complete DMEM 10%; all products
from Sigma, St. Louis, MO). Cells were cultured with media alone or
different concentrations of peptide Ag for 96 h. Culture wells
were pulsed with 1 µCi/well [3H]TdR for the
final 24 h of the 96 h incubation period.
[3H]TdR uptake was detected using a topcount
microplate scintillation counter (Packard Instruments, Meriden, CT),
and results are expressed as the mean of triplicate cultures ±
SEM (background counts subtracted). Supernatants collected at 24 and
48 h from replicate cultures were assayed for IFN-, TNF-,
IL-4, and IL-5 levels using ELISA Minikits (Endogen, Cambridge,
MA).
Histological evaluation
Mice were anaesthetized and sacrificed by total body perfusion through the left ventricle using chilled 3% glutaraldehyde in PBS, pH 7.3. Spinal cords were dissected out and cut into 1-mm thick segments and postfixed in OsO4, dehydrated, and embedded in Epon (Electron Microscopy Sciences, Ft. Washington, PA). Toluidine blue-stained sections from 10 segments per mouse were read and scored blinded by Dr. Mauro Dal Canto at Northwestern University (Chicago, IL).
Statistical analyses
Comparison of the percentage of animals showing clinical disease
between any two groups of mice was done by 
2
using Fisher’s exact probability. Comparisons of the mean day of onset
of relapse and mean peak disease severity between any two groups of
mice were analyzed by the Student’s t test.
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Results |
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To gain a clearer understanding of the role of the CD28/B7
costimulatory pathway in the initiation of EAE, we attempted to induce
EAE in NOD mice deficient in CD28/B7 costimulation. Wild-type,
CD28-/-, B7-1-/-, and
B7-2-/- NOD mice were immunized with 200 µg
PLP56–70 in CFA and monitored for clinical signs
of disease for 35–50 days postimmunization. Clinical and histologic
signs of EAE were not inducible in CD28-deficient NOD mice (Fig. 1
A and Table I). B7-1-deficient mice developed a
slightly milder disease course when compared with the wild-type NOD
controls (Fig. 1B) displaying a similar disease incidence,
but a slightly delayed onset and reduced clinical severity (Table I).
Compared with wild-type NOD controls, clinical signs of EAE in
B7-2-deficient NOD females were significantly impaired (Fig. 1C). B7-2-/- mice had a
similar disease incidence, but a significantly delayed disease onset
and reduced clinical and histologic disease severity compared to
controls (Table I). The mild course of EAE seen in
B7-2-/- mice was a consistent finding in four
separate experiments. Thus, CD28 costimulation was required for the
clinical and histological manifestations of EAE in the NOD mouse. As
the clinical severity in B7-2-/- mice was
significantly reduced (p = 0.03) as compared
with B7-1-/- mice, the data also suggests that
B7-2 plays a more predominant role than B7-1 in induction and
progression of EAE in the NOD mouse. It was not possible to assess EAE
induction in NOD mice deficient for both B7-1 and B7-2 as these mice
develop overt diabetes in a very accelerated fashion as compared with
wild-type NOD mice (B. Salomon and J. A. Bluestone, manuscript in
preparation) and were too sick to use in the EAE studies.
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We next determined the magnitude and phenotype of
PLP56–70-specific T cell responses in NOD mice
deficient in CD28/B7 costimulation.
PLP56–70-specific proliferation and Th1-derived
(IFN- and TNF-) and Th2-derived (IL-4 and IL-5) cytokine
responses in the lymph nodes draining the site of primary immunization
and splenocytes of wild-type, CD28-/-,
B7-1-/-, and B7-2-/-
NOD mice were determined upon in vitro stimulation with
PLP56–70 peptide 10 days following immunization.
Despite their failure to develop clinical EAE, T cells from
PLP-immunized CD28-deficient NOD mice responded similarly both in terms
of proliferation (Fig. 2) and
proinflammatory cytokine production (IFN- and TNF-) (Fig. 3) when compared with wild-type NOD mice.
By comparison, T cell proliferative responses were significantly
enhanced in both lymphoid compartments in B7-1-deficient NOD mice and
reduced in B7-2-deficient animals (Fig. 2). IFN- and TNF-
production in B7-1-deficient mice was significantly enhanced (21-fold
and 3-fold, respectively) in lymph node T cells (Fig. 3). Despite the
fact that clinical disease and T cell proliferation were significantly
impaired in B7-2-deficient NOD mice, T cells from these animals made
more IFN- (>20-fold) and TNF- (2.4-fold) than wild-type NOD T
cells (Fig. 3). IL-4 and IL-5 were not detectable in any of the culture
supernatants (data not shown). These results suggest that
PLP56–70-specific Th1 cells are being primed in
both B7-2- and CD28-deficient mice and that their failure to develop
clinical EAE is not due to an inability to produce Th1-type
cytokines.
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We next analyzed DTH reactivity as an in vivo measure of the
relative abilities of wild-type, CD28-/-,
B7-1-/-, and B7-2-/-
mice to mount a Th1-dependent Ag recall response. At day 30
postimmunization, representative mice were ear challenged with 10 µg
of the immunizing PLP56–70 peptide. As seen in
Fig. 4, DTH responses were reduced in all
of the knockout mice with the most significant decrease in
CD28-deficient mice. These results suggest that disruption of the
B7/CD28 costimulatory pathway abrogated the ability of CD28 knockout
mice to mount a normal DTH response to the disease-initiating epitope.
The results also suggest that severe defects in DTH responses, as seen
in the CD28-deficient mice, can be more predictive of clinical outcome
than are in vitro T cell proliferative responses or cytokine
assays.
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To attempt to compare the results obtained using the
costimulation-deficient mice to previous reports that used in vivo
therapy with intact mAbs, we immunized wild-type NOD mice with 200 µg
PLP56–70 in CFA and treated them with CD28/B7
antagonists every other day from day -2 until day 10 postimmunization.
Treatment with either CTLA-4Ig or with a combination of anti-B7-1
and anti-B7-2 mAbs resulted in a significant delay in disease onset
in wild-type NOD mice (mean day of onset = 23 and 24 days,
respectively) compared with that of control Ig-treated animals (mean
day of onset = 18 days) (Fig. 5 and
Table II). Disease severity was also
reduced in three of the four animals treated with CTLA-4Ig (Fig. 5 and
Table II). The individual contributions of B7-1 and B7-2 were examined
by treating at disease initiation with either mAb. Clinical disease was
not significantly affected by treatment with either anti-B7-1 or
anti-B7-2 alone when compared with NOD mice treated with a control
hamster Ig (Fig. 5 and Table II). Costimulatory blockade concomitant
with myelin peptide priming did not result in long-term peripheral
tolerance as indicated by the fact that clinical symptoms (Fig. 5),
DTH, and T cell proliferative responses (data not shown) developed
after the clearance of the Abs. DTH responses correlated with clinical
severity, while T cell proliferative responses did not.
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A). The groups treated with
anti B7-1 or anti B7-2 alone had significant inflammation accompanied
by a milder demyelination (Fig. 6, B and C).
Histological signs of disease were absent in the group treated with
both anti-B7-1 and anti-B7-2 (Fig. 6D), and only
mild inflammation was observed in the CTLA-4Ig-treated group (Fig. 6E). Overall, the histological evaluation of the target
organ corresponded closely with the clinical scores of each group at
day 25 postimmunization (see Fig. 5
). Collectively, these results imply
that T cell activation sufficient to initiate EAE requires either B7-1
or B7-2 costimulatory signaling via CD28. However, in light of the
significant reduction in disease noted in the
B7-2-/- mice (Fig. 1), functional conclusions
regarding the individual roles of B7-1 and B7-2 in EAE induction may be
more complicated than is easily determined by mAb therapy.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- production
was equivalent to or greater than wild-type levels. In contrast,
peptide-specific DTH responses in these animals were significantly
decreased. Lastly, development of EAE was significantly delayed in NOD
mice in which CD28 signaling was inhibited by in vivo administration of
a combination of anti-B7-1 plus anti-B7-2 or CTLA4-Ig.
Interestingly, unlike disease in mice deficient for either B7-1 or
B7-2, treatment with anti-B7-1 or anti-B7-2 alone was not
effective in inhibiting EAE. However, it is clear that the
anti-B7-1 and anti-B7-2 mAbs were functional because together
they efficiently delayed disease onset in wild-type NOD mice (Fig. 5
and Table II), and anti-B7-1 mAb therapy of B7-2-deficient animals
further reduced disease severity (A. M. Girvin and S. D. Miller,
unpublished observation). In our studies, blocking B7 molecules with
mAbs had moderate effects compared with NOD mice deficient in B7
molecules. Differential efficiency of mAb blockade in different
tissues, particularly peripheral lymphoid organs vs the CNS, may
explain this dichotomy. Also, mAb treatment only provides short-term
blockade, while costimulatory molecule-deficient animals provide
permanent blockade of costimulatory signaling. Each strategy has its
own advantages and drawbacks. Thus, it is critical to analyze both
before making definitive conclusions. Collectively, our results
indicate that the initiation of EAE in the NOD mouse is regulated by
B7/CD28 costimulation.
The failure to induce EAE in CD28-deficient NOD mice definitively
demonstrates the necessity for B7/CD28 interaction in EAE initiation
and progression. Despite their resistance to development of clinical
EAE, T cells from PLP56–70-primed CD28-deficient
NOD mice proliferate and secrete IFN- and TNF- at wild-type
control levels, indicating the protected phenotype is not due to a
blockade of T cell activation. The maintenance of T cell autoreactivity
in the lymphoid system suggests that alternative costimulatory
pathways, e.g., CD40/CD154 (26), can be sufficient for T
cell expansion and cytokine production. Based on the lack of CNS
inflammation and demyelination in these mice, it appears that
CD28-deficient T cells are not present in the CNS. C-C chemokines play
an important role in the recruitment of T cells to inflammatory sites,
and macrophage inflammatory protein-1 (MIP-1) has been shown to
be critical for the acute phase of EAE (27, 28). Herold et
al. have demonstrated that CD28-deficient T cells produce significantly
less MIP-1 than wild-type T cells (29). Thus, decreased
MIP-1 production by PLP56–70-specific T cells
from CD28-deficient NOD mice may in part account for the lack of
clinical disease due to inefficient migration to the CNS. Ongoing
studies are examining chemokine production by and the trafficking
patterns of CD28-deficient T cells to determine whether these animals
are protected from EAE because encephalitogenic T cells either cannot
enter the CNS target organ and/or undergo rapid apoptosis in the CNS
due to the absence of CD28 costimulation. Interestingly, CD28-deficient
NOD mice undergo accelerated and exacerbated insulitis and diabetes
(30). The reasons for these apparently contradictory
findings are unclear, but they may be organ or disease specific,
because the diabetes model is spontaneous while EAE is an induced
autoimmune response. CD28 costimulation has been found to be critical
for the spontaneous development of EAE (31). However, the
requirement for CD28 signaling was overcome by immunization with very
high doses of Ag.
Anti B7-1 mAb treatment of NOD mice results in a more severe and rapid onset of insulitis and diabetes (10). Interestingly, B7-1-deficient NOD mice had an EAE clinical course similar to wild-type controls. However, they developed enhanced PLP56–70-specific proliferative responses, and proinflammatory cytokine responses of lymph node cells were significantly greater than wild-type controls. These observations suggest that lack of B7-1 results in increased T cell activation in the NOD mouse. Autoimmune target tissue-specific up-regulation of B7-1 may function by binding to CTLA-4 with greater affinity than B7-2 and down-regulating T cell responses (32, 33, 34). However, B7-1-deficient animals exhibited significantly reduced DTH responses to the disease initiating peptide, suggesting that B7-1/CD28 interactions may also regulate the migration of T cells to nonlymphoid inflammatory tissues. Collectively, these results suggest that B7-1 plays dual roles in EAE by interacting with either CD28 or CTLA-4 to regulate disease.
It is interesting to speculate that the differences between the effects of anti-B7 mAbs on EAE induction in various reports may reflect strain differences in levels of expression of the individual B7 costimulatory molecules. A recent report has identified chromosomal regions encoding CD28/CTLA-4 and B7-1/B7-2 as susceptibility loci in the induction of EAE (35). It is possible that polymorphisms within these loci regulate differential expression of B7 costimulatory molecules in individual mouse strains. For instance, although B7-2 is predominantly expressed in naive SJL mice, we have reported that B7-1 cell-surface expression is highly up-regulated on APCs and T cells in the spleen and in the CNS of SJL mice undergoing relapsing EAE (36).
Based on our studies in costimulatory molecule-deficient NOD mice, it is clear that B7-2 plays an important role in initiation of EAE. B7-2-deficient mice developed a less severe clinical course of EAE with slower kinetics than wild-type animals and displayed reduced proliferative and DTH responses, suggesting that B7-2/CD28 interactions provide a critical costimulatory signal for expansion/survival of encephalitogenic T cells. The finding that B7-2 appears to play a dominant role in initiation of EAE is compatible with earlier reports examining the differential role of B7-1 and B7-2 in initiation of spontaneous diabetes in the NOD strain (10) and in graft rejection (37). We have reported that early treatment of NOD mice with anti-B7-2 mAb or human CTLA4-Ig resulted in a profound inhibition of diabetes onset. Interestingly, unlike anti-B7-1 therapy of diabetes, we failed to observe an exacerbated EAE disease course in either mice treated with anti-B7-1 mAb or in B7-1-deficient NOD mice, which may indicate fundamental differences in costimulatory molecule expression in naive NOD mice vs those injected with myelin peptides in CFA. The B7-2 predominance in initiation of EAE in the current study differs from EAE in the SJL mouse where blockade of B7-1-mediated costimulation in vivo with intact anti-B7-1 mAbs has been shown to inhibit disease initiation under suboptimal priming conditions (17, 38). However, these studies used intact Abs. Thus, it is unclear whether the effects on disease induction were due to specific "blockade" of B7-1-mediated signaling through CD28 and/or to up-regulation of B7-2 or other costimulatory molecules on relevant APCs, which in turn affected T cell activation. In this regard, we have previously reported that epitope spreading and subsequent disease relapses in SJL mice could be inhibited by treatment of mice during disease remission with anti-B7-1 F(ab) (18), but that administration of intact anti-B7-1 mAb resulted in accelerated clinical relapses, enhanced CNS pathology, and promoted epitope spreading (19). This dichotomy suggests that the anti-B7-1 F(ab) were blocking B7-1-mediated signaling, while the intact, bivalent mAb led to exacerbated disease via its ability to cross-link surface B7-1 molecules and signal APCs and/or activated T cells.
It is noteworthy that PLP56–70-specific T cells
from both B7-2- and CD28-deficient NOD mice produced normal or
significantly enhanced levels of IFN- and TNF- despite the fact
that clinical disease was reduced or absent in these animals. Similar
in vitro proliferation and cytokine production has been observed in T
cells isolated from
CD28-/-/RAG-1-/- mice
transgenic for a myelin basic protein-specific TCR despite their lack
of spontaneous development of EAE (31). Proinflammatory
cytokines, e.g., IFN- and TNF-, are thought to play an important
role in disease pathogenesis based on their coordinated expression in
the CNS during acute and relapsing phases of EAE (39, 40, 41, 42, 43).
However, our findings are consistent with a previous report showing
that systemic administration of IFN- inhibits induction of EAE
(44) and more recent studies showing that IFN--,
IFN- receptor-, and TNF--deficient mice develop EAE in some cases
more severe than littermate controls (45, 46, 47). Whether the
enhanced levels of IFN- and TNF- contributed to disease
protection in B7-2-deficient mice is not clear at this time.
In summary, our data show an absolute requirement for CD28 signaling and a predominant role for B7-2-mediated costimulation in the development of clinical EAE in NOD mice. Although continued investigation will be required to determine the separate functional roles of B7-1 and B7-2 in the initiation, progression and regulation of EAE, costimulatory molecules remain promising targets for immunotherapy of autoimmune diseases.
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Acknowledgments |
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Footnotes |
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2 J.A.B. and S.D.M. are co-senior authors.
3 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 E. Chicago Avenue, W213, Chicago, IL 60611. E-mail address:
4 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DTH, delayed-type hypersensitivity; PLP, proteolipid protein; NOD, nonobese diabetic.
Received for publication July 9, 1999. Accepted for publication October 18, 1999.
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H. Bour-Jordan, B. L. Salomon, H. L. Thompson, R. Santos, A. K. Abbas, and J. A. Bluestone Constitutive Expression of B7-1 on B Cells Uncovers Autoimmunity toward the B Cell Compartment in the Nonobese Diabetic Mouse J. Immunol., July 15, 2007; 179(2): 1004 - 1012. [Abstract] [Full Text] [PDF]
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C. Nicolo, G. Di Sante, M. Orsini, S. Rolla, S. Columba-Cabezas, V. R. Spica, G. Ricciardi, B. M. C. Chan, and F. Ria Mycobacterium tuberculosis in the adjuvant modulates the balance of Th immune response to self-antigen of the CNS without influencing a "core" repertoire of specific T cells Int. Immunol., February 1, 2006; 18(2): 363 - 374. [Abstract] [Full Text] [PDF]
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V. Taneja, N. Taneja, M. Behrens, M. M. Griffiths, H. S. Luthra, and C. S. David Requirement for CD28 May Not Be Absolute for Collagen-Induced Arthritis: Study with HLA-DQ8 Transgenic Mice J. Immunol., January 15, 2005; 174(2): 1118 - 1125. [Abstract] [Full Text] [PDF]
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J. Karlsson, M. Johannesson, T. Lindvall, P. Wernhoff, R. Holmdahl, and A. Andersson Genetic Interactions in Eae2 Control Collagen-Induced Arthritis and the CD4+/CD8+ T Cell Ratio J. Immunol., January 1, 2005; 174(1): 533 - 541. [Abstract] [Full Text] [PDF]
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 T. Rummel, J. Batchelder, P. Flaherty, G. LaFleur, P. Nanavati, J. M. Burns, and W. P. Weidanz CD28 Costimulation Is Required for the Expression of T-Cell-Dependent Cell-Mediated Immunity against Blood-Stage Plasmodium chabaudi Malaria Parasites Infect. Immun., October 1, 2004; 72(10): 5768 - 5774. [Abstract] [Full Text] [PDF]
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D. Yadav, V. Judkowski, M. Flodstrom-Tullberg, L. Sterling, W. L. Redmond, L. Sherman, and N. Sarvetnick B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets J. Immunol., September 15, 2004; 173(6): 3631 - 3639. [Abstract] [Full Text] [PDF]
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H. Wulff, H.-G. Knaus, M. Pennington, and K. G. Chandy K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity J. Immunol., July 15, 2004; 173(2): 776 - 786. [Abstract] [Full Text] [PDF]
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B. Greve, L. Vijayakrishnan, A. Kubal, R. A. Sobel, L. B. Peterson, L. S. Wicker, and V. K. Kuchroo The Diabetes Susceptibility Locus Idd5.1 on Mouse Chromosome 1 Regulates ICOS Expression and Modulates Murine Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2004; 173(1): 157 - 163. [Abstract] [Full Text] [PDF]
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cpm ± SEM (background
counts subtracted). T cells from all groups failed to respond to
OVA323–339 as an irrelevant peptide control (data not
shown). Results are representative of three separate experiments. *,
Proliferative responses in B7-1-/- mice were
significantly greater than wild-ype controls. **, Proliferative
responses of B7-2-/- mice were significantly less than
controls, p < 0.01.
