Table 2.
Protein- and peptide-based tolerogenic vaccines.
| Peptide-Based Tolerogenic Vaccines | Prophylactic Treatment | Therapeutic Treatment | Bystander/Infectious tolerance | Proposed Mechanism of Action | Ref. | ||||
|---|---|---|---|---|---|---|---|---|---|
| Route | Days | EAE Model | Route | Days | EAE Model | ||||
| Anti-DEC205-MOG35-55 | IV | -7 and -3 or -14 | C57BL/6 with lyophilized spinal cord or MOG35-55-specific T cell transfer |
IV | 7 and 11 | C57BL/6 with Lyophilized spinal cord | Maybe | Antigen targeting to cross-presenting CD8+ DEC205+ DCs resulted in the induction and expansion of Tregs and decreased the percentage of IFN-γ+ Th1 and IL-17+ Th17 cells. IP and SC administration were less efficacious. Tolerance was dependent on steady state DCs and TGF-β. | (117, 118) |
| Anti-Langerin-MOG29-59 | SC | -14 | C57BL/6 with MOG35-55-specific T cell transfer |
N/A | N/A | N/A | N/A | Antigen targeting to CD103+ Langerin+ migratory DCs resulted in the induction and expansion of MOG35-55-specific Tregs. Tolerance was dependent on vaccine-induced Tregs. | (118) |
| Anti-Treml4-MOG29-59 | SC | -14 | C57BL/6 with MOG35-55-specific T cell transfer |
N/A | N/A | N/A | N/A | Antigen targeting to lymphoid resident CD8+ Treml4+ DCs failed to suppress EAE. | (118) |
| Anti-DCIR2-PLP139-151 | IP | -10 | SJL with PLP139-151 |
N/A | N/A | N/A | N/A | Antigen targeting to CD8- DCIR2+ DCs resulted in the expansions of pre-existing Tregs and anergy/apoptosis of pathogenic T cells. Tolerance was dependent on steady state DCs. Anti-DCIR2-MOG29-59 failed to prevent MOG35-55-induced EAE in C57BL/6 mice (118). | (119) |
| Anti-Siglec-H-MOG35-55 | IP | -1 | C57BL/6 with MOG35-55 |
N/A | N/A | N/A | N/A | Antigen targeting to Siglec-H+ plasmacytoid DCs resulted in prolonged antigen presentation, reduced antigen-specific IFN-γ+ Th1 and IL-17+ Th17 cells and reduced MOG-specific antibodies. No increase in Tregs was observed. | (120) |
| Anti-BST2-MOG35-55 | IP | -1 | C57BL/6 with MOG35-55 |
N/A | N/A | N/A | N/A | Antigen targeting to BST2+ plasmacytoid DCs resulted in short term antigen presentation and did not suppress EAE. | (120) |
| GM-CSF- MBP69-87, PLP139-151, or MOG35-55 | SC | -21, -14, and -7 | Lewis Rat with MBP69-87, SJL with PLP139-151, and C57BL/6 with MOG35-55 |
SC | 12, 15, 17 and 19 or 9, 10, 12, and 14 |
Lewis Rat with MBP69-87 and C57BL/6 with MOG35-55 |
N/A | Antigen targeting to DCs resulted in the induction of MOG35-55-specific Tregs. GM-CSF-MOG and GM-CSF-PLP139-151 vaccines were efficacious tolerogens when included in CFA. Tolerance was dependent on vaccine-induced Tregs and low efficiency antigen recognition. | (121, 122) |
| Anti-DC-ASGPR-MOG1-125 | N/A | N/A | N/A | SC | 7, 14, 21, 35 and 63 | Cynomolgus macaques with Full-length human MOG |
N/A | Antigen targeting to DC-ASGPR+ skin macrophages resulted in the induction of MOG35-55-sepcific Tregs, increased serum levels of TGF-β1/2 and reduced percentages of activated CD4+ T cells. No reduction of MOG35-55 specific antibodies was observed. | (123) |
| M-CSF-MBP69-87 | SC | -21, -14 and -7 | Lewis Rat with MBP69-87 | SC | 9, 10, 12, and 14 or 10, 11, and 13 | Lewis Rat with MBP69-87 | N/A | Antigen targeting to macrophages. | (121) |
| IL-2-MBP69-87 | SC | -60, -42, and -20 or -35, -21, and -7 | Lewis Rat with MBP69-87 | SC | 5, 7, and 9 or 5, 7, 9, and 11 | Lewis Rat with MBP69-87 | N/A | Antigen targeting to T cell APCs. | (124) |
| IL-4-MBP69-87 | SC | -42, -28, and -14 | Lewis Rat with MBP69-87 | SC | 5, 7, and 9 or 5, 7, 9, and 11 | Lewis Rat with MBP69-87 | N/A | Antigen targeting to B cells did not suppress EAE. | (124) |
| IFN-β-Neuroantigen or IFN-β + Neuroantigen with peptides MBP69-87, PLP139-151, or MOG35-55 |
SC | -21, -14 and -7 | Lewis Rat with MBP69-87, SJL with PLP139-151, and C57BL/6 with MOG35-55 |
SC | 9, 10, and 12 or 9, 10, 12, and 14 or 13, 15, 17, and 19 or 15 alone | Lewis Rat with MBP69-87 and C57BL/6 with MOG35-55 |
Yes | Myelin antigen presentation in IFN-β conditioned environments resulted in the induction of Tregs. Tolerance was dependent on vaccine-induced Tregs. INF-β + OVA323-339 in Alum ameliorate EAE induced with OVA323-339/MOG35-55 in CFA. | (125, 126) |
| IL-16-MBP68-88 | SC | -31, -17 and -7 or -21, -14 and -7 | Lewis Rat with MBP69-87 | IV followed by IP | 8 and 12 or 10 and 12 | Lewis Rat with MBP69-87 | N/A | Myelin antigen presentation in IL-16 conditioned environments. | (127) |
| 24-mer S-antigen peptide-MOG38-51 or PLP139-151 | IV | -7 | SJL with PLP139-151 and C57BL/6 with MOG35-55 |
IV | 7 | SJL with PLP139-151 and C57BL/6 with MOG35-55 |
N/A | Myelin antigen presentation with immunosuppressive repeating peptides of S-antigen from Plasmodium falciparum increased expansion of antigen-specific Tregs. Tolerance was dependent on vaccine-induced IL-10. | (128) |
| pσ1-PLP139-151 or MOG29-146 |
Nasal | -21, -14, and -7 | SJL with PLP139-151 |
Nasal | 6 or 11 or 18 | SJL with PLP139-151 and C57BL/6 with MOG35-55 |
N/A | Antigen targeting to M cells resulted in the induction of IL-10 producing Tr1, induction of IL-4 producing Tregs and decrement of IL-21, IL-17 and IFN-γ production. Tolerance was dependent on vaccine-induced Tregs and IL-4. | (129, 130) |
| RBC-MOG35-55 | IV | -7 | C57BL/6 with MOG35-55 | IV | 5 or 11 | C57BL/6 with MOG35-55 | N/A | Targeting of antigen to RBC recycling pathway led to pathogenic effector cell depletion and reduced the percentage of IFN-γ and IL-17 producing T cells. | (131) |
| Splenocytes chemically coupled with full-length MPB, MBP72-89, MBP84-104, MOG35-55, spinal cord homogenate, or peptide cocktail |
IV | -7 | SJL with PLP139-151 or spinal cord homogenate, C57BL/6 with MOG35-55, and Lewis Rats with MBP72-89 |
IV | 3 or 4 or 16 or 30 | SJL with PLP139-151-specific T cell transfer and SJL with peptide cocktail |
N/A | Targeting of antigens to the apoptotic cell debris clearance pathway in spleen resulted in macrophage production of IL-10 and PD-L1 as well as induction of effector T cell anergy and/or deletion. Tolerance was partially dependent on vaccine-induced Tregs. IP and SC vaccination did not induce tolerance. | (132–137) |