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Review
. 2015 Jun;14(6):891-908.
doi: 10.1586/14760584.2015.1026330. Epub 2015 Mar 18.

Rheumatoid Arthritis Vaccine Therapies: Perspectives and Lessons From Therapeutic Ligand Epitope Antigen Presentation System Vaccines for Models of Rheumatoid Arthritis

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Review

Rheumatoid Arthritis Vaccine Therapies: Perspectives and Lessons From Therapeutic Ligand Epitope Antigen Presentation System Vaccines for Models of Rheumatoid Arthritis

Kenneth S Rosenthal et al. Expert Rev Vaccines. .
Free PMC article

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.

Conflict of interest statement

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.

Figures

Figure 1
Figure 1. A generic view of the multifocal nature of autoimmune diseases with rheumatoid arthritis as an example
(Center) For many of these diseases, there is no singular, identified cause, but many of the underlying mechanisms can create a synergistic feedback that result in progression. (Right) By various mechanisms, an APC may present self-antigen to autoreactive T cells. These cells may become resistant to Tregs and other regulatory mechanisms due to the persistence of activation signals. (Left) Autoreactive T cells, generally Th1 or Th17, become actively involved in an inflammatory cascade, featuring strongly in the dysregulation of the production of inflammatory (IL-1, IL-17, IL-23, TNF-α and IFN-γ) and regulatory (IL-4, IL-10, TGF-β) cytokines. (Top) Antibodies targeting self-antigens can initiate and exacerbate the inflammatory process. Autoanti-bodies facilitate recruitment of PMNs and monocytes, and augment local inflammatory reactions. (Bottom) In rheumatoid arthritis, cytokines produced by Th1 and Th2 cells, macrophages and other inflammatory cells stimulate the proliferation of synoviocytes. These synovial cells then form a granulation tissue (pannus) that invades and destroys articular cartilage and bone. Th1 and Th17 cells also induce the differentiation of macrophage-like precursor cells into osteoclasts that mediate bone resorption. APC: Antigen presenting cell; PMN: Polymorphonuclear leukocyte.
Figure 2
Figure 2. Effects of PG70 peptide and LEAPS–PG70 conjugates on in vitro immune cell responses of mice with PGIA
Spleen cells from BALB/c mice with PGIA were cultured without (none) or with the peptides (5 M). (A) T-cell proliferation, expressed as an SI, was significantly increased in the presence of PG70 and J–PG70 peptides, but not in the presence of derG–PG70 as compared to untreated cells. (B) As determined by the ratio of Th1 and Th2 cytokines (IF-γ:IL-4, measured by ELISA of supernatants), T cells showed a shift toward Th1 polarization in the presence of PG70 and J–PG70, but not in response to derG–PG70 as compared to untreated cells. This finding suggests that the J, but not the derG, LEAPS conjugate of PG70 is capable of steering PGIA spleen T cells toward the Th1 phenotype. LEAPS: Ligand epitope antigen presentation system; PGIA: Proteoglycan-induced arthritis; SI: Stimulation index.
Figure 3
Figure 3. Schematic view of disease progression and potential therapeutic interventions in RA
Therapeutic agents and strategies are listed, indicating the mechanism or targeted stage of disease. Antigen-specific immunomodulatory vaccines (LEAPS and others) act at an earlier point in the progression of RA, and with more specificity than current treatments and have the potential to halt arthritis progression. Therapies targeting the autoimmune pathology and joint symptoms (especially those used for early aggressive treatment) may delay disease progression, but are not curative for RA. DCs: Dendritic cells; DMARDs: Disease modifying anti-rheumatic drugs; LEAPS: Ligand epitope antigen presentation system; RA: Rheumatoid arthritis.

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