| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Rheumatology and Immunology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA 90033
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
enhance
lymphocyte production of active TGF-ß, we found that the addition of
these cytokines was unable to increase active TGF-ß to normal
concentrations. Although we observed that IL-10 inhibited the
production of active TGF-ß, antagonism of this cytokine was unable to
completely correct the defect. In two SLE patients with B cell
hyperactivity, spontaneous IgG production was almost abolished by the
combination of TGF-ß and IL-2. Therefore, decreased production of
each of these cytokines in SLE could be important in the perpetuation
of B cell hyperactivity. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Recently, studies from this laboratory have revealed that TGF-ß is an important costimulatory factor in the generation of CD8+ T cells that down-regulate B cell function (4). TGF-ß is a multifunctional family of cytokines important in tissue repair, inflammation, and immunoregulation (5). Lymphocytes and monocytes produce the ß1 isoform of this cytokine (6). TGF-ß is different from most other cytokines in that it is secreted as an inert precursor molecule and converted to its biologically active form extracellularly (5, 7). Although monocytes have been considered to be the principal source of this cytokine in human peripheral blood (8, 9), we report (10) that NK cells are also a major source of TGF-ß and can convert the latent complex to its active form. In addition, we have demonstrated that the combination of IL-2 and TGF-ß can condition activated CD8+ T cells to develop suppressor effector function (10).
Because of the apparent importance of TGF-ß in regulatory cell development and our previous observation of dysfunctional CD8+ T cells in SLE (11), we decided to quantify the production of this cytokine. Since active TGF-ß comprises only a small fraction of the total amount, a sensitive and specific bioassay was needed for this measurement. The genetically engineered mink cell line generated by Rifkin et al. provided such an assay (12).
Previously, we reported that anti-CD2 mAb can stimulate T cells to
proliferate in the absence of monocytes. Unlike anti-CD3, resting B
cells can serve as accessory cells for similar stimulation with
anti-CD2 (13). In a companion study in this issue, we demonstrate
that unlike anti-CD3, anti-CD2 is a potent inducer of active
TGF-ß (10). To broaden our capacity to induce TGF-ß production, we
describe herein that IL-2 and TNF- have this property, whereas IL-10
has the opposite effect. These findings are particularly relevant to
SLE, since production of IL-2 and TNF- production is decreased
(14, 15, 16) and IL-10 production is increased (17, 18). We report
decreased production of lymphocyte-derived TGF-ß in SLE, which cannot
be normalized by the addition of recombinant IL-2 and TNF- or by
antagonism of IL-10. To determine the possible clinical relevance of
cytokine production defects in SLE, we have initiated studies to
determine whether B cell hyperactivity in SLE can be down-regulated by
IL-2 and TGF-ß ex vivo and have obtained preliminary evidence to
support this possibility.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Thirty-eight subjects with a diagnosis of SLE that fulfilled at least four of the 1982 revised criteria for the classification of SLE (19) were studied. The group consisted of 35 women and 3 men (33 Hispanic, 3 Asian, 2 African American). The mean age was 34.3 years (range, 20–75 years). Nineteen patients were hospitalized, and 19 were attending the outpatient clinic. Most of the hospitalized patients were untreated before admission and were studied before they received corticosteroids. Outpatients were receiving <20 mg of prednisone, and none were receiving cytotoxic drugs. Disease activity was assessed with the SLAM (20) and SLEDAI (21) indices with mean values of 9.2 and 10.2, respectively. Healthy donors served as controls and were matched as closely as possible for age, sex, and ethnic group.
Reagents
Antibodies used were anti-CD2 (OKT11, American Type Culture
Collection (ATCC), Rockville, MD, and GT2 made available by Dr. Alain
Bernard, Nice, France) (22); anti-CD3 (454, a gift from Dr. William
Stohl, Los Angeles, CA) (23); anti-CD74 (L243, ATCC, MD); rTGF-ß1
and anti-TGF-ß (1D11.16), a murine IgG1, were kindly provided by
Dr. Bruce Pratt (Genzyme Pharmaceuticals, Farmington, MA) (24).
Anti-CD16 (3G8) was provided by Dr. Jay Unkeless, New York, NY. TNF-
and IFN-
were purchased from R&D Systems, Minneapolis, MN. IL-2 was
purchased from Cetus, Emmeryville, CA. IL-10 was kind gift from Satwant
Narula (Schering Plough Pharmaceuticals, Kenilworth, NJ), as was
anti-IL-10 (JES3–19F1) (25) and control rat IgG2a.
Isolation of blood mononuclear cells
PBMC were prepared from heparinized venous blood by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density gradient centrifugation. The mononuclear cells were washed in PBS with 5 mM EDTA (Life Technologies, Grand Island, NY) to remove platelets, which are a rich source of TGF-ß (26). Lymphocytes and monocytes were separated from PBMC by centrifugation through a continuous Percoll (Pharmacia) density gradient (27). The percentage of monocytes remaining in the high density, lymphocyte-enriched fraction was somewhat higher in SLE (8.5% vs 4.3%). The percentage of lymphocytes remaining in the monocyte-enriched low density cells was similar in SLE and controls (20.4 vs 21.3%).
NK and T cells were prepared as described previously (4). PBL were immediately rosetted with 2-aminoethylisothiouronium bromide-treated SRBC (28). The nonrosetting cells were then incubated with anti-CD3 and anti-CD74 (anti-HLA-DR) Abs on ice and depleted of reacting cells using immunomagnetic beads (Dynal, Great Neck, NY). The percentage of CD56+ cells in this fraction was similar in SLE and controls (84.0 vs 83.2%). T cells were prepared from rosetting cells by negative selection following depletion of CD16+ and CD74+ cells also using immunomagnetic beads (Dynal). The percentage of CD3+ cells in this fraction was usually >95%.
Cell culture procedures
Procedures for cell cultures have been described previously (4). In brief, 1 x 105 of the various mononuclear cell populations were added to the wells of 96-well flat-bottom microtiter plate (Greiner Rocky Mountain Scientific, Salt Lake City, UT). These plates were selected following a comparison of the nonspecific binding of TGF-ß to commonly used tissue culture plates. The lymphocytes were suspended in AIM V serum-free medium (Life Technologies) since serum contains significant amounts of latent TGF-ß. Some lymphocytes were stimulated with the optimal concentrations of anti-CD2 to induce TGF-ß production (GT2 1:40 and T11 1:80) hybridoma culture supernatants.
TGF-ß assay
Mink lung epithelial cells (MLEC) that had been transfected with an expression construct containing a plasminogen activator inhibitor (PAI-1) promoter fused to luciferase reporter gene were kindly provided by D. B. Rifkin, New York, NY. The procedure described by this group was used to assay TGF-ß (28). MLEC (2 x 104/well) were incubated with 200 µl of supernatant for 18 h at 37°C. To assay for luciferase activity, MLEC were lysed by a cell lysis reagent (Analytical Luminescence, Ann Arbor, MI). Cell lysates were then reacted with assay buffer and luciferin solution (both from Analytical Luminescence) immediately before being measured in a luminometer (Lumat, Berthold Analytical Instruments Inc., Nashua, NH). To measure total TGF-ß activity, the samples were heated at 80°C for 3 min to release the active cytokine from the latent complex. To measure active TGF-ß activity, the supernatants were examined without heating. In all assays, several concentrations of rTGF-ß were included to generate a standard curve. The variability of triplicate cultures was <10% of the mean value.
Possible effects of TGF-ß and IL-2 on spontaneous Ig production in SLE
PBMC (2 x 105) from patients with active SLE were cultured in serum-free (AIM V) culture medium in the wells of a 96-well flat-bottom microtiter plate. For the first 3 days, the PBMC were cultured at 37°C in 5% CO2 in a humidified incubator with or without IL-2 (10 U/ml) and/or TGF-ß (10 pg/ml). The medium was then removed, and after the cells were washed, fresh serum-free medium was added, and the cells were cultured for 7 more days. The supernatants were harvested and assayed for IgG content by an ELISA, as described previously (29).
Statistical analysis
The significance of the results was analyzed by Student’s t test or the Mann-Whitney test performed using GBSTAT software (Professional Statistics and Graphics Computer Program, Dynamic Microsystems Inc., Silver Spring, MD).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To verify the specificity of the TGF-ß bioassay used, we added a
neutralizing anti-TGF-ß mAb to the culture supernatants of
unstimulated and anti-CD2-stimulated PBL. In the four experiments
shown in Table I
, this procedure
abolished >98% of the mink cell response.
|
A). Constitutive
production of total TGF-ß by control PBL was somewhat more than that
of patient lymphocytes (623 ± 107 vs 385 ± 98 pg/ml). The
response to anti-CD2 by control PBL was significantly more vigorous
than SLE PBL (1289 ± 224 vs 586 ± 99, p =
0.03). NK cells were the principal source of this cytokine. During this
48-h culture period, production of total TGF-ß by T cells was barely
detectable. Although we had an insufficient amount of blood from SLE
patients to prepare B cells, the amount of total TGF-ß produced by
this lymphocyte subset from healthy donors was generally <200 pg/ml
(see Ref. 10, Table IV).
|
B. Similar to levels of the latent complex,
active TGF-ß detected in culture supernatants from controls was
approximately twice as much as that in SLE patients. As with total
TGF-ß, NK cells were the principal source of active TGF-ß, and
control NK cells produced significantly more than those from SLE
patients (98 ± 37 vs 39 ± 13 pg/ml, p =
0.01). Active TGF-ß from T cells was not detectable, and that from
control B cells was only barely detectable (results not shown; see Ref.
10, Table V). The response to stimulation with anti-CD2 was significantly greater in controls (p < 0.001). Again NK cells appeared to be the predominant source of this cytokine. However, since the relative increase by NK cells was less than that of PBL, other lymphocyte populations might contribute to the extracellular conversion of latent to active TGF-ß. Production of this cytokine by T cells was negligible during this interval. Thus, defects in both total and active TGF-ß were documented in SLE that could be largely attributed to NK cells.
Since monocytes are a major source of TGF-ß, we compared the
production of the total and active form in SLE and controls (8, 9). As
shown in Table II, there were no
significant differences in the two groups.
|
show that SLE production of TGF-ß was
always lower than that of control donors. Most striking was the
difference in the production of total and active TGF-ß following
stimulation with anti-CD2, a difference that increases with
time.
|
It has been established that blood mononuclear cell
production of IL-2, TNF-, and IFN- is decreased in SLE and that
IL-10 production is increased (14, 15, 16, 17, 18). We selected, accordingly, these
four cytokines for study. PBL from healthy controls were incubated for
48 h with doses over a 3-log concentration range. Figure 3 shows that IL-2 and TNF- increased
the production of active TGF-ß in a dose-dependent manner. IFN-,
however, had no effect, and IL-10 was suppressive.
|
). In this small group, constitutive
production of active TGF-ß was significantly decreased in SLE. The
addition of IL-2 and TNF- proportionally increased levels of active
TGF-ß in both groups but was unable to correct the defect.
|
). The
addition of anti-IL-10 increased active TGF-ß in both SLE and
controls, and this effect was relatively greater in SLE so that the
differences between these two groups were no longer significant.
Following anti-CD2 stimulation of PBL, anti-IL-10 had no effect
on TGF-ß activity. Since monocytes are the principal source of IL-10,
PBMC were cultured in parallel with PBL in three experiments with
similar results (not shown).
|
In view of recent evidence that TGF-ß is an important
costimulatory factor in the development of T suppressor cells (4), the
decreased amounts of active TGF-ß in SLE we have documented might
contribute to the inability of CD8+ T cells to
down-regulate B cell activity. We have recently observed that a brief
exposure of CD8+ T cells from healthy individuals to
TGF-ß and IL-2 enables them to down-regulate Ig production (Figure 6
in 10 . We considered that similar exposure of SLE lymphocytes to
these cytokines might condition them to down-regulate spontaneous IgG
production. Examples of this cytokine-mediated suppression of Ig
production are shown in Figure 5. PBMC
from two SLE patients were exposed to IL-2 (10 U/ml), TGF-ß (10
pg/ml), or both of these cytokines for 72 h and subsequently
cultured for an additional 7 days. In case 1, neither IL-2 nor TGF-ß
alone had significant effects, whereas in case 2 each of these
cytokines appeared to have some effect. In both cases, a brief exposure
of PBMC to both IL-2 and TGF-ß resulted in the suppression of
spontaneous IgG production by 85%. The mechanism responsible for this
effect is the subject of current investigation.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In an accompanying report, we have found that NK cells are the
principal source of both total and active TGF-ß produced by
unstimulated lymphocytes (10). In SLE and healthy controls, NK cells
produced substantially more TGF-ß than T cells (Fig. 1).
Decreased amounts, however, of both constitutive and induced NK
cell-derived TGF-ß were found in SLE, and these defects were found in
amounts of the total and active form of this cytokine. Thus, in
addition to the well-known defect of NK cell cytotoxic activity in SLE
(31, 32), production of TGF-ß appears to be decreased as
well.
While resting human T cells produced trivial amounts of TGF-ß during the first 48 h of culture, stimulated T cells can produce significant quantities of this cytokine (33). Although many T cells appear to be chronically stimulated in SLE (34, 35), they produced only minimal amounts of TGF-ß.
Other sources of TGF-ß include B cells and monocytes. Although we
also reported that resting B cells from healthy donors produce small
amounts of TGF-ß (10), these lymphocytes have the capacity to produce
this cytokine (36, 37). Moreover, IgG secreted by Ag-activated B cells
has been found to be complexed latent TGF-ß (38). When this complex
is bound to FcR on macrophages, latent TGF-ß is converted to its
active form and may be immunosuppressive (39). Monocytes have been
considered to be the principal hemopoietic source of TGF-ß (8, 9).
Differences in monocyte-derived total and active TGF-ß between SLE
patients and controls were not found (Table II).
It is important to emphasize that this report concerns short term production of TGF-ß. We have focused our attention on this interval because CD8+ T cells require the presence of picogram per milliliter quantities of active TGF-ß coincident with activation for development of down-regulatory function (10).
Although stimulated T cells do not produce much TGF-ß during the initial 72 h, they can produce considerable quantities of latent TGF-ß at later periods (33; K. Ohtsuka and D. A. Horwitz, unpublished observations).
Decreased concentrations of TGF-ß in SLE did not appear to correlate with disease activity. To date, TGF-ß production has been measured in a group of 10 subjects with rheumatoid arthritis, and a modest decrease of anti-CD2-induced total and active TGF-ß has been observed. Larger numbers of RA patients are required to determine the significance of this finding.
Unlike anti-CD3, anti-CD2 mAbs strongly stimulate lymphocytes to produce total and active TGF-ß (10). Following stimulation with anti-CD2, both production of total and active TGF-ß was markedly reduced in SLE. Because the lymphocyte mitogenic response to anti-CD2 in SLE is also reduced (40, 41), decreased TGF-ß production might reflect decreased signaling through the CD2 pathway rather than a decreased capacity of SLE lymphocytes to produce TGF-ß. We, therefore, turned our attention to cytokine regulation of TGF-ß production.
Concentrating on cytokines known to be abnormally produced in SLE, we
have shown that both TNF- and IL-2 increase lymphocyte-derived
active TGF-ß and that IL-10 has the opposite effect. To our
knowledge, these findings have not been previously described. Using
other cellular targets, IL-2 has been reported to increase TGF-ß
production by mouse macrophages, and IL-10 has suppressed bone
marrow-derived TGF-ß (42, 43).
Significantly, adding IL-2 and or TNF- to SLE lymphocytes or
antagonizing IL-10 did not normalize active TGF-ß production in SLE.
Thus, decreased TGF-ß production did not appear to be secondary to
other obvious cytokine defects. Other mechanisms need to be identified.
Recently, it has been reported that murine peritoneal macrophages use plasmin bound to the cell surface to convert latent to active TGF-ß (44). Human monocytes and NK cells appear peculiarly suited to converting TGF-ß to its active form by plasmin activity, since these cells constitutively express urokinase plasminogen activator receptors on their cell surface. T cells, by contrast, only express these receptors after activation (45). Of interest, plasminogen activator activity is decreased in SLE (46, 47, 48). Thus, decreased conversion of latent to active TGF-ß might be due to this decreased enzymatic activity.
TGF-ß can have beneficial or deleterious effects in lupus. SLE-like autoantibodies appear in TGF-ß knockout mice (49), and the introduction of TGF-ß genes into the skeletal muscle of the lupus-prone MRL/lpr mice decreased autoantibody production (50). Recently TGF-ß has been reported to promote the growth of murine CD4+ cells and CD8+ cells (51, 52). With human peripheral blood cells, we have found that TGF-ß costimulates CD8+ T cells to develop down-regulatory activity (4, 10). TGF-ß is also an immunosuppressive cytokine, as it inhibits T and B cell proliferation, NK cell cytotoxic activity, and the generation of T cell cytotoxicity (5, 53, 54, 55). As stated above, TGF-ß complexed to IgG can be immunosuppressive (39, 56).
The net biologic effect of TGF-ß is determined by the local cytokine concentration and the cell types affected. Whereas picogram quantities of TGF-ß are needed for suppressor cell induction (10), nanogram amounts are generally required for suppressive effects 53–55). De Jong et al. showed that TGF-ß had costimulatory activity for naive CD4+CD45RA+ cells but suppressed the proliferation of activated or memory CD4+CD45RO+ cells (57). Thus, TGF-ß may promote the maturation of immature cells and have the opposite effect on mature cells. TGF-ß may promote the maturation of immature cells and have the opposite effect on mature cells. TGF-ß production in the kidneys contributes to the chronicity of glomerulonephritis (58).
It is well established that SLE patients lack regulatory cells capable of controlling B cell hyperactivity (2). Because both TGF-ß and IL-2 production are decreased in SLE, and this combination of cytokines can induce down-regulatory T cell function in healthy individuals (10), we have asked whether these cytokines can reconstitute regulatory cell function. This remarkable inhibition of spontaneous Ig synthesis in two individuals with active SLE after exposure of their PBMC to TGF-ß and IL-2 is an encouraging preliminary result.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. D. A. Horwitz, Department of Medicine, Division of Rheumatology and Immunology, University of Southern California School of Medicine, HMR 711, 2011 Zonal Avenue, Los Angeles, CA 90033. E-mail address:
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; MLEC, mink lung epithelial cells.
Received for publication September 4, 1997. Accepted for publication November 17, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-secreting cells in the peripheral blood. Arthritis Rheum. 39:379.[Medline]
. J. Exp. Med. 166:991.This article has been cited by other articles:
|
|
 |
|
  V. Saxena, D. W. Lienesch, M. Zhou, R. Bommireddy, M. Azhar, T. Doetschman, and R. R. Singh Dual Roles of Immunoregulatory Cytokine TGF-{beta} in the Pathogenesis of Autoimmunity-Mediated Organ Damage J. Immunol., February 1, 2008; 180(3): 1903 - 1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-K. Kang, M. Liu, and S. K. Datta Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells J. Immunol., June 15, 2007; 178(12): 7849 - 7858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. Wang, P. Wang, J. D. Gray, and D. A. Horwitz IL-2 Is Essential for TGF-beta to Convert Naive CD4+CD25- Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells J. Immunol., February 15, 2007; 178(4): 2018 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Sela, N. Mauermann, R. Hershkoviz, H. Zinger, M. Dayan, L. Cahalon, J. P. Liu, E. Mozes, and O. Lider The Inhibition of Autoreactive T Cell Functions by a Peptide Based on the CDR1 of an Anti-DNA Autoantibody Is via TGF-{beta}-Mediated Suppression of LFA-1 and CD44 Expression and Function J. Immunol., December 1, 2005; 175(11): 7255 - 7263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-K. Kang, M. A. Michaels, B. R. Berner, and S. K. Datta Very Low-Dose Tolerance with Nucleosomal Peptides Controls Lupus and Induces Potent Regulatory T Cell Subsets J. Immunol., March 15, 2005; 174(6): 3247 - 3255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Sela, R. Hershkoviz, L. Cahalon, O. Lider, and E. Mozes Down-Regulation of Stromal Cell-Derived Factor-1{alpha}-Induced T Cell Chemotaxis by a Peptide Based on the Complementarity-Determining Region 1 of an Anti-DNA Autoantibody via Up-Regulation of TGF-{beta} Secretion J. Immunol., January 1, 2005; 174(1): 302 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Riemekasten, D. Langnickel, P. Enghard, R. Undeutsch, J. Humrich, F. M. Ebling, B. Hocher, T. Humaljoki, H. Neumayer, G.-R. Burmester, et al. Intravenous Injection of a D1 Protein of the Smith Proteins Postpones Murine Lupus and Induces Type 1 Regulatory T Cells J. Immunol., November 1, 2004; 173(9): 5835 - 5842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, J. D. Gray, H. Soucier, and D. A. Horwitz Natural and Induced CD4+CD25+ Cells Educate CD4+CD25- Cells to Develop Suppressive Activity: The Role of IL-2, TGF-{beta}, and IL-10 J. Immunol., May 1, 2004; 172(9): 5213 - 5221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, M. N. Koss, F. Quismorio Jr., J. D. Gray, and D. A. Horwitz CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-{beta} Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome J. Immunol., February 1, 2004; 172(3): 1531 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Horwitz, S. G. Zheng, and J. D. Gray The role of the combination of IL-2 and TGF-{beta} or IL-10 in the generation and function of CD4+ CD25+ and CD8+regulatory T cell subsets J. Leukoc. Biol., October 1, 2003; 74(4): 471 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wang, M. Khalil, J. Ravetch, and B. Diamond The Naive B Cell Repertoire Predisposes to Antigen-Induced Systemic Lupus Erythematosus J. Immunol., May 1, 2003; 170(9): 4826 - 4832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Schotte, P Willeke, S Rust, G Assmann, W Domschke, M Gaubitz, and B Schluter The transforming growth factor-{beta}1 gene polymorphism (G915C) is not associated with systemic lupus erythematosus Lupus, February 1, 2003; 12(2): 86 - 92. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Zinger, E. Eilat, A. Meshorer, and E. Mozes Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW)F1 mice via active suppression Int. Immunol., February 1, 2003; 15(2): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gergely Jr., B. Niland, N. Gonchoroff, R. Pullmann Jr., P. E. Phillips, and A. Perl Persistent Mitochondrial Hyperpolarization, Increased Reactive Oxygen Intermediate Production, and Cytoplasmic Alkalinization Characterize Altered IL-10 Signaling in Patients with Systemic Lupus Erythematosus J. Immunol., July 15, 2002; 169(2): 1092 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Singh, F. M. Ebling, D. A. Albuquerque, V. Saxena, V. Kumar, E. H. Giannini, T. N. Marion, F. D. Finkelman, and B. H. Hahn Induction of Autoantibody Production Is Limited in Nonautoimmune Mice J. Immunol., July 1, 2002; 169(1): 587 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Kolowos, U S Gaipl, R E Voll, C Frank, J P Haas, T D Beyer, J R Kalden, and M Herrmann CD4 positive peripheral T cells from patients with systemic lupus erythematosus (SLE) are clonally expanded Lupus, May 1, 2001; 10(5): 321 - 331. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Mishra, D. R. Brown, I. M. Olorenshaw, and G. M. Kammer Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells PNAS, February 15, 2001; (2001) 51507098. [Abstract] [Full Text]
|
|
|
|
|
|
M. Khalil, K. Inaba, R. Steinman, J. Ravetch, and B. Diamond T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus J. Immunol., February 1, 2001; 166(3): 1667 - 1674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
