Preclinical models of arthritis for studying immunotherapy and immune tolerance

Abstract

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.

Keywords: arthritis; experimental; rheumatoid; therapeutics.

Figure 1

Disease progression of rheumatoid arthritis - created with BioRender.com.

Figure 2

CIA and AIA models of arthritis. (i) CIA mice are injected with heterologous or autologous collagen in the presence of an adjuvant. (ii) in AIA models, mice are first immunised with an unrelated antigen in the presence of an adjuvant and then rechallenged with the same antigen in the joint. These models may employ the use of TCR transgenic T cells. (iii) The antigens in both models are initially presented by dendritic cells to CD4 T cells within the T cell zone of the lymph nodes. These CD4 T cells then interact with B cells within the follicle to produce antibodies. (iv) In the AIA models, the inflammation within the joint to the exogenous antigen triggers the activation of bystander T cells resulting in the targeting of joint antigens. (v) In both models, antigens within the joints become targeted by the immune response. (vi) This results in the destruction of cartilage and bones within the joints - created with BioRender.com. AIA, antigen-induced arthritis; CIA, collagen-induced arthritis; TCR, T cell receptor

Figure 3

Benefits of using animal models for studying rheumatoid arthritis. Animal models allow researchers to study various aspects the disease that would otherwise be impractical to study in human patients. (A)(i)The experimental design of animal models allow researchers to monitor disease progression at various time points. Specific aspects of the disease can also be examined through the use of (ii) transgenic animals, (iii) TCR transgenic T cells and (iv) fluorescently labelled cells. (B) Interventions including (i) antigen-specific immunotherapies and (ii) drug treatments can also be studied in detail. (C) Tissues including the (i) thymus, (ii) spleen, (iii) lymph nodes and (iv) synovial tissue can be collected from animals at any time point. (D) This allows for detailed analysis of various cell populations using techniques such as (i) flow cytometry, (ii) RNA sequencing and (iii) cytokine assays. (E) Another major advantage of animal models is the use of live imaging techniques including (i) intravital imaging using multiphoton microscopy and (ii) whole tissue imaging using techniques such as MRI scanners. Similarly, tissues collected from culled animals can be imaged by (iii) histology or (iv) immunofluorescence - created with BioRender.com.