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Immunology. Sep 2004; 113(1): 89–98.
PMCID: PMC1782553

Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance

Abstract

Agonistic antibodies against CD137 act as costimulators in the activation of CD8 T cells. They enhance the immune response against syngeneic tumour grafts and suppress T cell-dependent humoral immune responses in vivo. The present study was undertaken to determine whether suppression of antibody production by anti-CD137 mAb affects the development of collagen-induced arthritis (CIA). Male DBA/1J mice were immunized with bovine collagen II (CII) and treated with an agonistic anti-CD137 mAb or an isotype-matched control mAb. Mice were assessed regularly for macro- and microscopic signs of arthritis and for the appearance of collagen-specific antibody production. Interferon (IFN)-γ determination, FACS analysis of splenocytes and histopathological joint examinations were performed after the animals were killed. Administration of anti-CD137 mAb at the time of collagen immunization blocked the development of disease and inhibited the humoral immune response against CII. Agonistic anti-CD137 mAb exhibited therapeutic efficacy even after the immune response to CII had succeeded and the disease became apparent. Furthermore, it induced a protective memory in the animals, enabling resistance to subsequent challenges with the pathogenic antigen. Our results suggest a key role for CD137 in the pathogenesis of CIA. This model provides insights into immunoregulatory conditions that control the pathogenesis of autoimmune diseases.

Keywords: collagen-induced arthritis, CD137, costimulator, therapeutic antibodies

Introduction

Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are chronic, inflammatory autoimmune diseases of the joint with unknown aetiology.1 Collagen-induced arthritis (CIA) is an experimental mouse model for the study of these diseases.2 B and T lymphocytes participate in the pathogenesis of CIA, as demonstrated by transfer experiments with collagen-specific T cells and autoantibodies into SCID or T cell-depleted mice.3,4 Inflammatory arthritic reactions have been shown to occur in the absence of antibodies in the animal model as well as in human disease; however, joint destruction depends on the presence of collagen II (CII)-specific autoantibodies.5,6

A series of monoclonal antibodies against cell surface-bound or soluble components of the immune system such as CD4, TCR, MHC-II, CD25, CD28, B7 or TNFR has been reported to block the induction of CIA provided their administration occurs prior to or at the time of immunization with CII713

CD137 (4–1BB) is a costimulatory molecule expressed on activated T cells, NK cells and dendritic cells (DCs).1418 4–1BBL, the natural ligand for the CD137 receptor, is expressed constitutively on B cells, activated macrophages and dendritic cells.19,20 Activation through the CD137 receptor by an agonistic antibody leads to preferential activation of CD8+ T cells and protects CD8+ T cells from activation-induced cell death.15,2123 The antibody enhances the production of cytokines [interferon (IFN)-γ, tumour necrosis factor (TNF)-α] by CD8+ T cells and their development into antigen-specific CTLs which eradicate syngeneic tumour grafts effectively in mice.22,24 Of particular relevance to the present study is the fact that agonistic antibody to the CD137 molecule blocked T cell-dependent humoral immune response25 and inhibited or reversed acute disease in systemic lupus erythematosus-prone mice.26,27 We therefore examined the influence of anti-CD137 mAb on the incidence and the course of CIA.

Materials and methods

Mice

Male DBA/1JBom mice (H-2q) were purchased from M and B (Ry, Denmark) and maintained under pathogen-free conditions. Mice were used for experiments at the age of 8–12 weeks.

Induction and assessment of arthritis

Lyophilized bovine collagen II (bCII) (MD Biosciences, Zuerich, Switzerland) was dissolved in 0·05 m acetic acid to a concentration of 2 mg/ml and shaken overnight at 4°. bCII was emulsified with an equal volume of complete Freund's adjuvant (Gibco BRL, Grand Island, USA). Mice were injected subcutaneously into the base of the tail with 100 μl of emulsion containing 100 μg of bCII and boosted at day 21 by intraperitoneal injection with 100 μg of bCII dissolved in phosphate buffered saline (PBS).

Paws were inspected regularly for signs of inflammation and measured with a mechanical calibrator (Oditest, Kroeplin, Germany) for 100 days. An arthritic index was obtained by scoring all four limbs on a scale of four grades of severity. The maximum possible score per animal was 12. The grades were: 0 = normal, 1= redness and swelling limited to one digit, 2 = redness and swelling limited to two or more digits or moderate redness and swelling of the ankle or wrist, 3 = severe redness and swelling of the entire paw or ankylosis.

Antibodies

The agonistic rat antimouse anti-CD137 mAb (clone 3H3) and its control rat antihuman CD137 mAb (clone 9D6), both IgG2a, were prepared as described.22 Mice were injected intravenously one to three times with 200 μg of antibody as indicated.

Enzyme-linked immunosorbent assay (ELISA) for anti-CII antibodies

Serum Ab levels of antimurine CII-reactive IgG were measured by ELISA following the instructions of the supplier (MD Biosciences, Zuerich, Switzerland). Briefly, wells of flat-bottomed 96-well culture plates coated with mouse CII were incubated at 4° overnight with 100 μl of diluted serum samples (1:10000) or with different concentrations of a standard antibody (polyclonal antiserum from mice immunized with CII). After washing, 100 μl of a secondary antibody solution (peroxidase-conjugated goat antimouse IgG) were added. After 2 hr of incubation at room temperature wells were washed and incubated with 100 μl of enzyme-substrate solution (orthophenylenediamine in urea-H2O2 buffer) at room temperature for 20 min. The reaction was stopped by adding 50 μl of stop solution (2·5 N sulphuric acid). The OD values were read at 490 nm using an ELISA microplate reader (Milenia Kinetic Analyzer, Diagnostic Products Corp., Los Angeles, USA). A log–log standard curve was generated based on the OD values of standard antibody dilutions (0·5; 1; 2; 4; 8; 16 units/ml). The antibody concentrations (units/ml) of test samples were calculated using regression analysis (SOFTmax PRO for Windows and Macintosh, Molecular Devices Corp., Sunnyvale, USA).

ELISA for serum IgG

Blood from DBA/1 J mice was taken at days 0 and 8 and 28 days after immunization with bCII. Total serum levels of IgG, IgG1 and IgG2a were measured by using commercial mouse Ig ELISA quantitation kits (Bethyl Laboratories, Montgomery, TX, USA) and an ELISA starter accessory package (Bethyl Laboratories) according to the manufacturer's instructions.

Histological analysis of the joint

Mice were killed and limbs were removed surgically and fixed in 4% buffered formalin. After decalcification in EDTA the tissue was embedded in paraffin. Five-μm sections were cut and stained with haematoxylin and eosin.

Flow cytometry

Spleens of anti-CD137 treated and non-treated mice were removed and placed in 60 × 15 mm Petri dishes (one for each organ) containing 3 ml RPMI [10% fetal calf serum (FCS)]. Organs were cut into small pieces and then squeezed. Clumps were removed by straining through a 70-μm nylon mesh (Falcon, Becton Dickinson, Franklin Lakes, NJ, USA). The suspension was treated with ammonium chloride (ACK lysing-buffer) to lyse red blood cells (RBCs). After counting the cells, single cell suspensions (1 × 106 cells/ml) were washed with PBS twice and stained using a predetermined optimal concentration of appropriate FITC- or PE- conjugated monoclonal antibodies. Anti-CD4 (clone RM4-5), anti-CD8 (clone 53–6·7), anti-CD25 (clone 7D4), anti-CD45RB (clone 16 A), anti-CD3 (clone 17A2) and anti-CD19 (clone 1D3) from BD Biosciences (Heidelberg, Germany) were used. After 30 min of incubation cells were washed twice, resuspended in 0·2 ml PBS containing 1% paraformaldehyde (Sigma, St Louis, MO, USA) and subjected to FACSCalibur analysis. Frequencies of expression of cell surface markers were calculated with the CellQuest software (Becton Dickinson, Heidelberg, Germany) and the absolute cell numbers of the different lymphocyte subsets were counted.

Detection of IFN-γ-producing cells by ELISpot

Cell suspensions were obtained as above and viable lymphocytes were isolated using a density separation medium (Lympholyte-M®, Cedarlane, Ontario, Canada). To an antimouse IFN-γ precoated 96-well ELISpot plate (AID, Straßberg, Germany), triplicates of 100 μl medium or CII (0·2 mg/ml, Arthrogen-CIA T cell grade type II collagen, MD Biosciences, Zuerich, Switzerland) were added plus 100 μl lymphocyte suspension (6 × 105 cells/well). After incubating overnight at 37° in CO2, plates were washed three times and a biotinylated secondary antibody (rat antimouse IgG1 mAb) was added at room temperature for 2·5 hr. The secondary antibody was detected by incubation with streptavidin-HRP for 2 hr and with substrate solution for another 30 min at room temperature. The reaction was terminated by washing. Spots were counted using an ELISpot reader (ImmunoSpot® Analyzer, CTL Cellular Technology Ltd; Cleveland, Ohio, USA). Differences in IFN-γ production were analysed by Student's t-test.

Results

Anti-CD137 mAb inhibits the humoral immune response against CII and prevents the development of CIA

All animals immunized with bCII, in the absence or presence of a control antibody, produced collagen-specific antibodies and developed CIA. In contrast, animals immunized with bCII but treated with three doses of anti-CD137 lacked all clinical signs of arthritis during 100 days of observation (Fig. 1a,b,c) and failed to produce CII-specific humoral antibodies (Fig. 1d). This inhibition of the humoral immune response against CII after treatment with anti-CD137 mAb was associated with slightly reduced serum IgG levels (data not shown) and IgG isotypes (IgG1 and IgG2a). It was not associated with an IgG isotype switch as measured at day 8 (IgG1: bCII group 4978 ± 73 pg/ml; bCII + anti-CD137 group 3884 ± 780 pg/ml; IgG2a: bCII group 1093 ±74 pg/ml; bCII + anti-CD137 group 862 ± 13 pg/ml) or at day 28 (IgG1: bCII group 4662 ± 26 pg/ml; bCII + anti-CD137 group 3392 ± 475 pg/ml; IgG2a: bCII group 1060 ± 80 pg/ml; bCII + anti-CD137 group 769 ±67 pg/ml) after immunization.

Figure 1
Prevention of CIA and inhibition of humoral immune response against CII in anti-CD137-treated mice. DBA/1J mice (n = 15) were immunized twice with CII (days 0 and 21) and were not treated (n = 5; circle), treated three times (days 0, 6 and 21) with isotype-matched ...

Anti-CD137 mAb protects bCII-treated mice against challenge

Two questions were examined in the experiment documented in Fig. 2. First, is it necessary to follow the previously published protocol for effective suppression of humoral immunity and to administer three doses of anti-CD137 mAb,25 or will one dose be sufficient? Secondly, does anti-CD137 mAb merely block a concurrent autoimmune response or does it generate a lasting condition that protects recipients against a subsequent encounter with the pathogenic antigen?

Figure 2
Anti-CD137 treatment induces a long-lasting protection against bCII. DBA/1J mice were immunized with bCII (days 0 and 21) and treated with anti-CD137 mAb once on day 0 (n = 5, c, d) or three times on days 0, 6 and 21 (n = 4, a, b). After 112 days mice ...

In addition to the standard protocol of three anti-CD137 administrations (Fig. 2a,b), we injected five animals with a single dose of anti-CD137 at the time of bCII immunization (Fig. 2c,d). Two of the five mice receiving a single CD137 mAb treatment failed to develop CIA, as did all triple-dose-treated animals (Fig. 2a,c). Three of five developed abortive, markedly delayed disease which disappeared before day 110. A second exposure of the animals to bCII, 112 days after the first, demonstrated significant protection of the animals that had received three doses of anti-CD137 mAb with the first immunization, and moderate protection in three animals that had received a single dose of antibody. The levels of anti-CII antibodies followed a similar pattern, in that a single injection of anti-CD137 mAb was not as fully effective as a triple treatment but provided substantial and lasting suppression of collagen-specific antibody production (Fig. 2b,d).

Delayed anti-CD137 treatment reduces severity of disease

Having established that a single injection of anti-CD137 on the day of immunization inhibits the development of CIA, we were interested to determine whether a single administration of the antibody after immunization with CII affected the manifestation of disease. The results of two separate experiments are shown in Fig. 3. A single injection of anti-CD137 14 days after immunization suppressed bCII-induced arthritic disease significantly (Fig. 3a,c). The production of anti-CII antibodies was reduced accordingly (Fig. 3b,d).

Figure 3
Delayed treatment with anti-CD137 antibody protects mice from the development of CIA. DBA/1J mice were immunized with bCII (days 0 and 21) and treated (triangles) or not treated (circles) with a single injection of anti-CD137 mAb on day 14 after primary ...

Anti-CD137 mAb shows therapeutic efficacy when given at the time of disease onset

Five mice were immunized with bCII and injected with a single dose of anti-CD137 mAb when the first signs of arthritis became visible. Data in Fig. 4 show that treatment stopped or suppressed the development of arthritic disease in two animals, whereas three mice developed severe disease. The anti-CII antibody titres reached peak levels around day 40, as is usual in animals that received bCII antigen in the absence of CD137 mAb (Fig. 1d), but their decline was accelerated. Antibodies became undetectable in four animals at day 66 and in one animal at day 80.

Figure 4
Treatment with anti-CD137 mAb at onset of the disease influences the course of CIA. DBA/1J mice (n = 5) were immunized (bCII on days 0 and 21) and treated with a single injection of anti-CD137 mAb when the first clinical signs of arthritis appeared (score ...

Lack of histopathological joint involvement in mice exposed to bCII in the presence of anti-CD137 mAb

DBA/1J mice were immunized twice with CII (day 0 and 21) and were not treated or treated three times (days 0, 6 and 21) with anti-CD137 antibody. Histopathological examinations of the joints were performed 89 days after immunization with bCII. The examination of a knee joint from an arthritic mouse (scored 10) showed destruction of cartilage with marked synovial proliferation and fibroblast infiltration (Fig. 5b). In contrast, joints from mice treated with three doses of anti-CD137 mAb were indistinguishable from the joints of normal control animals (Fig. 5a,c).

Figure 5
Anti-CD 137 treatment protects joints from destruction through CIA. DBA/1J mice were killed on day 89 after priming and histology sections were prepared from knee joints and stained with haematoxylin/eosin from mice which were not immunized/not treated ...

Treatment with anti-CD137 mAb increases the number of CD4+, CD8+ and CD4+ CD25+ T cells, but decreases the number of B cells

DBA/1 J mice were immunized with CII (days 0 and 21) and were treated or not with anti-CD137 mAb (days 0, 6 and 21). Twenty-eight days post-priming the mice were killed and a single cell suspension was prepared from splenocytes. The effect of anti-CD137 mAb treatment on distinct lymphocyte subsets was analysed by flow cytometry using fluorescent antibodies against the T cell markers CD3, CD4, CD8, CD19, CD25 and CD45RB.

As can be seen in Fig. 6 and Table 1, the relative percentages (11·2% versus 35·7%) and the total numbers of CD3+ T cells (Table 1) increased after injections of anti-CD137. This increase was more pronounced in the CD8+ T cell compartment (2·4% versus 16·5%) compared to CD4+ T cells (8·1% versus 19·4%). The increase in CD8+ T cell frequency was associated with a decrease in fluorescent intensity. The increase in T cells was accompanied by an increase in the CD3+ CD45RB+ cell fraction (12·1% versus 37·2%) and the CD4+ CD25+ double-positive cell fraction increased slightly (1·5% versus 2·3%). For the absolute cell numbers of the different lymphocyte subsets see Table 1. Otherwise, the relative percentages of B cells decreased (75·9% versus 44·8%) after three injections of anti-CD137, but the total number of B cells in the spleens was unchanged (Table 1). The observed phenotypic changes in the lymphocyte composition after anti-CD137 treatment occurred independently of bCll immunization.

Figure 6
Treatment with anti-CD137 antibody inreases the numbers of CD8+, CD4+ T cells and of CD4+ CD25+, CD3+ CD45RB+ and decreases the numbers of B cells. Twenty-eight days post-priming (bCII on days 0 and 21, anti-CD137 mAb or control mAb on days 0, 6 and 21) ...
Table 1
Effect of anti-CD137 mAb treatment on lymphocyte subsets cell counts in the spleen

As found in previous experiments,26 after treatment with anti-CD137 mAb we observed an increase in spleen weight (Fig. 7b) and an increase in number of splenocytes (Table 1), but relatively to the spleen weight the cell number decreased in the spleens.

Figure 7
Anti-CD137 mAb treatment in DBA/1J mice induced splenomegaly and IFN-γ production in spleen cells. DBA/1J mice (each group n = 3) were immunized with bCII on days 0 and 21, treated with anti-CD137 mAb (days 0, 6 and 21) and killed on days 7, 21 ...

Spleen cells from anti-CD137-treated mice produce large amounts of IFN-γ

It has been suggested that the effect of anti-CD137 treatment is mediated by augmenting IFN-γ production and activation of macrophages or granulocytes, resulting in depletion of autoreactive B cells.27 We therefore analysed IFN-γ production in spleen cells at various times after bCII+-anti-CD137 treatment (Fig. 7a). Injections of anti-CD137 alone resulted in the increased production of IFN-γ, as did bCII immunization plus anti-CD137 treatment. The increased production of IFN-γ correlates positively with spleen size (shown at 28 days after treatment) (Fig. 7b).

Discussion

The induction of CIA in susceptible mice involves the activation of helper T cells and of B cells.3,4,28 The disease is transferable within susceptible mouse strains with antigen-specific helper T cells or with serum from arthritic animals.5,29,30 Agonistic anti-CD137 mAb has been reported to block the generation of T helper cell-dependent antibodies when given at the time of antigen immunization,25 but not when given after the initiation of T dependent humoral immune response. Given the pathogenic role of T cell-dependent autoantibodies in inflammatory autoimmune disease, it seemed of interest to determine whether anti-CD137 inhibits the induction of such diseases. It has been shown, indeed, that the antibody blocks and reverses the spontaneous occurrence of spontaneous systemic lupus erthematosus (SLE) disease in mice.26 In this study we therefore examined the influence of anti-CD137 mAb on the induction of CIA.

Our results show that the antibody inhibited the production of CII-specific antibodies and blocked the appearance of macroscopic or microscopic signs of arthritic disease. Anti-CD137 mAb falls thereby into the category of several immunomodulatory agents that abrogate the development of autoimmune disease by means of immune-suppression.1113,31,32 A common characteristic of those reagents is that they lose efficacy once autoimmune disease is established.13,31 Only in rare instances were slight and partial effects noted in the treatment of established CIA with these substances.12,33,34

From a therapeutic viewpoint the anti-CD137 mAb stands out for two reasons: it exhibits therapeutic efficacy when administered at a time when signs of autoimmunity are evident and it endows mice with lasting resistance to subsequent disease induction. The efficacy after the manifestation of disease points perhaps to a desirable clinical applicability of CD137 manipulation. The long duration of the therapeutic effect, that exceeds the life span of the antibody by far, suggests that CD137 engagement not only prevents and reverses the pathogenic autoimmune mechanism but establishes an active and lasting mechanism of immune suppression. The finding may be taken to suggest that anti-CD137 does not merely act as an immunosuppressive, but as an immunoregulatory reagent.

The biological effects of anti-CD137 demonstrate a somewhat dichotomic effect. Several studies have shown an enhacement of the CD8+ T cell-mediated CTL response.15,16,2123 Others demonstrated a suppression of the CD4+ T cell-dependent humoral immune response.2527 This suppression may occur via a direct interaction of the antibody with CD4+ T cells, or by inhibiting T cell priming at the DC interface.26

The postulated T cell/DC relationship does not rule out an involvement of additional regulatory cells which could endow the process with the exquisite antigen specificity that is seen in the autoimmune reaction. A role of antigen-specific CD8 regulatory/suppressor T cells has been suggested previously, as anti-CD137 mAb preferentially stimulates the survival and activation of CD8 T cells.25 The longevity of anti-CD137-mediated protection against CIA induction is certainly consistent with an extended presence of antigen-specific regulatory cells and with an extensive literature on CD8+ T cells, which are known to regulate autoimmunity.3542 The recent characterization of class I-restricted regulatory T cells in humans in vitro3741 and the regulatory functions of CD8+ CD28 T cells in an autoimmune disease model are of great interest in this regard.42 In contrast to our results and the probably inhibitory autoimmune function of enhanced IFN-γ levels, these CD8+ CD28 regulatory T cells did suppress IFN-γ production of antigen-specific CD4+ T cells, the suppression required cell-to-cell contact, and was dependent on the presence of APCs.42

Of particular interest is the accelerated decline of CII-specific antibodies in mice that were treated with anti-CD137 mAb, because Cll-induced antibodies may function as causative agents of destructive joint disease. Rapid decay of autoantibodies has been observed in the development of SLE disease after the treatment of NZB/W F1 mice with anti-CD137 mAb. Also in that model, we observed a long-lasting suppression of humoral autoimmune response against self-antigens and an extended protection against autoimmune disease.26 In pursuing this notion we noted that anti-CD137 mAb treatment caused a marked reduction only in the relative percentages and not in the total cell numbers of B cells in the spleen, paralled by a marked increase in the frequency of IFN-γ-producing immunocytes. The finding is, to some extent, in agreement with observations in another recently presented mouse SLE model.27 The authors attributed the inactivation of B cells to the activity of macrophages that had been activated by IFN-γ-secreting T cells. In this context it is important that CD137 is expressed only on activated T cells14 and constitutively on DCs. Triggering of CD137 on DCs leads to an increased secretion of interleukin (IL)-6 and IL-12 and the treatment of naïve mice with anti-CD137 mAb enhances the ability of DCs to stimulate T cell proliferation in response to antigens in vitro.17,18 It is therefore likely that anti-CD137 mAb triggered DCs activate T cells by enhanced IL-12 secretion and up-regulation of stimulatory molecules on the surface of DCs and thus may lead to enhanced IFN-γ production by T cells, especially CD8+ T cells. Consequently, therapeutic efficacy of IFN-γ modified DCs on the course of acute experimental allergic encephalomyelitis (EAE) in Lewis rats has been shown.43

It seems noteworthy that the suppression of autoantibody production and of CD4+ T helper cell function is associated with a marked increase in the frequency of functional splenocytes, as indicated by spleen enlargement and by the increased production of cytokines. It would appear that autoantigen-specific lymphocytes remain silent because their response to autoantigen is overwhelmed by inhibitory or regulatory immune functions. In the reverse, this notion would imply that inflammatory autoimmunity may be the result of deficient immune regulation. Our presented data qualify CIA and its prevention by anti-CD137 mAb as a promising experimental model to examine these pathogenetic aspects of autoimmune diseases.

Acknowledgments

This work was supported by the Fortuene Program, Medical Faculty, University of Tuebingen.

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