Table 3.
Strategies for lowering celiac disease epitopes.
| S.No. | Approach | Target | Features | Remarks | References |
|---|---|---|---|---|---|
| (A) Genetic Modification | |||||
| 1. | RNAi | Prolamins: α, γ, ω gliadins | 90% reduction in prolamins | Gene silencing | (17) |
| 2. | RNAi | HLA DQ2-α-II, DQ2-γ-VII, DQ8-α-I and DQ8-γ-I | 86.5% reduction in ω, α genes and 74% reduction in γ-gliadin gene promoter | Gene silencing | (143) |
| 3. | RNAi | All gliadin proteins | Use of specific inverted repeat sequences and hairpin construct | Gene silencing | (144) |
| 4. | RNAi | α-gliadins | Specific genetic deletion of storage protein fraction | Gene silencing | (145) |
| 5. | RNAi | HMW-glutenins | Reduced HMW-glutenin content in wheat | Gene silencing | (146) |
| (B) Non-transgenic | |||||
| 1. | CRISPR/Cas9 | Gliadin proteins, particularly α-gliadins | Mutant lines had reduced gliadin contents | Reduction in α-gliadins | (147) |
| 2. | Breeding | Gliadin proteins, particularly α-gliadins | Breeding wheat with CD specific non-immunogenic wild relatives of wheat | Reduction in α-gliadin epitopes | (152, 153) |
| 3. | Wheat deletion lines | ω, γ gliadins, and LMW-glutenins on short arm of chromosome 1D | Reduced ω, γ gliadins, and LMW-glutenins in wheat | Reduction in CD-eliciting epitopes | (151) |
| 4. | Wheat deletion lines | α-gliadins on short arm of chromosome 6D | Reduced α-gliadins in wheat | Reduction in CD-eliciting epitopes | (148) |
| 5. | Wheat deletion lines | Mutant line lacking Gli-D2 | Reduced α-gliadins in wheat | Reduction in CD-eliciting epitopes | (150) |
| 6. | Wheat deletion lines | α-gliadins on short arm of chromosome-6 | Reduced α-gliadins in wheat | Reduction in CD-eliciting epitopes | (149) |
| (C) Microbial degradation | |||||
| 1. | Aspergillus niger, Flavobacterium meningosepticum, Sphingomonas capsulate, and Myxococcus xanthus | Gluten | Reduction by gluten hydrolysis through enzyme prolyl endopeptidases | Reduction in gluten content | (155, 156) |
| (D) Probiotics supplementation | |||||
| 1. | Lactobacillus sanfranciscensis LS40 and LS41 and L. plantarum CF1 | Improved nutritional content by increasing availability of free Ca, Mg and Zn in gluten-free bread | Enhanced nutrient absorption | (164) | |
| 2. | VSL#3 | Gluten | Digestion of proline-rich gluten peptides through bacterial proteases | Reduction in gluten content | (161, 162) |
| 3. | L. acidophilus, L. sanfranciscensis | Gluten | Degradation of ω-gliadins and HMW-glutenins | Reduction in gluten content | (165) |
| 4. | Bifidobacterium bifidum CECT 7365 | Gut mucosa | Exerted protective effect on gut mucosa by increasing production of MCP-1 and TIMP-1 | Beneficial to gut mucosa | (157) |
| 5. | B. bifidum IATA-ES2, B. longum ATCC 15707 | Gut Health | Reduced levels of IL-12 and IFN-secretion in CaCo2 cell cultures | Reduction in CD immunogenicity | (166) |
| 6. | B. longum CECT 7347, B. bifidum CECT 7365 | Gut Health | Reduced TNF-α and IFN-γ and increased IL-10 production | Reduction in CD immunogenicity | (167) |
| 7. | B. breve B632, BR03 | Gut Health | Restored normal gut microflora in 40 children suffering from CD | Reduction in CD immunogenicity | (158) |
| 8. | B. lactis | Gut Health | Prevented cellular damage of epithelial cells by preserving tight junctions | Reduction in CD immunogenicity | (168) |
| 9. | Bifidobacterium spp. | Gut Health | Reduced inflammatory response in CaCo-2 cells by lowering the production of IL-1β, NF-kappaB, and TNF-α | Reduction in CD immunogenicity | (169) |
| 10. | B. longum CECT 7347 | Gut Health | Increased villus width, enterocyte height & IL-10 levels; reduced gut mucosal inflammation in animal model | Reduction in CD immunogenicity | (170) |
| 11. | B. infantis Natren Life Start (NLS) | Gut Health | Improvement in digestive symptoms in CD patients | Reduction in CD immunogenicity | (163) |
| 12. | L. casei ATCC 9595 | Gut Health | Reduced TNF-α in HLA-DQ8 transgenic mice | Reduction in CD immunogenicity | (171) |
| (E) Gluten sequestering polymers | |||||
| 1. | Poly (hydroxyethyl methacrylate-co-styrene sulfonate) (P[HEMA-co-SS]) | Gluten | Sequesters gluten in small intestine, decreases formation of CD-eliciting gluten peptides and reduces the severity of immune response | Prediction* | (172, 173) |
| 2. | Ascorbyl palmitate | Gluten | Decreases gliadin availability and deamination by TG2 | Prediction* | (174) |
| (F) Vaccination | |||||
| 1. | Nex Vax® Vaccine (ImmusanT, Cambridge, USA) | HLA-DQ2 | Builds up resistance against gluten peptides | Clinical Trial | (175) |
| (G) Enzymatic | |||||
| 1. | Prolylendopeptidase from Flavobacterium meningosepticum | Gluten | Detoxifying immunogenic peptides | Reduction in gluten content | (176) |
| 2. | Cysteine proteinase EP-B2 from barley | Gluten | Gluten hydrolysis and degradation to small non-immunogenic peptides | Reduction in gluten content | (177, 178) |
| 3. | ALV003 (Alvine Pharmaceuticals, San Carlos, CA, USA), consisting of barley cysteine proteinase EP-B2 and Sphingomonas capsulate PEP | Gluten | Drug reduced gliadin-induced T-cell response and harmful effect on intestinal epithelial cells in patients with CD | Clinical Trial | (179, 180) |
| 4. | A. niger prolyl-endopeptidase (AnPEP) and amaranth flour blend (AFB) | Gluten | Reduction in immunoreactive gluten content in wheat dough | Reduction in gluten content | (181) |
| 5. | AnPEP | Gluten | Production of gluten free foods below 20 mg gluten/kg food | Reduction in gluten content | (182) |
| 6. | AnPEP | Gluten | Degradation of ω-gliadins and HMW-glutenins | Reduction in gluten content | (165) |
| 7. | AnPEP | Gluten | Enzyme degraded the immunogenic proline-rich residues in gluten peptides of wheat flour by 40% | Reduction in gluten content | (183) |
| 8. | Engineered endopeptidase (Kuma030) | Gluten | Reduced gliadin content of foods below threshold value of 20 mg/kg | Reduction in gluten content | (184) |
| 9. | Proteolytic enzymes from Nepenthes spp. | Gluten | Low gliadin content due to gliadin digestion and reduced IELs | Reduction in gluten content | (185) |
| (H) Anti-inflammatory drugs | |||||
| 1. | Glucocorticoids-Prednisone, Fluticasone propionate | B and T-cell proliferation | Improvement in weight, sugar absorption, small intestinal enzymatic activity and intestinal histology in CD patients and reduction in lymphokine levels | Prediction* | (186, 187) |
| 2. | Anti-interferon-γ (infliximab, certolizumab and adalimumab) and Anti TNF-α (itolizumab) | Targets activation of metalloproteine-ases (MMPs) | MMPs induces pre-inflammatory response, blocking them reduces inflammation | Prediction* | (188–190) |
| 3. | Anti-interleukin 15 | Cytotoxic T lymphocytes | Reduction in intestinal damage caused by T-cells in mouse models | Prediction* | (175) |
| 4. | Interleukin 10 | Gliadin induced T-cell activation | IL-10 used for treatment of Th1 mediated autoimmune disorders | Prediction* | (191) |
| (I) Modified Gluten | |||||
| 1. | Genetically modified gluten | Gluten | Reduction in T-cell activation; Transamidation by attaching lysine methyl ester to glutamine residue of α-gliadin | Prediction* | (192) |
| 2. | Chemo-enzymatic-Microbial transglutaminase | Glutamine in gluten proteins | Transamidation of glutamine with n-butylamine under reducing conditions | Prediction* | (193) |
| 3. | Enzymatic-Microbial Chymotrypsin and transglutaminase | Gluten proteins | Transpeptidation reaction-Binding of valine or lysine to gluten proteins | Prediction* | (194) |
| (J) Transglutaminase inhibitors | |||||
| 1. | Cystamine and cysteamine | Cystamine oxidizes two vicinal cysteine residues on TG2, whereas, cysteamine acts as competitive inhibitor for transamidation reactions catalyzed by TG2 | Can reduce the activity of TG2 | Prediction* | (195) |
| 2. | Inhibitor Zed1227 | Reduce the activity of TG2 | Prediction* | (196) | |
| 3. | Reversible T2G inhibitors: •Synthetic polymer poly (hydroxymethyl methacrylate- co- styrene sulfonate) •Anti-gliadinIgY •Dihydroisoxazo-les •Cinnamoytriazo-le •Aryl β-aminoethyl ketones |
Covalent modification of enzyme | GTP and GDP are mostly used to inhibit TG | Prediction* | (192, 197) |
| (K) Others | |||||
| 1. | Modulation of tight junctions by AT1001 peptide, Larazotide acetate from Vibrio cholera | Zonulin | Antagonizes zonulin activity and prevents opening of intestinal epithelial tight junctions. Inhibits paracellular movements of gluten peptides across tight junctions in intestine | Prediction* | (198–200) |
| 2. | Blocking HLADQ2 or HLADQ8 by HLA blockers | HLADQ2/ HLADQ8 | To avoid presentation of gliadin peptides by antigen-presenting cells to CD4+ T cells | Prediction* | (138) |
| 3.Blocking of Interleukin-15 (a) |
Anti-IL-15 monoclonal antibodies | IL-15 | Neutralizes enterocyte apoptosis and down-regulates adaptive immune response in lamina propria | Prediction* | (138, 201, 202) |
| (b) | AMG 714 (Anti-IL-15 monoclonal) | IL-15 | Reduces immune response to gluten intake | Clinical Trial: Phase 2 | (203) |
| 4. | Antagonist of ω-secalin gene (Decapeptide QQPQRPQQPF) | K562(S) cells | Prevents agglutination of k562 cells and hence preventing cell mucosa immune activation | Prediction* | (154) |
| 5. | Tolerogenic nanoparticles | Antigen presentation w/o co-stimulation on synthetic antigen presenting cell. Anti-FAS ligand antibody delivers apoptotic signal | Direct action on effector T cells; inhibition of CD4+ and CD8+ T-cell activation | Prediction* | (204–206) |
*
Predictions represent results based on experimental lab studies and no clinical trials.