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*
Department of Internal Medicine, Section of Rheumatology, and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510; 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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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Costimulatory antagonists have recently been examined as possible therapeutic approaches to treat autoimmune disease in several mouse models. Some studies demonstrated an amelioration of disease with the use of anti-B7.1/7.2, anti-CD28, or CTLA4 Ig in murine models of multiple scleroses (experimental allergic encephalomyelitis (EAE)3), diabetes, and systemic lupus erythematosus (SLE) (4, 5, 7, 8, 9). In contrast, other studies using B7-blocking agents alter autoimmune pathology in mouse models depending on the timing and on how these agents are administered (5, 6, 8, 9, 10). For example, actively induced EAE is ameliorated by sustained anti-B7.1 treatment but is exacerbated by anti-B7.2 treatment (5). In the nonobese diabetic (NOD) mouse model of diabetes, anti-B7.2 mAbs administered at the time of onset of insulitis blocked the development of diabetes, whereas anti-B7.1 treatment exacerbated diabetes in spite of the fact that both diseases, EAE and NOD diabetes, are thought to be mediated by Th1 lymphocytes (6). Moreover, in the murine EAE model, intact anti-B7.1 enhanced EAE in vivo if given after the first episode of disease, whereas Fab fragments of anti-B7.1 mAbs blocked the progression of disease, suggesting that anti-B7.1 may impart regulatory signaling (9).
The current studies were designed to investigate the role of B7.1 and B7.2 costimulation in a mouse model of human SLE. MRL-lpr/lpr mice develop an autoimmune disorder resembling human SLE and characterized by hypergammaglobulinemia, the production of high titers of autoantibodies, such as those specific for dsDNA and small nuclear ribonucleoprotein particles (snRNP) as well as severe lymphadenopathy, glomerulonephritis, and skin disease. Two approaches were used to interfere with the biological functions of the B7 molecule in MRL-lpr/lpr mice. First, mice were treated with anti-B7.1 and/or anti-B7.2 blocking Abs throughout the development of disease. Secondly, parallel studies were performed with B7.1- and B7.2-deficient mice backcrossed into the MRL-lpr/lpr background. Mice were examined for the specificity, titers, and isotypes of autoantibody responses as well as for the presence of specific pathology in the kidney. Our observations demonstrate that the blocking of B7.1 or 7.2 alone by Ab treatment or the genetic deletion of either B7.1 or B7.2 did not ameliorate the presence or titers of autoantibodies. Surprisingly, kidney pathology was enhanced and/or altered in some B7-deficient mice as compared with aged-matched wild-type MRL-lpr/lpr mice. Simultaneous treatment with both anti-B7.1 and anti-B7.2 is required to be effective in interfering with the development of anti-snRNP and anti-dsDNA autoantibodies. This result confirms that B7-CD28 costimulatory pathway is critical in regulating certain autoimmune parameters in MRL-lpr/lpr mice. Alternative or compensatory pathways of costimulation for T cell activation may exist in the absence of either B7.1 or B7.2. An understanding of the induction phase of autoimmunity and the breakdown of immunological tolerance is crucial for understanding both the genesis and therapeutic intervention of autoimmune diseases such as SLE.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As a measure of their biological activity, anti-B7.1 and anti-B7.2 mAbs were examined for their ability to inhibit primary MLR. Primary one-way MLR was performed by culturing 5 x 105 C57BL/6 spleen cells with equal numbers of irradiated (3000 rad) C3H/HeJ spleen cells in complete medium (200 µl/well) in 96-well flat-bottom microtiter plates (Costar, Cambridge, MA) in the absence or presence of indicated mAbs. Each condition was set up in triplicates. After 66 h of incubation at 37°C with 5% CO2, the culture was pulsed with [3H]thymidine (1 µCi/well) and harvested onto glass fiber filters 6 h later. The results are expressed as the mean of percentage of inhibition ± SD, which was determined by the formula [(cpm without mAb - cpm with mAb)/cpm without mAb] x 100.
In vivo efficacy of anti-B7.1 and anti-B7.2 Ab treatment
Anti-B7 mAbs were examined for their ability to inhibit lymph node T cell responses to a model Ag, OVA. PBS, anti-B7.1, anti-B7.2, or anti-B7.1 + anti-B7.2 Abs were injected into normal B10.A mice (100 µg/mouse i.v. and 500 µg/mouse i.p.) on day 0. The mice were immunized with 100 µg OVA/CFA via footpad and in the base of the tail on day 1. Immunized mice then received a second identical injection of Abs on day 4. All animals were sacrificed 8 days after immunization. Lymph node T cells (1 x 105 cells/well) were purified by magnetic bead separation columns (Miltenyi Biotec, Auburn, CA) and cocultured with irradiated spleen cells (5 x 105 cell/well) and OVA in triplicate wells for 72 h. The culture was then pulsed with [3H]thymidine (1 µCi/well) and harvested onto glass fiber filters 24 h later. The results are expressed as the mean of cpm ± SD.
Anti-B7.1/B7.2 Ab treatment
Anti-B7.1/B7.2 Ab treatment protocols for MRL-lpr/lpr mice were based on previous studies for which efficacy in the treatment of EAE and diabetes was observed (4, 5, 6). MRL-lpr/lpr mice (5–8 wk old, The Jackson Laboratory, Bar Harbor, ME) were injected with rat anti-murine B7.1 (1G10, IgG2a) and/or anti-B7.2 (2D10, IgG2b) mAbs three times a week at the dose of 100 µg/mouse i.p. over the entire course of the study. A minimum of 10 MRL-lpr/lpr mice were used in each treatment group. One group received control isotype Ab (2-4A1) i.p., whereas other treatment groups received anti-B7.1 and/or anti-B7.2 mAb, respectively. Serum samples were collected every 2–3 wk and examined for the presence of antinuclear autoantibodies (ANA) by indirect immunofluorescence and by ELISA for anti-dsDNA and anti-snRNP as described below.
Genetic deficient mice
B7.1- and B7.2-deficient mice on a 129 and BALB/c background,
respectively, were derived as previously reported (11) and
backcrossed to the third generation with MRL-lpr/lpr mice
(The Jackson Laboratory). The intercrossed F3 generation was used in
the present experiments. PCR analysis was performed to confirm
B7.1-deficient, B7.2-deficient, and lpr/lpr genotypes (Fig. 1
). As controls, heterozygous B7.1
deficient or B7.2-deficient, MRL-lpr/lpr N3 mice, wild-type
MRL-lpr/lpr mice, and wild-type 129 mice were examined in
parallel studies. Serum samples were collected every 2 wk starting from
wk 7 and analyzed for the presence of anti-snRNP and anti-dsDNA
autoantibodies, and their individual Ig isotype analyses were
additionally performed on the samples. Kidney pathology was also
examined at the indicated time points as detailed below.
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The presence of anti-snRNP autoantibodies was examined by ELISA. Native murine snRNPs were purified from Ehrlich ascites cells as previously described (12). In brief, native snRNP Ag was coated on a U-shaped vinyl plate (Costar) overnight at 4°C. Plates were incubated with 1% BSA/PBS followed by a 10-2 dilution of serum samples incubated at room temperature for 2 h. Anti-mouse IgG-alkaline phosphatase (Southern Biotechnology Associates, Birmingham, AL) was then added to the plate followed by incubation with p-nitrophenylphosphate substrate (Sigma, St. Louis, MO). OD405 nm was measured at various time points (Titertek Multiskan, Titertek Instruments, Huntsville, AL). Experimental values from separate experiments were normalized to a single MRL-lpr/lpr positive control serum used in every assay (arbitrarily defined as 100 U).
Anti-dsDNA autoantibody was examined by commercially available ELISA (Elias USA, Osceola, WI). In brief, 10-2 serum dilution were incubated at room temperature for 2 h on plates coated with recombinant plasmid dsDNA. Thereafter, goat anti-mouse IgG-alkaline phosphatase (Sigma) was applied to the plate followed by p-nitrophenylphosphate substrate, as described above.
Indirect immunofluorescence (ANA)
Indirect immunofluorescence assays were performed with the use of commercially available cell substrates (Quidel, San Diego, CA). In brief, 30 µl of a 1:40 dilution of serum were placed on slides coated with human epithelial cells (HEp-2) and incubated at room temperature for 1 h. After a 5-min wash in PBS-Tween (0.1%), FITC-conjugated anti-mouse IgG (Sigma) was applied to individual wells and incubated in the dark at room temperature for 1 h. After another 5-min wash, wells were examined by UV fluorescence microscopy.
Kidney pathology
Kidneys from experimental and control mice were collected at the indicated time points and immediately immersed in 10% formalin (Fisher, Pittsburgh, PA). Thin sections and hematoxylin and eosin staining were performed by Yale Dermatopathology Laboratory. Blinded samples were examined for pathology at x20 and x40 magnification. Pathology was assessed for the presence of endovasculitis, glomerular crescents, lymphoid hyperplasia, wire loop formation, and mesangial hypercellularity as previously reported (13). Tissue sections were scored on a scale of 0 (no pathology) to 3+ (most severe pathology) for each parameter.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The blocking effect of anti-B7.1 and anti-B7.2 mAbs was
examined in vivo by examination of the induction of T cell responses to
OVA. As illustrated in Fig. 2, T cell
responses from anti-B7.1 + anti-B7.2 cotreated mice were
significantly suppressed as compared with that from untreated and
anti-B7.1 or anti-B7.2 single Ab-treated mice. However,
anti-B7.1 or anti-B7.2 single Ab treatment also significantly
suppressed T cell response when compared with untreated mice. Anti-B7.2
had greater blocking efficacy than did anti-B7.1 in that higher
stimulatory concentrations of OVA were present.
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). However, anti-B7.1 +
anti-B7.2 Abs inhibited T cell proliferation up to 50%. Anti-B7.1
or anti-B7.2 single Ab treatment inhibited T cell proliferation
20–30%, significantly lower than combined anti-B7.1/B7.2
treatment but significantly higher than the isotype control
responses.
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We examined how blocking the biological function of B7
costimulation by Ab treatment or gene deletion would affect the
expression of autoantibodies in MRL-lpr/lpr mice. The
majority of mice in the seven experimental groups were negative for
autoantibodies as assessed by indirect immunofluorescence (ANA) and
ELISA before anti-B7.1/B7.2 Ab treatments (Table I).
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,
Fig. 4). These results were consistent
with another experiment in which mice were given identical Ab treatment
for a longer duration and in groups of mice receiving either
anti-B7.1 or anti-B7.2 individually (12 wk of treatment, data
not shown). The spectra of ANA patterns were primarily a homogeneous
nuclear pattern, consistent with anti-DNA autoantibodies, and a
speckled nuclear pattern, typically associated with autoantibodies to
the snRNP complex. A smaller frequency of sera revealed a nucleolar
staining pattern, although all three patterns were observed in
anti-B7.1/B7.2-treated mice or in wild-type MRL-lpr/lpr
mice. The frequency in which individual patterns were observed or the
age at which mice became ANA positive did not significantly differ
between the experimental groups (data not shown).
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, Fig. 4). There was no significant difference
in the onset or development of ANA between the homozygous and
heterozygous B7.1- or B7.2-deficient MRL-lpr/lpr mice
(p < 0.05). These results indicate that
blocking both B7.1 and B7.2 molecules with specific Ab or completely
eliminating either B7 molecule did not significantly alter the
spontaneous development of autoantibodies in
MRL-lpr/lpr mice. Anti-dsDNA and anti-snRNP autoantibodies
The presence of Abs to dsDNA and/or the snRNP complex is an
important diagnostic criteria for human SLE and in murine models of the
disease. We examined whether anti-B7.1/7.2 Ab treatment or B7.1 or
B7.2 gene deletion would alter the spontaneous production of
anti-dsDNA and anti-snRNP autoantibodies in
MRL-lpr/lpr mice. As described earlier, serum samples were
collected at regular intervals, and autoantibody production was
identified by ELISA. Both anti-dsDNA and anti-snRNP
autoantibody production were significantly inhibited by simultaneous
anti-B7.1 and anti-B7.2 Ab treatment (Fig. 3A).
Treatment with anti-B7.2 Ab alone inhibited the production of
anti-dsDNA autoantibody production while having no effect on
anti-snRNP autoantibody production. In contrast, treatment with
anti-B7.1 alone did not affect the development of either
anti-snRNP or anti-dsDNA autoantibody production (Fig. 5A).
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, B
and C). There was no significant statistical difference in
anti-dsDNA or anti-snRNP autoantibody production between the
homozygous and heterozygous B7.1- or B7.2-deficient
MRL-lpr/lpr mice at the conclusion of the study (22 wk
of age). An extensive analysis of anti-snRNP and anti-dsDNA autoantibody isotypes in B7.1-deficient and B7.2-deficient mice was performed because prior studies have demonstrated that the absence of B7 molecules greatly affects the formation of germinal centers and Ab class switching (14). B7.2-deficient mice provided soluble immunogens in the absence of adjuvant can generate IgM Abs but fail to develop IgG class Ab or germinal centers (14). Our studies demonstrated that IgG1 and IgG2a autoantibodies specific for both DNA and snRNPs develop essentially the same in B7.1- or B7.2-deficient mice in titers comparable with those of wild-type MRL-lpr/lpr mice (data not shown).
Surface expression of the B7 molecules was examined by flow cytometry to investigate whether the expression of B7.2 is altered in the absence of the B7.1 molecules (or, conversely, if B7.1 levels are altered in the absence of B7.2). Aged MRL-lpr/lpr mice possess a majority of splenic T lymphocytes of an activated phenotype (CD44high, L-selectinhigh), although the role of the B7-costimulatory molecules in this phenotype is not known (15). Preliminary studies indicate that some homozygous B7.1-deficient mice may express B7.2 at higher levels than do heterozygous B7.1-deficient or wild-type MRL-lpr/lpr mice (data not shown).
Kidney pathology
Glomerulonephritis is one pathologic hallmark of SLE. The examination of kidney sections from normal mice showed preservation of the renal architecture with normal vessels and glomeruli (data not shown).
Homozygous B7.1-deficient MRL-lpr/lpr mice demonstrated
large perivascular mixed lymphoid hyperplasia which included activated
lymphocytes, plasma cells, and mononuclear cells (Table II, Fig. 6). The vessels showed marked myointimal
proliferation and infiltration of the myointimal region with
lymphocytes, but there was no evidence of endovasculitis. The
glomerular lesions consisted of a marked increased in cellularity,
focal and segmental areas of necrosis, and karyorrhexis and focal
crescent formation. The glomerular lesions were much more severe
lesions in that necrosis and crescent formation was diffusely
distributed on almost all glomeruli. In contrast, the heterozygous
B7.1-deficient MRL-lpr/lpr mice had glomerular and vascular
lesions similar to those of the MRL-lpr/lpr wild-type mice.
The perivascular lymphoid infiltrate was similar in intensity to the
wild-type MRL-lpr/lpr mice with striking endovasculitis.
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, Fig. 6). The
perivascular lymphoid hyperplasia was almost completely absent. The
vessels showed no evidence of endovasculitis and were mostly normal.
The glomeruli demonstrated only mild mesangial hyperplasia with only
focal and segmental areas of karyorrhexis and leukocytic infiltration.
Although B7.2-deficient mice had significantly milder
glomerulonephritis, this strain exhibited striking skin lesions with
severity and frequency far exceeding age-matched wild-type
MRL-lpr/lpr mice (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Many previous studies indicate that Ab production by autoreactive B
cells in lupus is promoted by 
ß T cell help in a cognate- and
contact-dependent manner (3, 18, 19, 20). For example,
neonatal thymectomy of MRL-lpr/lpr mice abrogated IgG
anti-dsDNA synthesis and glomerulonephritis and decreased mortality
(19). Th cell dependence of IgG anti-DNA production
and nephritis was supported by similar results obtained after treatment
of these animals with an anti-Thy-1.2 Ab (21) or with
anti-CD4 Abs (3, 21, 22). The necessity of Th cells
for autoantibody production in murine lupus is further supported by
studies of other autoimmune strains, such as SNF1, in which
CD4+ T cells drive anti-DNA production in
vitro and in vivo and accelerate disease when transferred to
prenephritic mice (23, 24). Genetic-based studies also
support the notion that CD4+ T cells are
necessary for autoantibody synthesis. MRL-lpr/lpr mice
lacking CD4+ T cells and have diminished IgG
anti-DNA synthesis and nephritis (25, 26). These
studies provide a simple, concise model for lupus, in which pathogenic
autoantibody production by B cells requires autoreactive T cell help.
In contrast to some models of autoimmunity, lupus-prone mice appear to
possess normal central mechanisms of thymic tolerance
(27, 28, 29, 30).
Because lupus autoimmunity requires activation of autoreactive T and B cells, it would seem likely that costimulatory signals are critical in regulating recognition of self Ag by T cells (31). In lupus-prone (NZB/NZW)F1 mice, both anti-B7.1 and anti-B7.2 mAbs are needed to prevent the development and progression of lupus, with B7.2 assumed to provide a more critical role in Th2-mediated cytokine production (7). CTLA4-Ig suppressed the lupus-like illness in the NZB/NZW F1 mouse model and prolonged life even when the treatment was administered late in disease (4). The mice treated with CTLA4-Ig did not make Abs to dsDNA at any time during the course of treatment, including the 3 mo of observation after treatment was stopped. Suppression of autoantibody production was accompanied by a significant reduction in the severity of lupus nephritis.
These studies are consistent with the observations presented here in which both anti-B7.1 and anti-B7.2 Abs are required to be effective in inhibiting anti-snRNP and anti-dsDNA autoantibody production. The absence of either B7 molecule and anti-B7.1 or anti-B7.2 single treatment alone did not prevent the expression of MRL-lpr/lpr autoimmunity. The treatment protocols that we used in this study were based on those in which efficacy was observed in models of EAE and diabetes (4, 5, 6). However, it is possible that anti-B7 Ab treatment was ineffective because T cell encounters with autoantigen, either nucleosomes or snRNPs, occur early in life before the detection of overt autoantibody synthesis or pathology.
The spontaneous autoimmune disease in B7.1- or B7.2-deficient or anti-B7.1- or anti-B7.2-treated MRL-lpr/lpr mice may indicate that alternative/compensatory costimulation pathways exist for T cell activation in this mouse model. One possibility is that B7.1 compensates for costimulation in the absence of B7.2 (and vice versa). Alternatively, CD40-CD40L may substitute for the requirement of B7. MRL-lpr/lpr mice deficient in CD40L fail to develop normal T cell-dependent humoral immune responses, Ig isotype switching, and germinal center formation (32). In murine lupus, complete long term suppression of disease was observed only with the inhibition of both the CD28-B7 and the CD40-CD40L pathways (33). A recent study suggests that a new costimulation molecule, inducible costimulator, may play an important role in human T cell activation in addition to CD28-B7 and CD40-CD40L pathways (34). In our preliminary studies, we have identified a population of CD40Lhigh, B220+ cells in B7.1-deficient MRL mice that are not present in wild-type MRL-lpr/lpr. Our ongoing studies are aimed at identifying the importance of these cell surface molecules in the development of lupus autoimmunity in the absence of B7.
On the basis of prior studies, we anticipated that interfering with the biological function of B7.2 should impede isotype switching of autoantibodies in spontaneous disease (14). This notion is based on the absence of isotype switching or germinal center formation after i.v. immunization of B7.2-deficient mice or in mice treated with anti-B7.2 blocking Abs (14, 35). We have found that isotype switching of anti-DNA and anti-snRNP indeed occurred in both B7.1-deficient and B7.2-deficient MRL-lpr/lpr mice (data not shown). The ability to develop mature autoantibody subsets in these mice may be due to the strength of TCR signaling, although the source of endogenous autoantigen and its avidity for TCR in MRL-lpr/lpr mice is not known. Although titers and isotypes of autoantibodies from B7.2-deficient mice resembled those of wild-type mice, overall kidney pathology was generally less severe in the absence of B7.2. It is possible that the fine specificity of nephritogenic Abs in the B7.2-deficient mouse differs from that in other mice. It is also not clear why skin lesions arise with higher frequency and severity in the absence of B7.2, although pathological examination is presently under way, although recent studies in long term allograft survival (36) and experimental autoimmune thyroiditis (37) suggested that B7.2 has a more important role in providing the negative signaling by engaging with CTLA-4 molecule.
It is clear that the full activation of T cells does not always require B7-CD28 signaling (38, 39, 40). Indeed, CD28-deficient mice can develop virtually normal effector and memory T cell immunity to viral challenge (15, 39, 41). Although it has been shown that CD28-mediated signaling may reduce the threshold number of TCRs required to activate a T lymphocyte (42), it is possible that the strength of autoantigenic peptide stimulation to the TCR may also influence the outcome of T cell tolerance vs activation. For example, a weak interaction of autoantigen with TCR, even in the absence of B7-CD28 signaling, may not allow for the induction of peripheral T cell tolerance. In contrast, strong signals via TCR may bypass strict requirements for B7 costimulation. By these mechanisms, autoreactive T cells may then be allowed to remain in the MRL-lpr/lpr repertoire even in the absence of B7 costimulation.
It is clear from our studies that a greater understanding of the role of B7-mediated costimulation in lupus autoimmunity may be required to fully appreciate the potential therapeutic benefits of manipulating costimulatory pathways.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mark J. Mamula, Yale University School of Medicine, 333 Cedar Street, LCI 609, New Haven, CT 06510. E-mail address:
3 Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; SLE, systemic lupus erythematosus; NOD, nonobese diabetic; snRNP, small nuclear ribonucleoprotein particles; ANA, antinuclear autoantibodies.
Received for publication January 6, 1999. Accepted for publication June 8, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells. J. Immunol. 156:4041.[Abstract]
/ß+ and abnormal lpr and gld cell populations. J. Exp. Med. 170:1869.ß T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. J. Immunol. 158:2464.[Abstract]
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