Journal: Best practice & research. Clinical gastroenterology

Article Title: Therapeutic approaches for celiac disease

doi: 10.1016/j.bpg.2015.04.005

Figure Lengend Snippet: Investigational approaches targeting the factors contributing to celiac disease pathogenesis. Long, Pro- and Gln-rich fragments of gluten survive gastrointestinal breakdown by luminal and brush border enzymes and consequently enter the lamina propria. Production of non-toxic cereals lacking antigenic peptides or sourdough fermentation during baking could avoid the ensuing immune response. Alternatively, gluten-sequestering polymers, oral proteases, and probiotics may reduce the exposure to immunogenic gluten peptides. At the intestinal epithelium, compromised epithelial barrier function enables paracellular and transcellular transport of gluten peptides. Antagonists of zonulin and inhibitors of the peptide-sIgA-CD71 transport pathway could reduce this paracellular and transcellular permeability, respectively. Gluten peptides induce epithelial and other cells to secrete IL-15, resulting in an increase in the number of IELs. These IELs are subsequently activated by epithelial MICA/B-NKG2D and CD94/NKG2C-HLA-E interactions that stimulating cytotoxic effects on epithelial cells. Neutralizing IL-15-mediated effects could provide a therapeutic benefit for celiac patients. Most gluten peptides survive gastric digestion and are excellent substrates of TG2 in the lamina propria. The resulting deamidated gluten peptides are then recognized by CD4+ T cells in the context of HLA-DQ2 or –DQ8 on antigen presenting cells. Thus, either TG2 inhibitors or HLA blockers are potential drug candidates. The T-cell response in the mucosa could be suppressed by anti-CD3-antibodies or peptide vaccination, or by blocking T-cell homing with anti-integrin α4β7 or CCR9 antagonists. Upon activation, gluten reactive T cells secrete inflammatory cytokines including IFN-γ and TNF that contribute to enteropathy. Anti-IFN-γ– and –TNF-antibodies could be considered as therapeutic targets. Finally, through interactions with T cells, B cells differentiate into plasma cells that produce autoantibodies against TG2. B-cell depletion with anti-CD20 antibodies is yet another possible therapeutic strategy. Further means to prevent or treat celiac disease in the future is modifying the inflammatory immune response by hookworm infection or with steroid therapy. Abbreviations: sIgA, secretory IgA. TG2, transglutaminase 2; HLA, human leukocyte antigen; IFN-γ, interferon gamma; TNF, tumor necrosis factor.

Article Snippet: Anti-CD3 Teplizumab Monoclonal antibody MacroGenics, USA Phase II in T1D Anti-CD3 Otelixizumab Monoclonal antibody Tolerx, USA Phase III in T1D Anti-CD20 Rituximab Monoclonal antibody Biogen Idec, USA Approved Anti-CD20 Tositumab Monoclonal antibody GlaxoSmithKline, USA Approved Anti-CD20 Ibritumomab Monoclonal antibody Spectrum, USA Approved Anti-TNF-α Infliximab Monoclonal antibody Janssen Biotech, USA Approved Anti-TNF-α Certolizumab Monoclonal antibody UCB, USA Approved Anti-TNF-α Adalimumab Monoclonal antibody AbbVie, USA Approved Anti-integrin α4β7 Vedolizumab Monoclonal antibody Millennium Pharmaceuticals, USA Approved IL-2/IL-15R Beta Hu-Mik- Beta-1 Monoclonal antibody National Cancer Institute, USA Phase I Anti-gluten AGY Polyclonal antibody Igy, Canada Phase I Pancrelipase Creon Enzyme cocktail Sheffield Teaching Hospitals, UK Phase 4 TG2 inhibitor Dihydroisoxazoles Small molecule Sitari Pharmaceuticals, USA Discovery TG2 inhibitor ZED-101 Small molecule Zedira, Germany Discovery TG2 inhibitor Cinnamoyl triazoles Small molecule University of Montreal, Canada Discovery HLA-DQ2 blocker Dimeric analogue of gluten peptide Peptide Stanford University, USA & University of Oslo, Norway Discovery HLA-DQ2 blocker Azidoproline analogue of gluten peptide Peptide Leiden University, Netherlands Discovery Gluten tolerization Bifidobacterium Infantis Probiotic Universidad de Buenos Aires, Argentina Exploratory Gluten tolerization Genetically modified Lactococcus lactis Probiotic ActoGeniX, Belgium Discovery Gluten-sequestering polymers P(HEMA-co-SS) (BL-7010) Polymer resin University of Montreal, Canada Phase I + II Open in a separate window RA, rheumatoid arthritis; HLA, human leucocyte antigen; IBD, inflammatory bowel disease; UC, ulcerative colitis; GvHD, graft versus host disease; TG2, transglutaminase 2; T1D, type 1 diabetes; P(HEMA-co-SS), poly(hydroxyethyl methacrylate-co-styrene sulphonate); Approved, Approved in other diseases.

Techniques: Permeability, Blocking Assay, Activation Assay, Infection

Journal: Best practice & research. Clinical gastroenterology

Article Title: Therapeutic approaches for celiac disease

doi: 10.1016/j.bpg.2015.04.005

Figure Lengend Snippet: Potential therapies for celiac disease.

Article Snippet: Anti-CD3 Teplizumab Monoclonal antibody MacroGenics, USA Phase II in T1D Anti-CD3 Otelixizumab Monoclonal antibody Tolerx, USA Phase III in T1D Anti-CD20 Rituximab Monoclonal antibody Biogen Idec, USA Approved Anti-CD20 Tositumab Monoclonal antibody GlaxoSmithKline, USA Approved Anti-CD20 Ibritumomab Monoclonal antibody Spectrum, USA Approved Anti-TNF-α Infliximab Monoclonal antibody Janssen Biotech, USA Approved Anti-TNF-α Certolizumab Monoclonal antibody UCB, USA Approved Anti-TNF-α Adalimumab Monoclonal antibody AbbVie, USA Approved Anti-integrin α4β7 Vedolizumab Monoclonal antibody Millennium Pharmaceuticals, USA Approved IL-2/IL-15R Beta Hu-Mik- Beta-1 Monoclonal antibody National Cancer Institute, USA Phase I Anti-gluten AGY Polyclonal antibody Igy, Canada Phase I Pancrelipase Creon Enzyme cocktail Sheffield Teaching Hospitals, UK Phase 4 TG2 inhibitor Dihydroisoxazoles Small molecule Sitari Pharmaceuticals, USA Discovery TG2 inhibitor ZED-101 Small molecule Zedira, Germany Discovery TG2 inhibitor Cinnamoyl triazoles Small molecule University of Montreal, Canada Discovery HLA-DQ2 blocker Dimeric analogue of gluten peptide Peptide Stanford University, USA & University of Oslo, Norway Discovery HLA-DQ2 blocker Azidoproline analogue of gluten peptide Peptide Leiden University, Netherlands Discovery Gluten tolerization Bifidobacterium Infantis Probiotic Universidad de Buenos Aires, Argentina Exploratory Gluten tolerization Genetically modified Lactococcus lactis Probiotic ActoGeniX, Belgium Discovery Gluten-sequestering polymers P(HEMA-co-SS) (BL-7010) Polymer resin University of Montreal, Canada Phase I + II Open in a separate window RA, rheumatoid arthritis; HLA, human leucocyte antigen; IBD, inflammatory bowel disease; UC, ulcerative colitis; GvHD, graft versus host disease; TG2, transglutaminase 2; T1D, type 1 diabetes; P(HEMA-co-SS), poly(hydroxyethyl methacrylate-co-styrene sulphonate); Approved, Approved in other diseases.

Techniques: Genetically Modified