Table 1.
The roles of treatment measures regulating co-inhibitory molecules for T1D.
| Treatment measures | Related mechanisms | Ref. |
|---|---|---|
| CTLA-4 | ||
| CTLA4-Ig | Selectively block CD28 co-stimulation and defend against potentially autoreactive T cells. | (7, 103) |
| sub-immunogenic vaccination with strong agonistic insulin mimetope | Suppress effector T cells via inducing human insulin-specific Foxp3+ Treg with upregulated Foxp3, CTLA4, IL-2Rα, and TIGIT expression. | (104) |
| PD-1 | ||
| anti-PD-1 immunotoxin | Selectively target and deplete PD-1-expressing cells. | (97) |
| Genetically engineered PD-L1-overexpressing platelets | Suppress autoreactive pancreatic T-cell activity and reverse diabetes in novel hyperglycemic NOD mice. | (17) |
| PFK15 | Increase the expression of PD-1 and LAG-3 on CD4 T cells, inhibit glycolysis utilization of diabetogenic CD4 T cells and reduce T cell responses to β cell antigen. | (105, 106) |
| Low-molecular-weight dextran sulfate | Increase PD-1 expression in T cells, reduce interferon-γCD4 and CD8 T cells, and enhance the number of foxp3 cells. | (107, 108) |
| Intralymphatic injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) | Delay the progression of T1D with immunomodulatory effects including increased PD-1+ CD69+ cells in both CD8+ and double negative T cells. | (109, 110) |
| LAG3 | ||
| stable peptide-MHC class II complexes (pMHCII) | Induce T cell suppression and thereby inhibit diabetes progression in NOD mice with LAG-3 deficiency. | (111) |
| CYM-5442 | Induce the expression of negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla to inhibit the autoimmune ability of T cells | (112) |
| oral Salmonella-based anti-CD3 mAb combined therapy | Immunosuppressive CD4CD25Foxp3 Treg and CD4CD49bLAG3 Tr1 cells. | (113) |
| anti-IL-7Rα antibodies | Delay T1D incidence and upregulates LAG-3, Tim-3, and PD-1 on peripheral blood CD4 and CD8 T cells from prediabetic NOD mice. | (114) |
| Aire-overexpressing DCs | Upregulate CD73, Lag3, and FR4 that mediate self-tolerance, and decrease CD4+IFN-γ+ autoreactive T cells in STZ-T1D mouse-derived splenocytes, which is associated with Aire-overexpressing DCs-induced T1D prevention and delay. | (115) |
| Tim | ||
| Tim-3 ligand galectin-9 | Enhance apoptosis of CD4+ Tim-3+ Th1 cells and downregulate Th1 immune response, and anti-Tim-3 monoclonal RMT3-23 antibody suppresses the TNF-α production and activation of DC. | (116, 117) |
| TIGIT | ||
| Teplizumab | Increase the percentage of KLRG1+TIGIT+CD8+ T cells. | (118) |
| soluble receptor for advanced glycation end products (sRAGE) | Reverse RAGE ligand-induced downregulation of key genes for Treg homeostasis and activation, including FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, and CCR4. | (119, 120) |
| Alefacept | Hypo proliferative CD8 memory cells expressing exhaustion-associated markers including TIGIT and KLRG1. | (121) |
| BTLA-HVEM | ||
| tDCs and multiligand-DCs | Suppress the function of effector T cells and induce self-tolerance. | (122) |