Progress for Autoimmune Disease Vaccine (Part One)

  • Autoimmune diseases are disordered caused by an immune response of the body's immune system to its own components, and are the result of abnormal regulation in the basic process of immune tolerance recognized by itself or non-self. According to the target antigen distribution to which the autoimmune response is directed, it can be classified into an organ-specific or organ-non-specific autoimmune disease. The former includes multiple sclerosis, myasthenia gravis and insulin-dependent diabetes mellitus, the latter including systemic lupus erythematosus and rheumatoid arthritis.

    Autoimmune diseases can be controlled by pathogen infection, using immunosuppressive agents, anti-inflammatory drugs, cytokines, specific antibodies and oral autoantigens. The most common treatment is to use immunosuppressive agents before cell differentiation. Block antigen specific cell activation and amplification. These treatments are effective in reducing clonal expansion and altering early signaling pathways. However, once an autoimmune response is established, immunological interference to the differentiated cell subset or at the site of the inflammatory response to eliminate the target tissue immune response becomes less effective. Moreover, current immunosuppressive therapies require continuous use because the immune system is not in a long-term tolerant state, and continuous use of immunosuppressive agents can lead to long-term toxicity and protective immune responses to viruses, bacteria and other pathogens. Significant inhibition, and non-specific inhibition of these immunosuppressive agents may cause serious complications during treatment.

    Each pathogen has an analogue whose chemical composition is very similar and can lead to an immune cross-reactivity. Moreover, since the latter has knocked out the harmful substances in the original virus or the toxins of the bacteria, it is biologically harmless. Pathogenic analogs can be used in vaccine research, and therapeutic vaccines for a variety of autoreactive diseases can be developed based on similarities to autoantigens.

    1.  Current advances in the development of vaccines for autoimmune diseases.

    Autoimmune diseases vaccines are primarily based on DNA, altered peptide ligands, T cells, and T cells receptors.

    1.1. DNA Based Vaccines

    DNA vaccines have high priority because they usually have lower immunogenicity compared to other conventional vaccine types. DNA vaccine encoding autoantigen of autoimmune disease is not only safe and well tolerated but also stable, inexpensive and easy to scale up. More importantly, DNA vaccination can be easily improved. A DNA vaccine consisting of some cytokine genes and genes encoding self-peptide proteins can significantly enhance the immune effect. This indicates that the DNA vaccine plays an important role in regulating the immune system and may have clinical application value in the treatment of autoimmune diseases.

    1.2. Peptide-based Vaccines

    One of the most accurate selections of vaccine components exists in epitope-based peptide vaccines, where the peptide can mimic naturally processed epitopes to act as tolerogens in autoimmune diseases. Altered peptide ligands (APLs) are analogs of immunogenic epitopes that are modified by the introduction of one to several amino acid substitutions while retaining MHC binding properties. APLs induce antigen-specific Th2 T cell responses that may inhibit disease activity, therefore, have been designed as a vaccine for the prevention of autoimmune diseases.

    1.3. T Cell Vaccines

    The T cell vaccines for the treatment of autoimmune diseases is to generate an immune response against the pathogenic autoreactive T cells by isolating autoantigen-specific T cell clones from the intended recipients and after attenuation / inactivation, re-injecting the isolated cells as a vaccine to stimulate endogenous regulatory circuits. T cell vaccines are safe, effective, well-tolerated, have no side effects and could be applied despite the autoantigens are unknown.

    1.4. T Cell Receptor Peptide Vaccines

    The synthetic T cell receptor (TCR) peptide vaccines are typically derived from the hypervariable region of the TCR molecule or idiotypic determinants of CDR3 / CDR2. They could induce specific regulatory immunity and modulate the activity of autoreactive T cells in several autoimmune diseases, leading to clinical benefit.

    2. Currently developed autoimmune diseases and vaccines

    2.1 Multiple sclerosis (MS)

    Multiple sclerosis is a self-reactive, CD4+ T lymphocyte-mediated, autoimmune disease of the nervous system characterized by perivascular mononuclear cell infiltration and white matter demyelination in the central nervous system. It is a myelin basic protein (MBP). Experimental autoimmune encephalomyelitis is an ideal animal model of multiple sclerosis, and has the same characteristics as multiple sclerosis in clinical, biochemical, immunological and pathological aspects.

    Cop1 is a therapeutic vaccine against relapsing-remitting multiple sclerosis that has passed clinical trials. It consists of a large amount of L-alanine, a small amount of L-glutamic acid, a slight amount of L-lysine and some L- A positively charged amino acid random copolymer formed by tyrosine mixing, which is similar in structure to positively charged MBP, has significant immunological cross-reactivity at antibody level and T cell level and MBP.

    Cop1 is not a universal immunosuppressive agent, it only works on MS and EAE. However, the inhibitory effect of Cop1 in EAE is a common phenomenon that is not limited by specific populations, disease types or encephalogenic substances used to induce EAE. The immunosuppressive effects of Cop1 include competitive inhibition of encephalitin and inhibition of specific regulatory T cells (Treg). Cop1 competitively inhibits the binding of MBP or other myelin-related proteins to MHC class II molecules and T cell receptors, and it is effective in replacing myelin-derived peptides from the binding sites of MHC class II molecules. Treg can be isolated from the peripheral immune system of Cop1-treated animals, which are CD4+CD25+Treg subpopulations that secrete immunosuppressive IL4, IL-10 and TGF-β, which inhibits immune responses against MS. Greatly, it can protect EAE in an uninterrupted way.

    2.2 Myasthenia gravisMG

      MG is a chronic progressive autoimmune disease acquired at the neuromuscular junction, and its autoimmune attack is mainly focused on the nicotinic acetylcholine receptor (AchR) located on the postsynaptic muscle terminal plate. Experimental autoimmune myasthenia gravis (EAMG) is a well-recognized animal model of MG.

    T cells play an important role in the development of MG: 195-212 and 259-271 of the AchRα subunit are immune-dominant T cell epitopes of SJI mice and BALB/C mice that are highly reactive to myogenic ability. The "double-altered peptide ligand" formed by the two "single altered myogenic peptide-free peptides" (Ala207~Lys262) obtained by substituting Ala207 and Lys262 for the corresponding amino acids in 195~212 and 259~271, respectively APL specifically regulates autoimmune responses associated with MG and EAMG in vivo and in vitro without interfering with immune responses against other antigens.

    Dual APL may also immune-modulate other determinants other than 195-212 and 259-271 in the AchR molecule by epitope extension. The mechanism of dual APL inhibitory effects may be the induction of immunosuppressive effects mediated by regulatory cells and/or immunosuppressive cytokines such as TGF-β. It induces the inhibitory activity of immune-regulatory T cells by up-regulating the expression of CTLA4 on the surface of CD4+CD25+ regulatory T cells and down-regulating the expression of CD28, and also down-regulating the secretion and up-regulation of Th1 type cytokines (IL-1, IFN-γ). Secretion of IL-10 and TGF-β leads to apoptotic lymph node cells. Dual APL also down-regulates the adhesion of T-cells in their own reactive T cells, interfering with signaling and migration-related events.

    The ultimate efficacy of dual APL is to improve the established EAMG symptoms. Dual APL can activate the inhibition of EAMG-related reactions, alleviate the EAMG symptoms of BALB/C mice and female Lewis rats induced by 259-271 specific T cell lines, and significantly down-regulate the clinical symptoms of C57BL/6 mice sensitive to AchR. Clinical studies have also shown that dual APL down-regulates the autoimmune response of MG patients, which specifically inhibits the proliferative response of peripheral blood lymphocytes of MG patients to eight myogenic dystrophic peptides, and immune-modulates MG-related responses. Dual APL has the specific therapeutic potential we desire and can be used as a therapeutic vaccine for new MG-specific therapies.

    To be continued in Part Two…

     

    Reference

    [1] Jones T B, Basso D M, Sodhi A, et al. Pathological CNS autoimmune disease triggered by traumatic spinal cord injury: implications for autoimmune vaccine therapy[J]. Journal of Neuroscience the Official Journal of the Society for Neuroscience, 2002, 22(7):2690.

    [2] Saad C G S, Borba E F, Aikawa N E, et al. Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases[J]. Annals of the Rheumatic Diseases, 2011, 70(6):1068-1073.

    [3] Zaccone P, Cooke A. Vaccine against autoimmune disease: can helminths or their products provide a therapy?[J]. Current Opinion in Immunology, 2013, 25(3):418-423.

    [4] Anderson R P, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy.[J]. Current Opinion in Immunology, 2013, 25(3):410-417.