Collagen-induced arthritis in common marmosets: a new nonhuman primate model for chronic arthritis
© Vierboom et al.; licensee BioMed Central Ltd. 2010
Received: 13 July 2010
Accepted: 26 October 2010
Published: 26 October 2010
There is an ever-increasing need for animal models to evaluate efficacy and safety of new therapeutics in the field of rheumatoid arthritis (RA). Particularly for the early preclinical evaluation of human-specific biologicals targeting the progressive phase of the disease, there is a need for relevant animal models. In response to this requirement we set out to develop a model of collagen-induced arthritis (CIA) in a small-sized nonhuman primate species (300 to 400 g at adult age); that is, the common marmoset (Callithrix jacchus).
Twenty-two animals divided into three experiments were immunized with collagen type II (CII) of either bovine or chicken origin with different immunization strategies. The animals were analyzed for clinical manifestation of arthritis, hematology and clinical chemistry, immunological responses against CII and histopathological features of the arthritis.
Clinically manifest arthritis was observed in almost 100% (21 out of 22) of the animals. Fifty percent of the animals developed semi-acute CIA while the other 50% displayed a more chronic disease. Both cellular (CD3/CD4 and CD3/CD8) and humoral responses (IgM and IgG) against CII were involved in the development of the disease. Besides mild histopathological changes in bone and cartilage, severe inflammation in extraarticular tissues like periosteum and subcutaneous tissues was observed.
This new model in marmosets more closely resembles chronic RA with respect to the chronic disease course and pathomorphological presentation than the more acute monophasic and destructive CIA model in macaques. This model can therefore fill a niche in preclinical testing of new human specific therapeutics.
The drug development industry continues to invest heavily in the development of new drugs against rheumatoid arthritis (RA) based on biological regulators and antagonists of proinflammatory molecules, such as monoclonal antibodies or soluble receptor molecules. The investments are based on the expectation that biological drugs will act more specifically and with less side effects than the classical broad-acting nonbiological disease-modifying and anti-inflammatory treatments. Biological molecules have their own safety problems that are not experienced with non-biological molecules, however, such as induction of neutralizing immunity or hypersensitivity reactions caused by massive cytokine release or activation of the complement system. Owing to the high species and target molecule specificity, biological drugs are often not active in lower animal models, such as mice and rats. This implies for a considerable proportion of the new biological therapeutics that the classical disease models are not a feasible option for preclinical safety and efficacy assessment, leaving nonhuman primates as the only relevant species .
The rhesus and cynomolgus macaque models of collagen-induced arthritis (CIA) provide useful disease models that have allowed for the efficacy evaluation of new therapeutics [2–4]. These models, however, also have a number of disadvantages. First, macaques are large-sized animals ( > 6 kg at adult age) requiring substantial quantities of test substance to achieve an effective dose. Second, the outbred nature of the model is translated into considerable clinicopathological heterogeneity between individual monkeys. As we strive to perform experiments with treatment groups comprising a small number of animals (usually five to seven animals), beneficial effects of less robust therapeutics are often overlooked. Third, the disease in macaques is often severe, short lasting and self-limiting, which limits the operational window of therapies that are administered after clinical manifestation of the arthritis.
Similar disadvantages in macaque models of another experimental autoimmune-inflammatory disorder modeled on multiple sclerosis - that is, experimental autoimmune encephalomyelitis (EAE) - have triggered the search for an alternative model that does not have these disadvantages. As reviewed elsewhere, the EAE model in common marmosets (Callithrix jacchus) provides a useful and often superior alternative [5–7]. The common marmoset is a small-sized Neotropical primate (±350 g at adult age) born as non-identical twins or triplets with chimeric bone marrows due to fusion of the placental bloodstreams . Immune cells of the hemopoietic systems of fraternal twins distribute equally over each sibling, and cells of the T-lymphocyte and B-lymphocyte lineage are educated in the same thymic compartments. This implies that the immune systems of twins are highly comparable , creating the unique situation that the twin sibling can be used as the optimal control for each monkey in an experimental group. Probably the most important feature of the model is that, in the clinical and pathological presentation, EAE in marmosets more closely resembles multiple sclerosis, whereas the corresponding models in rhesus monkeys rather resemble acute neuroinflammatory diseases, such as acute disseminated encephalomyelitis [10, 11].
The aim of the current study was to investigate whether the advantages of the marmoset as a model for EAE could be transferred to the CIA model. We report here that almost 100% of marmosets sensitized against commercial bovine or chicken-type collagen develop clinically manifest arthritis. About 50% of animals develop a long-lasting disease with a mainly relapsing/remitting course. In the remaining 50% of animals, a more short-lasting disease course was observed. Pathomorphological changes in arthritic joints were consistent with moderate to marked inflammation of the synovium, fibrous capsule, periosteum and subcutis, accompanied by moderate edema, reactive synoviocytes and reactive blood vessels. Loss of chondrocytes and collagen disruption and small foci of bone resorption were present. In addition, several biomarkers were evaluated that have been developed for the CIA model in the rhesus monkey [3, 4, 12, 13] proved to be valid also in marmosets.
Materials and methods
Individual data of the monkeys
Origin of CIIa
Starting weight (g)
In accordance with the Dutch law on animal experimentation, all study protocols and experimental procedures were reviewed and approved by the Institute's Ethics Committee before the experiments started.
Induction of collagen-induced arthritis
For the pilot study (Experiment I) a semi-purified batch collagen type II (CII) was prepared, extracted from bovine hyaline cartilage. For Experiments II and III, two industry-grade commercially available types of CII were used, respectively of bovine (bo-CII) or chicken (ch-CII) origin (MD Biosciences, Zürich, Switzerland). Collagen was dissolved in 0.1 M acetic acid to a final concentration of 5 mg/ml and mixed with an equal volume of complete Freund's adjuvant (CFA) (DIFCO, Detroit, MI, USA). A stable emulsion was prepared by gentle stirring of the protein/CFA emulsion for 60 minutes at room temperature. CIA was induced by injection of 0.4 ml emulsion into the dorsal skin distributed over four spots of 100 μl. The final amount of CII the animals received was 1 mg/animal. When no clinical signs of arthritis were visible at day 28, the animals were boosted with CII in incomplete Freund's adjuvant (IFA) at day 35 (Experiment II)/day 28 (Experiment III) subcutaneously in the flank.
Clinical scoring and biomarker analysis
Integrated Discomfort Score
End of experiment
No general discomfort signs
Fever ( > 0.5°C)
Twice per week
Less mobility but no pain
Loss of appetite
Twice per week
Twice per week
Treatable pain without STS
Moderate redness + STS of joints
Twice per week
Normal flexibility of extremities
Twice per week
Severe redness + STS of joints
Twice per week
With joint stiffness
Serious untreatable pain
Serious immobility of joints
Twice per week
Body weight loss >25%
Twice per week
Hematology and clinical chemistry
All hematological and clinical chemistry analyses were performed at the Biomedical Primate Research Centre on a Sysmex Sf-3000 (Goffin Meyvis, Etten-Leur, The Netherlands) and a COBAS INTEGRA-400+ (Roche, Almere, The Netherlands), respectively.
Urinary excretion of the collagen crosslinks hydroxylysylpyrridinoline (HP) and lysylpyrridinoline (LP) were determined twice weekly, starting from the day of CIA induction. For that purpose, each animal's urine was collected overnight in a metabolic cage. After centrifugation, the clear supernatant was isolated and stored at -20°C. Reverse-phase high-performance liquid chromatography was used to determine HP and LP levels in hydrolyzed urine samples as described previously . The levels of HP and LP were normalized to creatinine levels (nmol levels/mmol creatinine) to compensate for a possible dilution by spilled drinking water.
Detection of anti-collagen type II antibodies (Experiments I and II)
Serum levels of antibodies directed against bo-CII and ch-CII of IgM and IgG isotypes were detected by ELISA . Serum samples (0.2 ml) were collected twice a week. Plates (96-well, F-form, microlon; Greiner bio-one, Alphen aan den Rijn, Netherlands) were coated overnight at 4°C with 100 μl of a 10 μg/ml solution of bo-CII/PBS. Plates were washed four times with PBS + 0.05 Tween-20 and subsequently blocked by a 1-hour incubation with 200 μl PBS + 1% BSA at 37°C and 5% CO2. Plates were washed four times, after which 100 μl diluted serum was added (CII-IgG => 1:25; IgM => 1:25) in PBS + 1% BSA and incubated overnight at 4°C. After an additional incubation for 2 hours at 37°C, 5% CO2 in a humidified atmosphere, plates were washed four times with PBS + 0.05 Tween-20.
Plates were subsequently incubated for 1 hour with a secondary detector antibody (AP-conjugated goat anti-human IgM1, 10,000 in PBS + 1% BSA or AP-conjugated goat anti-human IgG1, 10,000 in PBS + 1% BSA; Biosource, Camarillo, CA, USA). After washing, antibody binding was detected by adding 100 μl poly-nitrophenylphosphate diluted in Tris buffer (Sigma Chemicals, Zwijndrecht, The Netherlands). Color development was determined by absorbance at 405 nm.
Flow cytometry and carboxyfluorescein succinimidyl ester staining (Experiment II)
To determine the phenotype of proliferating cells, 4 × 106 viable peripheral blood mononuclear cells (PBMC), axillar lymph node mononuclear cells, inguinal lymph node mononuclear cells and spleen mononuclear cells were suspended in 1 ml PBS and incubated for 7 minutes at room temperature with carboxyfluorescein succinimidyl ester (final concentration, 1.5 μM; Fluka, Buchs, Switzerland). The labeled cells were cultured for 7 days with antigens under the standard culture conditions described above. For flow cytometric analysis we used the following commercially available labeled mAbs directed against human CD markers: anti-CD3 with PerCP or Alexa Fluor 700 label (BD Biosciences, San Jose, CA, USA), allophycocyanin-labeled anti-CD4 (DakoCytomation, Glostrup, Denmark) and biotinylated anti-CD8 (Serotec, Düsseldorf, Germany). Flow cytometric analysis was performed on a FACSort flow cytometer using FACSDiva software (BD Biosciences). First, viable cells were gated using the live/dead fixable violet viability stain (Invitrogen Life Technologies, Breda, The Netherlands). Within the viable cell gate, lymphocytes/monocytes were selected using forward and sideward scatter. Within the lymphocyte/monocyte gate, CD3+ cells were selected. The CD3+ population in the carboxyfluorescein succinimidyl ester experiment consisted of CD4+ and CD8+ cells.
Ex vivoanalysis of proliferative responses (Experiment III)
The maximum blood sample that can be collected in 1 month from primates at the Biomedical Primate Research Centre should not exceed 1% of the body weight. For an average adult common marmoset weighing 350 g, this equals a maximum monthly blood sample of 3.5 ml. Hence, volumes of up to 1 ml at 4-week intervals were collected into heparinized Vacutainer tubes (Greiner bio-one). To measure the development of ch-CII-specific cellular responses with time, PBMC were isolated from heparinized venous blood using lymphocyte separation medium (ICN Biomedical, Aurora, OH, USA).
Overlapping peptide set derived from chicken-origin collagen type II fragment number 11 after cyanobromide digestion
Amino acid numbersa
Amino acid sequence
124 to 149
140 to 165
155 to 180
170 to 195
185 to 210
200 to 225
215 to 240
230 to 255
245 to 270
pep 10 a
251 to 276
GPKGQTGEPGIAGF K GEQGPKGETG
260 to 285
275 to 300
290 to 315
305 to 330
320 to 345
335 to 360
350 to 375
365 to 380
370 to 395
374 to 400
where cpm is counts per minute. SI >2.0 was considered relevant.
Incidence of collagen-induced arthritis
To establish reproducibility of the induction protocol, ch-CII was selected for the third experiment (n = 6) - the most commonly used autoantigen for CIA induction in rodents. The images in Figure 2b confirm the high incidence of CIA in this species (five out of six animals), as well as the variable disease course. The one case in which clinical signs were not observed during the 100-day observation period did display weight loss, suggestive of subclinical disease.
In conclusion, sensitization of marmosets against CII by a first immunization with collagen in CFA followed by booster immunizations with collagen in IFA reproducibly induces clinical arthritis in marmoset monkeys.
Clinical and pathological presentation
In the rhesus monkey model of CIA, the urinary excretion rate of the major collagen crosslinks LP and HP was identified as a valid biomarker of joint erosion.
In Experiment II, the time for which the animals stayed in the metabolic cage was reduced to 16 or 17 hours to limit the discomfort experienced as a consequence of isolation and separation. The amount of urine excreted by the common marmoset is far less (2 to 10 ml) then that observed with the rhesus monkey (300 to 400 ml), resulting in a large variation in measurements (data not shown).
In Experiment III, we returned to the 24-hour collection to compensate for the circadian rhythm in urine excretion observed for HP/LP excretion. In this experiment it was observed that the production of HP and LP was less affected by the disease (Figure 6). Only severely diseased animals show a marked change in the excretion of HP/LP.
Profiles of autoreactive T cells and antibodies
The autoimmune attack on the joints in CIA models in mice, rats and rhesus monkeys is mediated by interplay of anti-CII T cells and humoral factors. In both rodent CIA models  as well as the CIA model in the rhesus monkey , a key pathogenic role of IgM autoantibodies was found. Rhesus monkeys that were genetically resistant to CIA were found incapable of producing adequate amounts of anti-collagen IgM . Second, pre-sensitization of rhesus monkeys with heat-denatured CII not only abrogated the capacity to produce anti-CII IgM, but also induced resistance to CIA . The relation between both autoimmune parameters and disease was therefore also tested in the novel CIA model in marmosets.
Two types of analysis have been performed with cells from the monkeys. A longitudinal analysis of T-cell immunity development was performed with freshly isolated PBMC (Experiment III) at 28-day interval and a biodistribution analysis of CII-responsive T cells at necropsy. Moreover, we performed a fine specificity analysis of the T-cell response against CII as well as CD4/CD8 phenotyping of the CII-responsive T cells (Experiment II). Owing to limitations in the available venous blood volume that can be collected per month during the course of a study, this assay was performed only at necropsy when sufficient cells could be obtained.
We report the development of a new preclinically relevant model of arthritic disease in the common marmoset. The marmoset is a small-sized Neotropical primate that gains increasing popularity as a model of human diseases. The advantages compared with other frequently used nonhuman primates, such as the rhesus monkey and cynomolgus macaque, are obvious. Marmosets breed easily in captivity, giving birth to four siblings per couple per year, which reach adulthood after 1.5 years of age. The small size, 350 to 400 g at adult age, implies that much lower amounts of test substance can be used compared with the more than 10-fold larger macaques. A particularly attractive aspect is that marmosets are born as complete bone marrow chimeras, which implies a high immunological similarity. This principle can be used in therapy trials with one twin sibling as the recipient of experimental treatment and the other sibling the recipient of placebo. Moreover, the allotolerance between twin siblings allows the transfer of suspected pathogenic T-cell specificities - a standard research tool in inbred rodent disease models, but one that is precluded by the genetic diversity in outbred macaque models.
For the development of a CIA model in the marmoset we relied on our experience with rat and rhesus monkey models of CIA [12, 14–16] and with the marmoset as a model of the chronic progressive immune-mediated inflammatory disorder multiple sclerosis, EAE [5, 7, 10, 11]. We chose to examine whether a similarly valid model for chronic progressive arthritis as for multiple sclerosis could be developed in the marmoset. The only difference between EAE and CIA is the immunizing antigen, being recombinant human myelin/oligodendrocyte glycoprotein for the EAE model and type II collagen for the CIA model.
Similar to the EAE model, we observed in the CIA model an almost 100% disease incidence (only one outlier in 22 cases) and a heterogeneous clinical course. This feature probably reflects the genetic heterogeneity of this outbred species. The variety of disease patterns included acute cases with a rapid disease onset without remissions, relapsing/remitting cases with alternating episodes of inflammation and recovery, and progressive cases with slowly incrementing disease scores. Especially in the more chronic cases, inflammation of individual joints is disseminated in time and space, suggesting competition between systemically acting proinflammatory mechanisms with locally acting anti-inflammatory mechanisms. This principle was also observed in the EAE model and has helped to identify the specificity and mode of action of the core pathogenic T cells (reviewed in ).
Histological examination of affected joints showed the same pathological aspects as observed in the rhesus monkey CIA model - namely, strong synovial hyperplasia forming pannus tissue overgrowing and eroding the cartilage surface and degradation of subchondral bone [3, 4]. Besides the clear articular pathology, extraarticular pathology could also be observed - such as inflammation of the subcutaneous tissue, inflammation of the periosteum, development of perivasculitis, presence of reactive blood vessels and angiogenesis. Together, the features discussed thus far mark a considerable improvement compared with the acute self-remitting CIA model in rhesus monkeys.
For the immune profiling we have focused on parameters that were found of pathogenic relevance in the rhesus monkey CIA model - namely, the capacity to generate IgM and IgG autoantibodies [14, 20] and the presence of a T-cell proliferative response . One of the few disadvantages of the marmoset model is the low amount of blood that can be collected for analysis of cellular immune reactions, which is about 3 ml per month. T-cell proliferation in PBMC was therefore only assessed once every 28 days. The results show a variable proliferative response, which displayed no obvious relation with the clinical course. The analysis at necropsy showed that the vast majority of CII-responsive T cells is located in the lymphoid organs, spleen and axillary lymph nodes in particular, which most probably explains this poor discrepancy. Only at necropsy could sufficient cells be obtained from blood and lymphoid organs for phenotyping of the CII-responsive cells and a fine specificity analysis of the anti-CII T-cell response. Interestingly, in the axillary lymph nodes that are located in the armpits, we observed not only the expected specific proliferation of CD4+ T cells, but also proliferation of CD8+ T cells. Although in several monkeys good proliferative responses were detected against the complete CII protein, none of the synthetic 25-mer peptides derived from the immunogenic CB11 fragment of ch-CII could stimulate proliferation.
The common marmoset may fill a niche as an attractive alternative nonhuman primate species for preclinical evaluation of new biologicals in the field of arthritis. The small size of the common marmoset compared with the rhesus monkey translates into lower caging, feeding and housing costs. This advantage coupled with the lower purchase price of common marmosets compared with macaques may translate into substantial cost savings when performing equivalent studies in rhesus monkeys. Furthermore, the marmoset is easier to handle than the aggressive rhesus monkeys, which need to be sedated for every handling [21, 22]. Of note is the fact that the evolutionary distance between the common marmoset and human is 33 million years while the evolutionary distance between the rhesus monkey and human is 23 million years . This translates into significant homology differences between human and the common marmoset, which is demonstrated by the fact that a substantial number of ELISAs that crossreact with rhesus cytokines do not crossreact with cytokines from the common marmoset (personal observation). Evaluation of a promising new compound for RA in the common marmoset will always require establishing crossreactivity of this new compound for targets in the common marmoset. For this purpose we have stored tissue in Oxidized Regenerated Cellulose at -80°C, allowing for immunohistochemistry and isolated mononuclear cells from axillar and inguinal lymph nodes, spleen and blood in liquid nitrogen for functional assays.
The common marmoset already plays an important role in diverse areas of research such as infectious diseases [24, 25], stem cell research, neural and cognitive sciences [5, 10, 26], reproductive biology, toxicology and drug development [27, 28]. We believe in the years to come that the CIA model in the common marmoset may fill a void for drug development in the area of immune-mediated inflammatory diseases.
bovine-origin collagen type II
bovine serum albumin
cyanogen bromide fragment 11
complete Freund's adjuvant
chicken-origin collagen type II
collagen type II
experimental autoimmune encephalomyelitis
enzyme-linked immunosorbent assay
fetal calf serum
- H & E:
hematoxylin and eosin
incomplete Freund's adjuvant
peripheral blood mononuclear cells
The authors thank our colleagues of the Animal Science Department of the Biomedical Primate Research Centre - in particular, the animal caretakers - for expert experimental support and for excellence in the care of the animals during the experiments. The authors would also like to thank Mr Henk Westbroek for graphic support.
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