Table 1.
Approaches to blunt the distinct stages of GVHD induction.
| Strategies (agent or cell) | Mechanism of action | Predominant clinical indication | References |
|---|---|---|---|
| REDUCING DONOR ANTI-HOST ALLOREACTIVE T CELLS | |||
| Anti-thymocyte globulin | Depletion of donor T cells | Prophylaxis and therapeutics | (45, 46) |
| Alemtuzumab | Depletion of CD52+ mature lymphocytes | Prophylaxis and therapeutics | (47–49) |
| Post-transplant cyclophosphamide | Depletion of rapidly proliferating alloreactive donorT cells | Prophylaxis | (50–54) |
| Exvivo depletion of CD45+ naïve T cells | Depletion of naive T cells | Depletion of naive T cells | (55) |
| BLUNTING TCR SIGNALS (Standard approaches usually in combinations) | |||
| Tacrolimus and Cyclosporine | Calcineurin inhibitors; blocks T cell proliferation and IL-2 transcription | Prophylaxis | (56, 57) |
| Methotrexate | Folate antagonist; inhibits T cell proliferation | Prophylaxis | (56, 58, 59) |
| Mycophenolate mofetil | Blocks de novo synthesis of purine metabolism; inhibits T cell proliferation | Prophylaxis | (56, 58, 59) |
| Sirolimus | mTOR inhibitors; block T cell activation | Prophylaxis | (56, 60, 61) |
| INHIBITING CO-STIMULATORY SIGNALS | |||
| CTLA-4 Ig | Inhibits CD28 mediated T cell activation | Prophylaxis | (62) |
| IMPAIRING ACTIVATING AND INFLAMMATORY CYTOKINE SIGNALS DRIVEN GVHD INJURY | |||
| Ruxolitinib, Pacritinib | JAK inhibitors; Block T cell activation, cytokine production, and proliferation | Therapeutics | (63–65) |
| Alpha-1-antitrypsin (AAT) | Reduces pro-inflammatory cytokine secretion, expands Treg numbers, Inhibits neutophil elastase, decreases CD8+ effector memory cells | Therapeutics | (66–68) |
| REGULATING HISTONE DEACETYLASE | |||
| Histone deacetylase inhibitors (vorinostat) | Reduce pro-inflammatory cytokine secretion, increase Treg numbers, modulate the function of APCs, upregulate IDO expression in DCs | Prophylaxis | (69–71) |
| BLOCKING T CELL CHEMOKINE RECEPTOR DIRECTED MIGRATION INTO GVHD ORGANS | |||
| CCR5 inhibitor (Maraviroc) | Prevents T cell infiltration into GVHD tissues | Prophylaxis | (72, 73) |
| α4β7 (Natalizumab, Vedolizumab) | Prevents T cell infiltration into intestines | Prophylaxis | (72, 73) |
| CELLULAR THERAPY | |||
| Mixed hematopoietic chimerism | Promotes immune tolerance | Prophylaxis | (74–76) |
| nTregs | Promotes immune tolerance | Prophylaxis and Therapeutics | (77–79) |
| iTregs | Promotes immune tolerance | Prophylaxis | (80–82) |
| Tr1 | Promotes immune tolerance | Prophylaxis | (83–85) |
| MSCs | Immunomodultaor, Tissue repair | Therapuetics | (86, 87) |