Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis

Abstract

The current status of therapeutic vaccines for autoimmune diseases is reviewed with rheumatoid arthritis as the focus. Therapeutic vaccines for autoimmune diseases must regulate or subdue responses to common self-antigens. Ideally, such a vaccine would initiate an antigen-specific modulation of the T-cell immune response that drives the inflammatory disease. Appropriate animal models and types of T helper cells and signature cytokine responses that drive autoimmune disease are also discussed. Interpretation of these animal models must be done cautiously because the means of initiation, autoantigens, and even the signature cytokine and T helper cell (Th1 or Th17) responses that are involved in the disease may differ significantly from those in humans. We describe ligand epitope antigen presentation system vaccine modulation of T-cell autoimmune responses as a strategy for the design of therapeutic vaccines for rheumatoid arthritis, which may also be effective in other autoimmune conditions.

Keywords:

• arthritis-specific antigens
• arthritogenic epitopes
• autoimmune disease
• bystander effect
• epitope spreading
• rheumatoid arthritis
• signature cytokine
• therapeutic vaccines

Financial & competing interests disclosure

The authors were supported by the NIAMS of NIH US Department of Health and Human Services as well as the CEL-SCI Corp. Research reported in this publication was supported by the NIAMS of NIH US under award numbers R43AR063504 for DH Zimmerman, R01AR064206 for K Mikecz, R01AR059356 for TT Glant and R01AR056999 for A Finnegan. K Rosenthal is the co-inventor on several patents on LEAPS technology and has been a grant recipient for other LEAPS applications in the past from NIAID. DH Zimmerman is an employee and stockholder of CEL-SCl Corp., inventor and co-inventor on multiple patents on LEAPS technology and a grant recipient from NIAMS for LEAPS. DH Zimmerman has also received grants for arthritis models and other LEAPS applications in the past from NIAID and NHLI. K Mikecz is a grant recipient from NIAMS for work on arthritis, co-inventor on a patent on LEAPS technology and a grant recipient from NIAMS for work in LEAPS models on arthritis and other arthritis studies. HL Steiner is an employee and stockholder of CEL-SCI Corp. and is a co-inventor on patent on LEAPS technology. RE Carambula is an employee and stockholder of CEL-SCI Corp. and is a co-inventor on patent on LEAPS technology. TT Glant is a co-inventor on patent on LEAPS technology, grant recipient from NIAMS for work on arthritis and a consultant on the Zimmerman grant from NIAMS for work on LEAPS and arthritis model. A Finnegan is a grant recipient from NIAMS for work on arthritis and is a consultant on the Zimmerman grant from NIAMS for work on LEAPS and arthritis model. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Animal experiments were approved by the Institutional Animal Care and Use Committee of Rush University Medical Center, Chicago, IL. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• When investigating autoimmune diseases such as rheumatoid arthritis, it is important to identify the antigens and antigenic epitopes that initiate and maintain the disease, as well as the signature cytokine(s) driving the disease pathogenesis in humans.

• Appropriate animal models should be identified and their relevance to human disease established with regard to the autoantigens and pro-inflammatory immune responses (T-cell response and cytokines) driving the disease.

• Passive administration of antibodies against inflammatory mediators (e.g., cytokines, receptors or other cell surface molecules) may offer some practical relief from arthritic symptoms, but will not address the initiators or the drivers of the autoimmune response unlike antigen-specific vaccination.

• Current treatments are not effective in a substantial number of cases, ablate responses that are important for immune protection and are contraindicated in many cases.

• Upon identification of an appropriate antigen(s), the vaccine formulation (including adjuvant) and route of administration must be determined so that the vaccine will activate the proper T-cell response to modulate the ongoing inflammatory response. Vaccines inducing antibody to autoantigens will likely exacerbate the condition.

• Practical considerations for stability, safety and dosing may involve changes to the structure, design, formulation or the route of immunization. As examples, we present two ligand epitope antigen presentation system vaccines for rheumatoid arthritis that modulate either Th1- or Th17-driven disease in different animal models, as indicated by cessation of disease progression and change in the production of signature cytokines.

Notes