Preclinical arthritis models suitable for the development of tolerogenic therapies
| Species | Induction of disease | Endogenous or exogenous antigen | Incidence rate (%) | Autoresponses involved | Is model synchronised? | Clinical course | Benefits for tolerance studies | Limitations for tolerance studies |
| Human | Spontaneous | Unknown | 1% of population | Generation of autoantibodies (CII, ACPA, RF) and autoreactive T cells. Formation of immune complexes | – | Genetic susceptibility or environmental exposure, Breach of tolerance, prearticular phase, articular phase, chronic | – | – |
| Mouse (BALBc or C57BL/6J) | Immunisation with ovalbumin in mice that have ovalbumin specific T cells | Exogenous leading to endogenous response | 80–100 | Generation of autoantibodies (CII, ACPA, RF) and autoreactive T cells. Formation of immune complexes | Yes | Breach of tolerance, prearticular phase, acute but can be made chronic with further challenge | Congenic markers distinguish between OVA specific and endogenous T cells. True breach of tolerance. Autoreactivity only occurs with articular challenge | Inflammation is self resolving. Only polyarthritic with further challenge |
| Mouse (BALB/cAnNCrl) | Immunisation with Human cartilage proteoglycan aggrecan | Endogenous | 100 | Generation of autoantibodies (PG, ACPA, RF) and autoreactive T cells | Yes | Breach of tolerance, prearticular and articular phase, chronic | Tetramers are available to characterise antigens specific T cells. | Can only be used in BALB/cAnNCrl mice purchased from Charles River |
| Rat (various) or Mouse (BALBc, DBA/1, C57BL/10 or C57/BL6*) | Immunisation with bovine, murine or chicken collagen II | Exogenous/ Endogenous | 70–100 | Generation of autoantibodies (CII, ACPA, RF) and autoreactive T cells | No | Breach of tolerance, prearticular and articular phase, chronic | Tetramers are available to characterise antigens specific T cells. Useful for studying effect of tolerance on both B and T cell responses. | Difficult to perform in C57BL/6 J mice which limits genetic manipulation |
| Mouse (HLA-DR1 on C57BL6xB10 background | Immunisation of genetically predisposed mice with bovine or mouse collagen II | Exogenous/endogenous | 70–100 | Generation of autoantibodies (CII, ACPA, RF) and autoreactive T cells | No | Breach of tolerance, prearticular and articular phase, chronic | Tetramers are available to characterise antigens specific T cells. Uses HLA associated with human RA. TCR skewed to DR1 restricted collagen | Require mixed background mice as well as DR1 gene. Breeding can be challenging |
| Rat (DA) or mouse† (CBA/Igb, DBA/1 or BALBc) | Immunisation with the adjuvant pristane | Endogenous due to adjuvant exposure | 50–80 | Generation of autoantibodies (CarP, RNPs, RF) and autoreactive T cells | Yes | Prearticular and articular phase, chronic | Strongly T cell dependent | Mostly limited to rats so genetic manipulation difficult. Expensive. |
*Must use chicken type II collagen.
†Delayed onset.
ACPA, antibodies (indicating loss of tolerance) to citrullinated proteins; CarP, carbamylated protein; CII, type II collagen; OVA, ovalbumin; PG, proteoglycan; RF, rheumatoid factor; RNP, ribonucleoprotein.