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The Journal of Immunology, 2002, 168: 2096-2099.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Attenuated Experimental Autoimmune Encephalomyelitis in Eta-1/Osteopontin-Deficient Mice1

Marianne Jansson, Vily Panoutsakopoulou, Jessica Baker, Ludger Klein and Harvey Cantor2

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Recent studies indicate that early T lymphocyte activation 1 (Eta-1), also known as osteopontin, is a cytokine contributing to the development of Th1 immunity. In the present report, the role of Eta-1 in experimental autoimmune encephalomyelitis (EAE), a disease associated with Th1 immunity, was examined by analysis of disease progression in Eta-1-deficient (Eta-1-/-) mice. Although incidence and onset of peptide-induced EAE were found to be similar in Eta-1-/- and Eta-1+/+ mice, Eta-1-/- mice displayed significantly lower mean maximal clinical score and faster recovery without spontaneous relapses. Accordingly, decreased inflammatory infiltration and demyelination were observed in the spinal cords of Eta-1-/- mice. Furthermore, in comparison to Eta-1+/+, Eta-1-/- CD4+ T cells had reduced expression of IFN-{gamma} and TNF-{alpha} upon ex vivo restimulation. Taken together, these results suggest that Eta-1 may sustain autoimmune responses by assisting in maintenance of Th1 immunity during EAE.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Production of certain cytokines by professional APC is an early essential step of Th cell polarization during the development of immune responses. Thus, production of IL-12 by dendritic cells triggers Th1 cell development, while early IL-10 production can reverse this development and may skew cells to become Th2 (1). Th1 and Th2 responses exhibit not only cytokine profile differences (2) but also differences in their functional properties, resulting in distinct impacts on immunity against pathogens and self. Studies in murine models demonstrate that Th1 polarization is associated with protective immune responses against several intracellular pathogens, but also linked to autoimmune diseases (3).

Experimental evidence suggest that early T lymphocyte activation 1 (Eta-1),3 also known as osteopontin (Opn), is a pleiotropic cytokine critical for the generation of Th1 immunity. Eta-1 is expressed by T cells early during bacterial infections (4) and was elevated in granulomatous responses (5), typically thought of as type 1 immune responses. In addition, enhanced expression of Eta-1 has been linked to resistance against certain intracellular microorganisms (4). Recently, Eta-1 was observed to be crucial for the induction of Th1-linked delayed-type hypersensitivity reaction to herpes simplex virus challenge (6). Importantly, stimulation with Eta-1 resulted in up-regulation of IL-12 expression by macrophages, whereas IL-10 expression was down-regulated (6), indicating that Eta-1 may act to determine the relative production of IL-12 and IL-10 by APC.

The balance of IL-10 and IL-12 has been reported to play a delicate role in experimental autoimmune encephalomyelitis (EAE) (7), the murine model for multiple sclerosis (MS). Production of IL-12 is essential for the generation of autoreactive EAE-inducing Th1 cells, whereas IL-10 production antagonizes the disease-promoting effects of IL-12 (7). In a recent study, modulation of the IL-10/IL-12 cytokine circuit by IL-12 decrease following IFN-{beta} administration inhibited development of epitope spreading and EAE progression (8).

In the present study, we demonstrate that mice deficient in Eta-1 (Eta-1-/-) production develop significantly milder EAE in comparison to wild-type controls. Furthermore, Eta-1-/- mice exhibit no relapses and CD4+ T cells from these mice express reduced levels of Th1 cytokines. These results suggest that Eta-1 may intensify autoimmune responses during EAE development by facilitating the skewing of Th cells toward type 1 immunity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

C57BL/6 x 129 Eta-1/Opn knockout (Eta-1-/-) mice (6, 9) were backcrossed to C57BL/6 for six generations. Wild-type (Eta-1+/+) littermate control mice were used for comparison in all experiments.

Induction of EAE

EAE was induced in mice by immunization with a 12-mer synthetic peptide (New England Peptide, Fitchburg, MA) representing aa 172–183 (PVYIYFNTWTTC) of proteolipid protein, PLP172–183 (10). One hundred fifty micrograms of PLP172–183 peptide and 300 µg of killed Mycobacterium tuberculosis (Difco, Detroit, MI) in CFA (Sigma-Aldrich, St. Louis, MO) were injected s.c. by means of three injections over the flanks. In addition, 400 ng of pertussis toxin (List Biological Laboratories, Campbell CA) was injected i.p. on days 0 and 2. Mice were monitored daily and assessed for clinical signs of disease in a blinded fashion according to the following criteria: 0, normal mouse without signs of disease; 1, limp tail; 2, limp tail and hind limb weakness; 3, partial hind limb paralysis; 4, complete hind limb paralysis; and 5, moribund state or death due to EAE. Mean clinical scores at separate days and mean maximal scores were calculated by adding scores of individual mice and dividing with number of mice in each group, also including mice not developing signs of EAE. Average day of onset was calculated by adding the first day of clinical signs of individual mice and dividing with number of mice in the group. Day of onset for mice that did not develop EAE was intentionally considered to be 1 day after completion of experiment.

Histology

Spinal cords were removed and fixed in 10% Formalin. Paraffin-embedded sections were stained with H&E or Luxol Fast Blue for visualization of inflammatory infiltrates and demyelination.

Cell cultures and cytokine determination

Draining lymph nodes and spleens were obtained from PLP172–183-immunized mice. Single-cell suspension was obtained and cells were suspended in labeling buffer (2% FBS in PBS) at a concentration of 107 cells/ml and incubated with 10 µg/ml purified anti-CD8 and anti-B220 and 5 µg/ml purified anti-CD11b and anti-GR-1 (all from BD PharMingen, San Diego, CA) for 30 min at 4°C. Cells were washed three times in labeling buffer and then resuspended at a concentration of 107 cells/ml in labeling buffer. To this cell suspension, 50 µl/ml washed Dynabeads M-450 Sheep anti-Rat IgG (Dynal, Lake Success, NY) was added, and the cells were again incubated for 30 min at 4°C. The bead-negative fraction of cells was collected using a magnet. CD4+ cells were enumerated and resuspended in complete medium (RPMI 1640 medium supplemented with 10% FBS (Sigma-Aldrich), L-glutamine, 2-ME, and antibiotics). Briefly, 1.5 x 105 cells were plated in triplicate wells in 96-well microtiter culture plates (Costar, Corning, NY) along with 3 x 104 spleen-derived CD11c+ dendritic cells, purified using anti-CD11c-conjugated MACS microbeads (Miltenyi Biotec, Auburn, CA) according to the manufacturer. PLP172–183 peptide was added to a final concentration of 10 or 50 µg/ml, while medium was added to control cultures. In parallel, CD4+ cells obtained from naive mice were cultured according to the same protocol with the exception that stimulation instead was provided by plate-bound anti-CD3 complex Ab (BD PharMingen) coated at a concentration of either 2.5 or 5.0 µg/ml. After 96-h cell culture supernatant was harvested and frozen at -80°C. Concentrations of IFN-{gamma}, IL-2, IL-4, IL-10, and TNF-{alpha} were analyzed using cytokine capture ELISA (OPTEIA; BD PharMingen).

Semiquantitative RT-PCR for cytokine mRNA detection

Spinal cords were extruded by flushing the vertebral canal with PBS and then rinsed in PBS. RNA was isolated using the RNeasy kit (Qiagen, Valencia, CA) according to instructions by the manufacturer. cDNA was reverse transcribed using oligo(dT) primer and semiquantitative PCR amplification of cytokine IFN-{gamma} and TNF-{alpha}, and housekeeping {beta}-actin mRNA was done using the following primers: IFN-{gamma}, antisense 5'-ACA CTG CAT CTT GGC TTT GC-3', sense 5'-CGA CTC CTT TTC CGC TTC CT-3'; TNF-{alpha}, antisense 5'-GTA TGA GAT AGC AAA TCG-3', sense 5'-TTC TGT CTA CTG AAC TTC-3'; {beta}-actin: antisense, 5'-TAA AAC GCA GCT CAG TAA-3'; and sense, 5'-TGG AAT CCT GTG GCA TCC-3'. Ratios of cytokine PCR products to housekeeping gene {beta}-actin PCR products for each sample were obtained using densitometry.

Statistical analysis

Statistical differences between groups with respect to disease score at specific days, mean maximal score, number of days with paralyzing disease, and number of inflammatory foci in spinal cord were evaluated using a nonparametric analysis Mann-Whitney U test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Considering that Eta-1-/- mice displayed impaired type 1 immune responses as well as marked resistance to development of herpes stromal keratitis, a Th1-linked autoimmune disease (6), we tested the role of Eta-1 in the development of EAE. Thus, EAE was induced in Eta-1-/- and Eta-1+/+ littermates by s.c. injections of a PLP-derived encephalitogenic peptide (PLP172–183) in CFA. Although disease onset and incidence were similar among Eta-1-/- and Eta-1+/+ mice (Fig. 1Go and Table IGo), the severity was substantially reduced in Eta-1-/-, and the mean maximal score was significantly lower when compared with the Eta-1+/+ score (Fig. 1Go and Table IGo). In addition, Eta-1-/- mice exhibited improved recovery from EAE by sustaining fewer days of paralysis and lower mortality (Fig. 2Go). Importantly, although many of the Eta-1+/+ mice experienced spontaneous relapses, none of the Eta-1-/- mice did (Fig. 2Go). Thus, peptide-induced EAE in Eta-1-/- mice appeared to be attenuated compared with disease in their Eta-1+/+ littermates.



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  		FIGURE 1. Eta-1-deficient mice develop attenuated EAE. Development of EAE was assessed for 35 days after immunization with PLP172–183 in Eta-1-/- (n = 22) and Eta-1+/+ (n = 23) littermate mice. From these mice, 11 (Eta-1-/-, n = 4; Eta-1+/+, n = 7) were monitored for a period of 70 days. Disease was scored as described in Materials and Methods. Depicted are mean clinical scores for Eta-1-/- and Eta-1+/+ mice at indicated days. *, p < 0.05; **, p < 0.01.

 

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  		Table I. EAE clinical disease in Eta-1-/- and wild-type littermate mice1

 


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  		FIGURE 2. Eta-1-deficient mice displayed milder EAE disease with fewer days of paralysis, lack of spontaneous relapsing disease, and decreased mortality. Mice (Eta-1-/-, n = 22; Eta-1+/+, n = 23) were scored for 35 days after PLP172–183 immunization. A, Average number of days mice experienced paralyzing disease corresponding to clinical score 3 or higher (assessed as described in Materials and Methods). B, Percentage of mice with history of paralysis (scores >= 3) that had spontaneous relapses to paralysis (scores >= 3). C, Mortality illustrates percentage of mice euthanized due to moribund state during a 70-day monitoring experiment. **, p < 0.01.

 
Histology of spinal cords was performed to examine whether differences in clinical symptoms of EAE between Eta-1-/- and Eta-1+/+ were reflected by inflammatory infiltration and demyelination in the CNS. As detected by H&E and Luxol Fast Blue stainings, spinal cord sections from Eta-1-/- mice exhibited significantly lower inflammatory infiltrates as well as demyelinated foci compared with cord sections from wild-type mice (Fig. 3Go).



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  		FIGURE 3. Decreased inflammation and demyelination in spinal cords of Eta-1-deficient mice. Representative histology of spinal cord longitudinal sections obtained 3 wk after EAE induction. Inflammatory infiltration and demyelination were visualized by Luxol Fast Blue and hematoxylin. Average number of inflammatory foci/ocular field ± SEM in spinal cords of Eta-1-/- (n = 4) and Eta-1+/+ (n = 4) mice as detected in H&E-stained sections. *, p < 0.05

 
To test the cytokine profile, CD4+ T cells obtained from draining lymph nodes and spleen at the onset of disease as well as during recovery (i.e., 3 and 5 wk after immunization) were restimulated ex vivo with PLP172–183. CD4+ cells obtained from Eta-1-/- mice during EAE onset and during the recovery secreted significantly less IFN-{gamma} and TNF-{alpha} in comparison to cells from Eta-1+/+, whereas IL-2 levels were found to be similar among the groups. Proliferation upon PLP-specific stimulation was similar for Eta-1-/- and Eta-1+/+ CD4 cells (data not shown). Expression of IL-4 and IL-10 was undetectable in cultures of cells from both groups of mice (data not shown). However, significantly elevated IL-10 was detected in parallel cultures of anti-CD3-stimulated CD4+ T cells obtained from naive Eta-1-/- mice compared with cultures of anti-CD3-stimulated CD4+ T cells from Eta-1+/+ littermates (Fig. 4GoB). In the same cultures the overall cytokine profile of Eta-1-/- vs Eta-1+/+ CD4+ T cells reflected a Th2 vs a Th1 phenotype, respectively (data not shown).



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  		FIGURE 4. Cytokines from CD4+ T cell cultures of Eta-1+/+ ({blacksquare}) and Eta-1-/- ({square}) mice. Cytokine expression in CD4+ T cells derived from EAE-induced mice and ex vivo restimulated with 10 and 50 µg/mlPLP172–183 peptide (A) and CD4+ T cells obtained from naive mice stimulated with 2.5 and 5.0 µg/ml plate-bound anti-CD3 (B). Cell culture supernatants were collected after 96 h and analyzed for content of IFN-{gamma}, IL-2, IL-10, and TNF-{alpha} using capture ELISA. Results are depicted as the mean cytokine expression for each group of mice ± SEM.

 
Furthermore, mRNA levels of IFN-{gamma} and TNF-{alpha} from spinal cords of Eta-1-/- and Eta-1+/+ mice were assessed. Similar to the T cell profile, Eta-1-/- mice displayed reduced levels of IFN-{gamma} and TNF-{alpha} mRNA at the site of inflammation compared with wild-type littermates (Fig. 5Go). Hence, the cytokine profile of CD4+ cells as well as the cytokine mRNA levels in the spinal cord suggest that Eta-1-/- mice exhibit reduced Th1 immunity, which may explain development of milder EAE in these mice.



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  		FIGURE 5. Cytokine mRNA expression in the CNS of EAE-induced Eta-1+/+ and Eta-1-/- mice. Levels of spinal cord cytokine IFN-{gamma} and TNF-{alpha} mRNA obtained 3 wk after EAE induction (by semiquantitative RT-PCR as described in Materials and Methods). Dotted lines represent mean ratios.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrate that Eta-1 expression has a significant role in sustaining autoimmune destruction as reflected by attenuated EAE development in Eta-1-deficient mice. Eta-1-/- mice displayed reduced mean maximal score, fewer days of paralyzing disease, and no spontaneous relapses. As a result, clinical disease in EAE-induced Eta-1-/- mice was a considerably milder form compared with the lethal and paralytic disease observed in Eta-1+/+ littermates. We have previously demonstrated that Eta-1-/- mice are resistant to the development of another autoimmune disease, herpes stromal keratitis (6), pointing to a general role of Eta-1 in Th1-mediated autoimmune destruction.

Certain downstream cytokines play a critical role in the initiation, propagation, and regulation of autoimmune responses. Upon ex vivo PLP peptide restimulation of CD4+ T cells and in analysis of spinal cord mRNA we determined the cytokine profile in Eta-1-/- mice to be skewed, as judged by reduced levels of IFN-{gamma} and TNF-{alpha}. Th1 cytokines have generally been considered to be encephalitogenic (11), although conflicting results with respect to EAE development in different cytokine-deficient mice point to complex regulation and function of individual cytokines (12, 13, 14). Nonetheless, TNF-{alpha} can provoke inflammatory responses (15) and transgenic expression of IFN-{gamma} and TNF-{alpha} in the CNS accelerates development of demyelinating disease (16, 17). Conversely, several studies indicate that skewing toward Th2 immunity is protective or alters the outcome of EAE (18).

The Th2 cytokine IL-10 appears to play a regulatory role during development of EAE (19). In our experiments, IL-10 production upon ex vivo PLP peptide restimulation of CD4+ T cells was undetectable, possibly due to the low prevalence of PLP-specific IL-10-producing T cells. Nevertheless, in parallel cultures, we observed that anti-CD3-stimulated CD4+ T cells from naive Eta-1-/- mice expressed elevated levels of IL-10 compared with CD4+ T cells from Eta-1+/+ littermates. Interestingly, IL-10 produced by Ag-nonspecific CD4+ T cells has been reported to antagonize encephalitogenic cytokine responses in EAE development (7) and, in the absence of Eta-1, immunoregulatory IL-10-producing cells may play a more dominant role by assisting toward early Th2 skewing. Alternatively, low production of IFN-{gamma} and TNF-{alpha} could account for blunted disease expression in Eta-1-/- mice.

EAE, a model for human MS, is thought to primarily be a T cell-mediated autoimmune disease. Eta-1 is expressed by both T cells and macrophages but it is not clear to what extent either source of Eta-1 contributes to the development of autoimmune disease. Since transfer of purified CD4+ T cells (107) from naive Eta-1+/+ but not Eta-1-/- donors into syngeneic RAG2-/- recipients induces significant EAE after immunization with PLP peptide (data not shown), T cell expression of Eta-1 may be critical for the development of EAE.

Eta-1 also initiates migration of macrophages and dendritic cells to sites of inflammation (20, 21, 22, 23) and may contribute in this way to the diminished inflammatory infiltration, decreased demyelination, and reduced Th1 cytokine mRNA in spinal cords of Eta-1-/- mice. Although the role of Eta-1-dependent chemotaxis, macrophage activation and type 1 cytokine expression to EAE remains to be elucidated, the importance of this cytokine to relapsing, progressive and lethal disease is clear. Since these disease elements represent the cardinal clinical features of MS, our findings highlight the importance of studies that correlate human Eta-1/Opn expression with radiographic and clinical signs of remission, relapse and disease progression in MS patients.

While our study was under review, experiments indicating the importance of Eta-1 to rodent EAE and human MS were published by another group (24). In agreement with our findings, Chabas et al. (24) reported nonprogressive EAE in Eta-1-deficient mice as well as decreased production of Th1 cytokines in response to myelin-derived peptide (in this case myelin oligodendrocyte glycoprotein (MOG) 35–55). In addition, their study noted up-regulation of Eta-1 in cDNA libraries obtained from patients with MS as compared with control libraries. Overall, the two independent studies of EAE induction using two distinct myelin-derived peptides (PLP172–183 vs MOG 35–55) provide strong support for a critical role of Eta-1 in demyelinating autoimmune disease.


   Acknowledgments
 
We thank S. Kissler for technical advice and A. Angel for assistance with this manuscript and graphics preparation


   Footnotes
 
1 This work was supported in part by National Institutes of Health Research Grants AI 12184, AI 48125, and AI 37562 (to H.C.). M.J. is a Fellow of the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) and L.K. is a Fellow of the Deutsche Forschungemeinschaft. Back

2 Address correspondence and reprint requests to Dr. Harvey Cantor, Dana-Farber Cancer Institute, 44 Binney Street, Boston MA 02115. E-mail address: Harvey_Cantor{at}dfci.harvard.edu Back

3 Abbreviations used in this paper: Eta-1, early T lymphocyte activation 1; Opn, osteopontin; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein. Back

Received for publication November 15, 2001. Accepted for publication January 9, 2002.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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 Arterioscler. Thromb. Vasc. Bio.Home page
M. Scatena, L. Liaw, and C. M. Giachelli
Osteopontin: A Multifunctional Molecule Regulating Chronic Inflammation and Vascular Disease
Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2302 - 2309.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. Kitamura, K. Iwabuchi, N. Kitaichi, S. Kon, H. Kitamei, K. Namba, K. Yoshida, D. T. Denhardt, S. R. Rittling, S. Ohno, et al.
Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice
J. Immunol., May 15, 2007; 178(10): 6567 - 6572.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. Forte, B. G. Gold, G. Marracci, P. Chaudhary, E. Basso, D. Johnsen, X. Yu, J. Fowlkes, M. Rahder, K. Stem, et al.
Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis
PNAS, May 1, 2007; 104(18): 7558 - 7563.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
M. Hashimoto, D. Sun, S. R. Rittling, D. T. Denhardt, and W. Young
Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls
J. Neurosci., March 28, 2007; 27(13): 3603 - 3611.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
S. T. Hikita, B. P. Vistica, H. R. Jones, J. R. Keswani, M. M. Watson, V. R. Ericson, G. S. Ayoub, I. Gery, and D. O. Clegg
Osteopontin is proinflammatory in experimental autoimmune uveitis.
Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4435 - 4443.
[Abstract] [Full Text] [PDF]

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 BrainHome page
M. Schroeter, P. Zickler, D. T. Denhardt, H.-P. Hartung, and S. Jander
Increased thalamic neurodegeneration following ischaemic cortical stroke in osteopontin-deficient mice
Brain, June 1, 2006; 129(6): 1426 - 1437.
[Abstract] [Full Text] [PDF]

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 JDRHome page
J. Sodek, A. P. Batista Da Silva, and R. Zohar
Osteopontin and Mucosal Protection
Journal of Dental Research, May 1, 2006; 85(5): 404 - 415.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. L. Shinohara, M. Jansson, E. S. Hwang, M. B. F. Werneck, L. H. Glimcher, and H. Cantor
T-bet-dependent expression of osteopontin contributes to T cell polarization
PNAS, November 22, 2005; 102(47): 17101 - 17106.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
B. Abel, S. Freigang, M. F. Bachmann, U. Boschert, and M. Kopf
Osteopontin Is Not Required for the Development of Th1 Responses and Viral Immunity
J. Immunol., November 1, 2005; 175(9): 6006 - 6013.
[Abstract] [Full Text] [PDF]

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 BloodHome page
A. C. Renkl, J. Wussler, T. Ahrens, K. Thoma, S. Kon, T. Uede, S. F. Martin, J. C. Simon, and J. M. Weiss
Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype
Blood, August 1, 2005; 106(3): 946 - 955.
[Abstract] [Full Text] [PDF]

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 JEMHome page
S. Hayer, G. Steiner, B. Gortz, E. Reiter, M. Tohidast-Akrad, M. Amling, O. Hoffmann, K. Redlich, J. Zwerina, K. Skriner, et al.
CD44 is a determinant of inflammatory bone loss
J. Exp. Med., March 21, 2005; 201(6): 903 - 914.
[Abstract] [Full Text] [PDF]

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 Physiol. GenomicsHome page
F. Giacopelli, R. Marciano, A. Pistorio, P. Catarsi, S. Canini, G. Karsenty, and R. Ravazzolo
Polymorphisms in the osteopontin promoter affect its transcriptional activity
Physiol Genomics, December 15, 2004; 20(1): 87 - 96.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. Sahai, P. Malladi, X. Pan, R. Paul, H. Melin-Aldana, R. M. Green, and P. F. Whitington
Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin
Am J Physiol Gastrointest Liver Physiol, November 1, 2004; 287(5): G1035 - G1043.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
W.-K. Suh, S. X. Wang, A. H. Jheon, L. Moreno, S. K. Yoshinaga, B. Ganss, J. Sodek, M. D. Grynpas, and T. W. Mak
The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization
PNAS, August 31, 2004; 101(35): 12969 - 12973.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Iwata, N. Awaya, L. Graf, C. Kahl, and B. Torok-Storb
Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells
Blood, June 15, 2004; 103(12): 4496 - 4502.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
J. Morimoto, M. Inobe, C. Kimura, S. Kon, H. Diao, M. Aoki, T. Miyazaki, D. T. Denhardt, S. Rittling, and T. Uede
Osteopontin affects the persistence of {beta}-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms
Int. Immunol., March 1, 2004; 16(3): 477 - 488.
[Abstract] [Full Text] [PDF]

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 BloodHome page
A. Chiocchetti, M. Indelicato, T. Bensi, R. Mesturini, M. Giordano, S. Sametti, L. Castelli, F. Bottarel, M. C. Mazzarino, L. Garbarini, et al.
High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation
Blood, February 15, 2004; 103(4): 1376 - 1382.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
G. A. Johnson, R. C. Burghardt, F. W. Bazer, and T. E. Spencer
Osteopontin: Roles in Implantation and Placentation
Biol Reprod, November 1, 2003; 69(5): 1458 - 1471.
[Abstract] [Full Text] [PDF]

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 JEMHome page
L. Steinman
Optic Neuritis, A New Variant of Experimental Encephalomyelitis, A Durable Model for All Seasons, Now In Its Seventieth Year
J. Exp. Med., May 5, 2003; 197(9): 1065 - 1071.
[Full Text] [PDF]

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 ScienceHome page
T. Blom, A. Franzen, D. Heinegard, and R. Holmdahl
Comment on "The Influence of the Proinflammatory Cytokine, Osteopontin, on Autoimmune Demyelinating Disease"
Science, March 21, 2003; 299(5614): 1845a - 1845a.
[Full Text] [PDF]

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 ScienceHome page
L. Steinman, S. Youssef, N. Van Venrooij, D. Chabas, S. E. Baranzini, S. Rittling, D. Denhardt, R. A. Sobel, C. Lock, R. Pedotti, et al.
Response to Comment on "The Influence of the Proinflammatory Cytokine, Osteopontin, on Autoimmune Demyelinating Disease"
Science, March 21, 2003; 299(5614): 1845b - 1845b.
[Full Text] [PDF]

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 JEMHome page
O. Aktas, S. Waiczies, A. Smorodchenko, J. Dorr, B. Seeger, T. Prozorovski, S. Sallach, M. Endres, S. Brocke, R. Nitsch, et al.
Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin
J. Exp. Med., March 17, 2003; 197(6): 725 - 733.
[Abstract] [Full Text] [PDF]

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