Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models.

Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies-(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)-to a newer approach-(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models.

Vaccination by Two DerG LEAPS Conjugates Incorporating Distinct Proteoglycan (PG, Aggrecan) Epitopes Provides Therapy by Different Immune Mechanisms in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit).

Why Don't We Have a Vaccine Against Autoimmune Diseases? - A Review.

This review examines some of the reasons why we don't have a vaccine against autoimmune diseases and highlights the progress that has been made. Many autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes (T1D), are driven by autoimmune T cell responses. Unlike vaccines for most infectious diseases, which elicit antibody responses, are intended for immuno-naive individuals and considered preventative, a vaccine for an autoimmune disease must be therapeutic and resolve or control the on-going autoimmune response and condition in the diseased host.

Lessons from next generation influenza vaccines for inflammatory disease therapies.

Lessons can be learned for treating inflammatory diseases such as rheumatoid arthritis (RA) from next generation approaches for development of universal influenza vaccines. Immunomodulation of inflammatory diseases, rather than ablation of cytokine or cellular responses, can address the root cause of the disease and provide potential cure. Like influenza, there are different antigenic 'strains' and inflammatory T cell responses, Th1 or Th17, that drive each person's disease.

Interactive Journal Club: Teaching an Old Dog New Tricks.

The interactive journal club incorporates basic principles of active and adult learning in a traditional education tool to maximize opportunity to develop critical thinking, communication skills, active reflection, and personal confidence in these skills. Following the choice of an appropriate article, the Designated Leader (DL) directs the discussion by presenting the title and data from the article with instructions for their analysis but without the author's text. The participants, except the DL, are viewing the article for the first time and are prompted in their review of the raw data to provide their own interpretation, discovery, and critique.

LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model.

The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu H-2 CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human 2 microglobulin peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors.

Concurrent treatment of chronic psoriasis and asthma with ustekinumab.

A 56-year-old woman with a 40-year history of guttate flares of psoriasis associated with stress and infection as well as chronic asthma was treated with subcutaneous injections of ustekinumab, repeated after 1 month and then every 3 months. Her psoriasis completely resolved, and her capacity for exercise was markedly increased and asthma maintenance medications were no longer needed. Ustekinumab is a human monoclonal antibody that binds the p40 subunit of IL-12 and IL-23 to limit the progression of the Th1 and Th17 inflammatory immune responses that maintain many autoimmune and inflammatory diseases.

LEAPS therapeutic vaccines as antigen specific suppressors of inflammation in infectious and autoimmune diseases.

The L.E.A.

J-LEAPS peptide and LEAPS dendritic cell vaccines.

The J-LEAPS vaccines contain a peptide from β-2-microglobulin covalently attached to disease-related peptides of 8-30 amino acids which contain a T cell epitope. The J-LEAPS vaccines can initiate a protective Th1 immune response or modulate an ongoing Th17 autoimmune response to the peptide. J-LEAPS vaccines activate and direct the nature of the subsequent immune response by promoting the maturation of precursor cells into a unique type of dendritic cell that produces interleukin 12, but not IL-1 or tumour necrosis factor, and presents the antigenic peptide to T cells.

Maturation of dendritic cell precursors into IL12-producing DCs by J-LEAPS immunogens.

LEAPS (ligand epitope antigen presentation system) vaccines consist of a peptide containing a major histocompatibility antigen binding peptide conjugated to an immune cell binding ligand (ICBL) such as the 'J' peptide from beta-2-microglobulin. Treatment of monocytes, monocytes plus GMCSF, or monocytes plus GMCSF and IL4 with JgD (containing a peptide from gD of herpes simplex virus type 1) or JH (with a peptide from HIV p17 gag protein) was sufficient to promote their maturation into Interleukin 12 producing dendritic cells. JgD-dendritic cells supported allotypic activation of T cells to produce Th1-related cytokines.

Immune peptide enhancement of peptide based vaccines.

Vaccines optimize the presentation of an immunogen to the immune system, oftentimes enhancing or replacing the natural activators of antigen presenting cells in order to promote the delivery and the response of T and B lymphocytes to the immunogen. The purpose of this series is to describe new technologies which allow vaccine design, based on our understanding of the immune response, using different approaches to immune peptide enhancement of peptide based vaccines. In this introduction to the series entitled, "Immune Peptide Enhancement of Peptide Based Vaccines", some of the immunological concepts relevant to vaccine design are presented.

The L.E.A.P.S. approach to vaccine development.

The Ligand Epitope Antigen Presentation System (L.E.A.

Strain-dependent structural variants of herpes simplex virus type 1 ICP34.5 determine viral plaque size, efficiency of glycoprotein processing, and viral release and neuroinvasive disease potential.

The ability of certain strains of herpes simplex virus type 1 (HSV-1) to cause encephalitis or neuroinvasive disease in the mouse upon peripheral infection is dependent on a combination of activities of specific forms of viral proteins. The importance of specific variants of ICP34.5 to neuroinvasive disease potential and its correlation with small-plaque production, inefficient glycoprotein processing, and virus release were suggested by comparison of ICP34.