| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Center for Neurologic Diseases and
Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
,
and TNF-
correlated with disease activity and severity, while
TGF-ß was the only factor that was up-regulated during the recovery
phase. Interestingly, TGF-ß was also expressed by neurons during
remission. This is the first study demonstrating the kinetics of the in
vivo expression of costimulatory molecules, their ligands, and
cytokines in an autoimmune disease model characterized by remissions
and relapses. Our data suggest that the targeting of costimulatory
molecules to block an immune response must take into account the
expression patterns in the target organ. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating central nervous system (CNS) disease that is initiated by encephalitogenic CD4+ Th1 cells (8, 9) which are specific to myelin Ags. Th2 cells are not encephalitogenic (10), and expression of Th2 cytokines in the CNS has been associated with protection from EAE (11, 12, 13). B7-1 and B7-2 are believed to differentially activate Th1 and Th2 cells in vitro (14) and in vivo (15, 16), although this idea is controversial (17, 18). In addition, blocking B7-1 or B7-2 has been shown to have differential effects on autoimmune responses in vivo depending upon the disease model studied (15, 19, 20, 21). Thus, treating proteolipid protein (PLP)-induced EAE with Ab to B7-1 reportedly prevents disease and promotes the development of Th2 cells, while treatment with anti-B7-2 resulted in the production of effector cells of a Th1 phenotype and increased disease severity (15). In contrast, blocking B7-1 worsened diabetes in nonobese diabetic mice (21), while B7-2 blockade was beneficial.
CTLA4 is a CD28 homologue that is expressed after T cell activation, interacts with B7-1/B7-2, and delivers a negative signal that terminates immune responses (22, 23). Gene knockout mice that lack CTLA4 develop severe autoimmunity and lymphoproliferative disorders and die soon after birth (24, 25). Interestingly, blocking CTLA4 in vivo has been shown to worsen autoimmune responses (26, 27) and prevent the induction of peripheral tolerance (28). These studies point out the complexity of costimulatory signaling in the initiation and maintenance of the autoimmune response in vivo.
There are data that indicate that there are differences in the expression patterns of B7-1 and B7-2 in vitro (29, 30) and in vivo (31). The patterns and kinetics of costimulatory molecule expression in the target organ during autoimmune responses have not been investigated. Such studies are essential for a better understanding of autoimmune responses in vivo and for the development of specific immunotherapeutic strategies. In this report, we investigated the expression patterns of costimulatory molecules, their ligands, and cytokines in the CNS during the natural course of relapsing murine EAE, an experimental model of the human disease multiple sclerosis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Female (PLJ x SJL/J)F1 mice were obtained from The Jackson Laboratory (Bar Harbor, ME) at 6 to 8 wk of age; the mice were used at 10 to 12 wk of age.
EAE induction
(PLJ x SJL/J)F1 mice were immunized s.c. in
the flank with 100 µg of mouse myelin basic protein (MBP) that had
been prepared as described previously (32) and emulsified in an equal
amount of CFA containing 2 mg/ml Mycobacterium tuberculosis
(Difco Laboratories, Detroit, MI). The animals received 200 ng of
pertussis toxin i.p. (List Biologic Laboratories, Campbell, CA) at
24 h postimmunization. The scoring of clinical disease was
performed daily as described previously (11, 33). In this model,
animals typically develop acute disease by days 8 to 12
postimmunization. In our study, the disease incidence was 100% and the
day of onset was day 10.78 ± 0.3 (mean ± SE from 28 mice in
several experiments). Onset was followed by a clinical remission
and then by one or more relapses. Figure 1
shows the time course of the disease in
individual mice as they were euthanized for one study. The mean day of
onset in this experiment was 10.73 ± 0.36, and the incidence was
100%.
|
The following Abs were obtained from PharMingen (San Francisco,
CA): anti-glutamate receptor
(N-methyl-D-aspartate receptor 1);
anti-glial fibrillary acidic protein (GFAP); purified rat IgG1,
IgG2a, and IgG2b; purified hamster IgG; FITC-rat anti-mouse CD11b;
FITC-rat anti-mouse CD45R/B220; FITC-rat anti-mouse B7-2/2D10;
FITC-rat anti-mouse B7-1/1G10; rat anti-mouse CD40; rat
anti-mouse IFN-/R4–6A2; rat anti-mouse IL-4/BVD4-1D11; rat
anti-mouse IL-10/JES5-2A5, rat anti-mouse IL-12/C17.8; and rat
anti-mouse TNF-/MP6-XT22. Anti-TGF-ß was obtained from R&D
Systems (Minneapolis, MN), and rat anti-mouse macrophage clone
F4/80 (Caltag, South San Francisco, CA), hamster anti-mouse CTLA4,
rat anti-mouse B7-2/2D10, rat anti-mouse B7-1/1G10, and
anti-mouse CD40L/gp39 were all purchased from TSD BioServices
(Germantown, NY). Purified hamster anti-mouse CD80 (clone 16-10A)
and CD86 (clone GL1) were obtained from PharMingen. Biotinylated swine
anti-rabbit Ig was obtained from Dako (Glostrup, Denmark), while
biotinylated anti-hamster IgG and biotinylated anti-rat IgG
were purchased from Vector Labs (Burlingame, CA).
Immunohistology
Spinal cords were collected at various time points after
immunization from three to eight mice in each experimental group: on
days 0, 4, and 7 (before clinical signs of disease); between days 11
and 14 (during the first attack and peak of the disease); on day 18
(remission phase); and between days 26 and 29 (relapses) (Fig. 1
).
Nonimmunized and CFA-immunized mice served as controls. Spinal cord
tissues were embedded in OCT, quick-frozen in liquid nitrogen, and kept
at -70°C until sectioning. Cryostat sections (14 µm) of spinal
cords were fixed with acetone or 4% paraformaldehyde and then labeled
with the Ab of interest. The sections were stained using the
avidin-biotin technique (Vectastain Elite kit; Vector Labs), visualized
with diamino-benzidine (Vector Labs), and counterstained in
hematoxylin. Isotype-matched Ig and omission of the primary Ab served
as negative controls. Each specimen was evaluated at three different
levels of sectioning or more. The whole tissue section (a longitudinal
spinal cord section) was evaluated for a given cellular marker at x40
magnification, and the results were expressed as the mean number of
labeled cells per 100 mm2 of spinal cord tissue. The
evaluation of cytokine expression was performed semiquantitatively
because of the tendency of cytokines to diffuse around cells. The
following arbitrary scale was used: - = no positive cells; + = 1 to 9
positive cells; ++ = 10 to 99 positive cells; +++ = 100 to 1000
positive cells; and ++++ = >1000 positive cells per 100
mm2 of tissue examined.
Preparation of cells from CNS and lymphoid tissue for FACS staining and analysis
Mice were sacrificed on days 10, 18, and 26 postimmunization as described above. The spleen, lymph node, spinal cord, and brain tissues were dissected and collected in RPMI 1640 media containing 10% heat-inactivated FCS. Tissues were minced using a tissue stringer; CNS tissue was cut in pieces with two scalpels. The cells were mechanically dissociated by trituration in medium using a long-necked Pasteur pipette. Cells were then washed three times by centrifugation at 125 x g for 10 min; viable cells were counted and then labeled with direct or indirect fluorescent Abs for 30 min and washed three times. The cells were fixed with 4% ice-cold paraformaldehyde for 10 min, and then the samples were analyzed by two-color flow cytometry on a FACS-scan (Becton Dickinson, Mountain View, CA). The data were analyzed using CellQuest software program.
Statistical analysis
The nonparametric Kruskal-Wallis test for multiple comparisons was used to analyze the immunohistochemistry data.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B7-2 is the major CD28 ligand expressed early during an immune
response (2, 29, 30), but little is known about the kinetics of the
tissue-specific expression of B7-2 during the course of an autoimmune
disease. Here, we studied the expression of B7-2 in the CNS in EAE and
its correlation with clinical disease and in situ cytokine production.
We show that B7-2 is detectable in the CNS as early as day 4
postimmunization (i.e., at the time of cellular infiltration and before
the onset of clinical signs of disease) (see Fig. 2). B7-2 expression is significantly
up-regulated during the acute phase of the disease and during relapses
(Figs. 2 and 3). Furthermore, the
kinetics of B7-2 expression coincided with the expression of IL-12 and
TNF- in the CNS (Table I).
Interestingly, IFN- was present in the inflammatory infiltrates only
during clinical attacks but not before clinical symptoms or during
recovery (Table I).
|
|
|
), indicating a down-regulation of B7-2
expression. We also detected B7-2 expression on CNS resident cells such
as microglia and astrocytes. Astrocytes were double-stained for GFAP
and B7-2; as shown in Figure 5A, there was an up-regulation
of B7-2 expression on astrocytes (58.6%) during acute disease but not
during remission.
|
|
There was no detectable staining for B7-1 in the CNS during the
preclinical or acute phases of EAE. However, B7-1 was significantly
up-regulated in the CNS during clinical remission (Figs. 2 and 3).
Interestingly, B7-1 was also expressed by neurons during remission
(Figs. 5B and 6). The neuronal
expression of B7-1 was confirmed using two different Abs, a rat
anti-mouse Ab and a hamster anti-mouse Ab. To confirm these
results, CNS tissue was dispersed into single-cell suspensions, and
two-color flow cytometry was performed. FACS analysis confirmed the
lack of B7-1 expression on resident or infiltrating CNS cells during
the preclinical and acute phases of EAE (Fig. 4). B7-1 expression was
demonstrated on neurons and astrocytes (Fig. 5) and on infiltrating
cells during clinical remission (Fig. 4). In the periphery, animals
immunized for EAE showed an increase in B7-1 expression in the
splenocytes on day 10 postimmunization compared with naive controls.
Surprisingly, B7-1 expression on T cells was decreased at a time when
the total expression of B7-1 by splenocytes was increased (Fig. 7). The total number of T cells in
the spleen was unchanged; since there is no B7-1 expression in the CNS
during this period, a migration of B7-1-expressing T cells appears
unlikely.
|
We studied the expression of CD28 in the CNS and its correlation
to disease activity. We show that CD28 is expressed on cells that
infiltrate the CNS as early as day 7 postimmunization. The number of
CD28-expressing cells increased significantly during clinical attacks
concomitant with an up-regulation of B7-2 expression in inflammatory
infiltrates (Figs. 2 and 3). Furthermore, the peak of CD28 expression
in the CNS correlated with the increase in Th1 cytokine expression
(Table I).
CTLA4 expression
Unlike CD28, CTLA4 is not constitutively expressed on the cell
surface of T cells but is detectable early after T cell activation (22, 34). As shown in Figures 2 and 8, we did
not detect any constitutive CTLA4 expression in the CNS. However,
CTLA4-expressing cells were seen in perivascular infiltrates by day 4
postimmunization. CTLA4 expression was up-regulated during acute
disease, peaked during remission, and persisted during relapses.
|
We found that CD40-expressing cells infiltrate the CNS as early as
day 4 postimmunization. CD40 expression increased significantly during
acute disease and subsequent relapses and decreased during remission
(Figs. 2 and 3). Furthermore, CD40L expression on infiltrating cells
increased during acute disease and peaked during relapses (Figs. 2 and 8). The appearance of CD40 in the CNS correlated with the expression of
the inflammatory cytokines IL-12, IFN-, and TNF- (Table I).
Cytokine expression in the CNS
There is evidence that costimulatory molecules may differentially
regulate Th cytokines (14), and that cytokines may regulate the
expression of costimulatory molecules during immune responses in vitro
(30, 35). We investigated the relationship between costimulatory
molecules and cytokine expression in the CNS of animals with relapsing
EAE. We found that the expression of IL-12, IFN-, and TNF-
correlated closely with clinical signs; IL-12 and TNF- expression
was noted before clinical onset, and all three cytokines peaked during
acute disease and during relapses (Table I and Fig. 9). In contrast, Th2 cytokines (IL-4 and
IL-10) were constitutively expressed in the spinal cord; their level of
expression did not correlate with disease activity or recovery (data
not shown). Interestingly, TGF-ß expression peaked during clinical
remission (Table I and Fig. 9). In addition, neurons expressed TGF-ß
during remission (Fig. 6). The expression of TGF-ß by neurons
occurred simultaneous to B7-1 expression by these cells (Figs. 5A and 6) and suggests a potential role for neuronal cells
in down-regulating the immune response in vivo.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
expression suggests that B7-2-expressing APCs (for
IL-12 and TNF-) or the T cells costimulated by these APCs (for
TNF-) may be the main source of these cytokines in the CNS. Our
results underline the importance of the CD28-B7-2 costimulatory pathway
in the initiation of T cell priming and also emphasize the role of this
pathway in the effector and maintenance phases of EAE. Several reports suggest that there is a redundancy of B7-1 and B7-2 function in T cell activation (18, 37), while other reports suggest differential roles for B7-1 and B7-2 in T cell differentiation (15, 16). In this report, we show that although B7-1 is up-regulated during the initial phases of the immune response in the peripheral lymphoid organs, it is not expressed in the CNS tissue until the remission phase of the disease. This finding was determined by immunohistochemistry and confirmed using two different Abs for immunohistology and by FACS staining of cells isolated from CNS tissues. Furthermore, we found a decrease in B7-1 expression on T cells in the periphery at a time when total B7-1 expression in splenocytes was increased compared with naive splenocytes. Thus, B7-1 expression during the course of EAE is differentially regulated in the peripheral lymphoid tissue and in the CNS. Therefore, blocking B7-1 may have a protective (15, 19, 20) or detrimental effect (38) on EAE depending upon the site of interaction, the timing of administration, and possibly whether the reagent crosses the blood-brain barrier. In support of this hypothesis, we have recently shown, using the Lewis rat model, that the systemic administration of CTLA4IgY100F, which selectively binds and blocks B7-1, was not protective or may even worsen disease, while the administration of APCs that had been treated ex vivo with CTLA4IgY100F and encephalitogenic peptide was protective (38). In the CNS, B7-1 expression peaked during remission and was detected on neurons as well as lymphoid cells. We also show the expression of B7-1 and B7-2 by astrocytes, which is a finding that was previously reported for cultured astrocytes (39) and microglia in vitro (40, 41, 42). These cell types are also known to express MHC class II molecules and play an important role in regulating the local immune response. There is recent evidence that B7-2 on T cells is posttranslationally modified and has a reduced affinity to CTLA4 but does not bind to CD28 (43). These observations raise the possibility that the B7-1 expressed by nonlymphoid cells in the CNS may be important in down-regulating the immune response through interactions with CTLA4. On the other hand, the expression of B7-1 on mononuclear infiltrates in the CNS during remission could be interpreted as a prelude to reactivation and the occurrence of a relapse. This interpretation would be more consistent with previous reports showing that a B7-1 blockade prevents clinical relapses and epitope spreading (20). It is important to point out that the type of cell expressing B7-1 and its interaction with CD28 or CTLA4 may play a crucial role in the modulation of an immune response in vivo. This might explain the apparently conflicting results seen with a B7-1 blockade in autoimmune diseases. In the EAE model in particular, B7-1 blockade was reported to exacerbate or protect from disease depending upon the timing of administration (19, 44). Our findings with B7-1 expression exclusively during remission do not agree with the findings by Miller et al. of an enhanced expression of B7-1 on mononuclear cells isolated from the CNS during acute EAE (20). The model used in that report was a PLP-induced disease in SJL mice. The priming Ag and the genetic background of the mouse strain may contribute to these differences.
The engagement of CTLA4 with B7 molecules transduces a negative signal which leads to the inactivation of T cells (22, 23, 24, 25, 45). In vitro, CTLA4 is expressed on T cells within 24 h of activation and is down-regulated after a few days (22, 34). Since all T cells are not activated synchronously, the number of T cells expressing CTLA4 at a given time point is lower than that of cells expressing CD28. The absence of CTLA4 staining in the CNS during the preclinical stages suggests that activated cells down-regulate their CTLA4 expression as soon as they penetrate the CNS, and expression of CTLA4 is seen only after T cells are reactivated locally. The peak expression of CTLA4 correlated with the appearance of B7-1 expression in the CNS, suggesting a potential regulatory role for B7-1-CTLA4 interaction, as discussed above (38).
Our immunohistologic data confirm an important role of CD40L-CD40 in the acute and relapsing phases of EAE. CD40 is constitutively expressed on B cells, dendritic cells, and monocytes/macrophages (46), while CD40L is transiently expressed on activated CD4+ T cells (47). An interaction of CD40 with its ligand is believed to be involved in T cell activation (48, 49) and is essential for B cell responses against thymus-dependent Ags (3, 50, 51). More recently, it was shown that CD40L is required for T cell costimulatory activation in PLP-mediated EAE (5), and that anti-CD40L protects against clinical EAE (52). Interestingly, in the study by Grewal et al. (5) B7-1 costimulation appears to mediate the effect of CD40L-CD40 costimulation in EAE. CD40-CD40L interaction is critical for IL-12 secretion by macrophages and dendritic cells (49, 53), which may explain the ability of anti-CD40L mAb to inhibit disease in animal models that are dependent upon the generation of a cell-mediated immune response.
As previously reported, the expression of Th1 cytokines correlated with disease activity in EAE (11, 54, 55). We found that TGF-ß expression correlated with recovery, which is consistent with the role of this factor in recovery from EAE (11, 56, 57, 58). This is the first report describing the simultaneous expression of TGF-ß and B7-1 by neurons in EAE during remissions. This finding suggests that neurons may play a role in the regulation of local inflammation by producing TGF-ß and by expressing B7-1 that can potentially interact with CTLA4 on the surface of T cells to induce anergy or the apoptosis of encephalitogenic T cells. Neuronal staining for B7-1 could be attributed to cross-reactivity with a neuronal Ag; however, the expression of B7-1 was confirmed using two different Abs, which decreases the likelihood of cross-reactivity, and the fact that staining was seen only during remission also makes this possibility unlikely. Neurons are not known to express MHC molecules, and consequently may not be able to provide signal 1 to T cells. However, signal 1 and signal 2 can be provided by two different cells in what has been termed trans-costimulation, in which one cell type provides signal 1, and another cell type provides signal 2 (59, 60). The TGF-ß detected in neurons is probably in a latent form, since latent TGF-ß is normally activated after being secreted (61). Thus, we cannot determine by immunohistology whether TGF-ß from neurons will end up being hydrolyzed to its active form. The factors that regulate the expression of costimulatory molecules and/or the secretion of suppressive cytokines or growth factors by neurons must be investigated.
In summary, this is the first demonstration of the kinetics of expression of costimulatory molecules and their ligands in vivo during the course of an autoimmune response characterized by clinical remissions and relapses. Further understanding of the mechanisms that regulate the local expression of costimulatory molecules and their ligands is essential for designing novel and specific therapies to block T cell activation in tissue-specific autoimmune diseases in humans.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Samia J. Khoury, Center for Neurologic Diseases, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: CD40L, CD40 ligand; EAE, experimental autoimmune encephalomyelitis; CNS, central nervous system; PLP, proteolipid protein; MBP, myelin basic protein; GFAP, glial fibrillary acidic protein.
Received for publication January 29, 1998. Accepted for publication March 25, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and tumor necrosis factor-ß. J. Neuroimmunol. 61:205.[Medline]
, interleukin 4, and TGF-ß in experimental allergic encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J. Neurosci. Res. 40:579.[Medline]
This article has been cited by other articles:
|
|
 |
|
  S. P. Dudhgaonkar, S. B. Janardhanam, K. N. Kodumudi, and M. Srinivasan CD80 Blockade Enhance Glucocorticoid-Induced Leucine Zipper Expression and Suppress Experimental Autoimmune Encephalomyelitis J. Immunol., December 1, 2009; 183(11): 7505 - 7513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Elyaman, E. M. Bradshaw, Y. Wang, M. Oukka, P. Kivisakk, S. Chiba, H. Yagita, and S. J. Khoury Jagged1 and Delta1 Differentially Regulate the Outcome of Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2007; 179(9): 5990 - 5998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhu, I. Guleria, A. Khosroshahi, T. Chitnis, J. Imitola, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury Differential Role of Programmed Death-Ligand 1 and Programmed Death-Ligand 2 in Regulating the Susceptibility and Chronic Progression of Experimental Autoimmune Encephalomyelitis J. Immunol., March 15, 2006; 176(6): 3480 - 3489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J S Sloka and M Stefanelli The mechanism of action of methylprednisolone in the treatment of multiple sclerosis Multiple Sclerosis, August 1, 2005; 11(4): 425 - 432. [Abstract] [PDF]
|
|
|
|
|
|
R. D. Stout, C. Jiang, B. Matta, I. Tietzel, S. K. Watkins, and J. Suttles Macrophages Sequentially Change Their Functional Phenotype in Response to Changes in Microenvironmental Influences J. Immunol., July 1, 2005; 175(1): 342 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Benou, Y. Wang, J. Imitola, L. VanVlerken, C. Chandras, K. P. Karalis, and S. J. Khoury Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis J. Immunol., May 1, 2005; 174(9): 5407 - 5413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. V. Mendez-Fernandez, M. J. Hansen, M. Rodriguez, and L. R. Pease Anatomical and Cellular Requirements for the Activation and Migration of Virus-Specific CD8+ T Cells to the Brain during Theiler's Virus Infection J. Virol., March 1, 2005; 79(5): 3063 - 3070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Imitola, M. Comabella, A. K. Chandraker, F. Dangond, M. H. Sayegh, E. Y. Snyder, and S. J. Khoury Neural Stem/Progenitor Cells Express Costimulatory Molecules That Are Differentially Regulated by Inflammatory and Apoptotic Stimuli Am. J. Pathol., May 1, 2004; 164(5): 1615 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Hirashima, T Fukazawa, K Abe, Y Morita, M Kusaoi, and H Hashimoto Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients Lupus, January 1, 2004; 13(1): 24 - 31. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Imitola, E. Y. Snyder, and S. J. Khoury Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis Physiol Genomics, August 15, 2003; 14(3): 171 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Delgado Inhibition of Interferon (IFN) {gamma}-induced Jak-STAT1 Activation in Microglia by Vasoactive Intestinal Peptide: INHIBITORY EFFECT ON CD40, IFN-INDUCED PROTEIN-10, AND INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION J. Biol. Chem., July 18, 2003; 278(30): 27620 - 27629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Salama, T. Chitnis, J. Imitola, M. J. I. Ansari, H. Akiba, F. Tushima, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis J. Exp. Med., July 7, 2003; 198(1): 71 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Srinivasan, I. E. Gienapp, S. S. Stuckman, C. J. Rogers, S. D. Jewell, P. T. P. Kaumaya, and C. C. Whitacre Suppression of Experimental Autoimmune Encephalomyelitis Using Peptide Mimics of CD28 J. Immunol., August 15, 2002; 169(4): 2180 - 2188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Singh, M. T. Wilson, S. Hong, D. Olivares-Villagomez, C. Du, A. K. Stanic, S. Joyce, S. Sriram, Y. Koezuka, and L. Van Kaer Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis J. Exp. Med., December 17, 2001; 194(12): 1801 - 1811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Magnus, A. Chan, O. Grauer, K. V. Toyka, and R. Gold Microglial Phagocytosis of Apoptotic Inflammatory T Cells Leads to Down-Regulation of Microglial Immune Activation J. Immunol., November 1, 2001; 167(9): 5004 - 5010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Im, D. Barchan, P. K. Maiti, S. Fuchs, and M. C. Souroujon Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4 J. Immunol., June 1, 2001; 166(11): 6893 - 6898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Kiefer, F Dangond, M Mueller, K V Toyka, D A Hafler, and H-P Hartung Enhanced B7 costimulatory molecule expression in inflammatory human sural nerve biopsies J. Neurol. Neurosurg. Psychiatry, September 1, 2000; 69(3): 362 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mathur, K. Herrmann, Y. Qin, F. Gulmen, X. Li, R. Krimins, J. Weinstock, D. Elliott, J. A. Bluestone, and P. Padrid CD28 Interactions with Either CD80 or CD86 Are Sufficient to Induce Allergic Airway Inflammation in Mice Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 498 - 509. [Abstract] [Full Text]
|
|
|
|
|
|
G. Reichmann, E. N. Villegas, L. Craig, R. Peach, and C. A. Hunter The CD28/B7 Interaction Is Not Required for Resistance to Toxoplasma gondii in the Brain but Contributes to the Development of Immunopathology J. Immunol., September 15, 1999; 163(6): 3354 - 3362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Soos, T. A. Ashley, J. Morrow, J. C. Patarroyo, B. E. Szente, and S. S. Zamvil Differential expression of B7 co-stimulatory molecules by astrocytes correlates with T cell activation and cytokine production Int. Immunol., July 1, 1999; 11(7): 1169 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chabot, G. Williams, M. Hamilton, G. Sutherland, and V. W. Yong Mechanisms of IL-10 Production in Human Microglia-T Cell Interaction J. Immunol., June 1, 1999; 162(11): 6819 - 6828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Metzler, C. Burkhart, and D. C. Wraith Phenotypic analysis of CTLA-4 and CD28 expression during transient peptide-induced T cell activation in vivo Int. Immunol., May 1, 1999; 11(5): 667 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Issazadeh, M. Zhang, M. H. Sayegh, and S. J. Khoury Acquired Thymic Tolerance: Role of CTLA4 in the Initiation and Maintenance of Tolerance in a Clinically Relevant Autoimmune Disease Model J. Immunol., January 15, 1999; 162(2): 761 - 765. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
