Table 2.
List of immunomodulatory therapies analysed in this review, their Therapeutic Goods Administration (TGA)/Food and Drug Administration (FDA) approval status and their mechanism of action
| Reference(s) | Therapeutic | TGA/FDA approval | Mechanism |
|---|---|---|---|
| Antifungals | |||
| [61] | Fluconazole | Yes/yes | Selective inhibitor of fungal cell wall synthesis |
| Corticosteroids | |||
| [43, 44, 54, 62, 63] | Dexamethasone | Yes/yes | A corticosteroid that acts on glucocorticoid receptors which suppresses neutrophil migration, macrophage activation and lymphocyte proliferation and decreases permeability of capillaries. More rapid onset and shorter duration of action than betamethasone |
| [62] | Hydrocortisone | Yes/yes | A corticosteroid that acts on glucocorticoid receptors which suppresses neutrophil migration, macrophage activation and lymphocyte proliferation and decreases permeability of capillaries. Less potent and shorter acting than dexamethasone |
| [54, 64] | Betamethasone | Yes/yes | A corticosteroid that acts on glucocorticoid receptors which suppresses neutrophil migration, macrophage activation and lymphocyte proliferation and decreases permeability of capillaries. More potent and longer lasting than dexamethasone and hydrocortisone |
| Inter-alpha inhibitor proteins | |||
| [65, 66] | Human plasma derived inter-alpha inhibitor proteins | No/no | Endogenous human plasma proteins that block the release of serine proteases protecting cells from cytotoxicity |
| Complement inhibitors | |||
| [67] | RLS-0071 | No/no | An amino acid peptide that binds to the C1q compliment protein preventing downstream signalling of the compliment pathway |
| TLR7 agonist | |||
| [41, 42] | (Gardiquimod) GDQ | No/no | An imidazoquinoline analogue that induces the activation of NF-κB in cells expressing human or mouse TLR7 |
| Antibiotics | |||
| [57] | Ceftriaxone | Yes/yes | A broad-spectrum cephalosporin antibiotic that inhibits the mucopeptide synthesis in the bacterial cell wall |
| [57] | Daptomycin | Yes/yes | A broad-spectrum cyclic lipopeptide antibiotic against Gram-positive bacteria. Disrupts bacterial cell membrane function |
| [58] | Vancomycin | Yes/yes | A glycopeptide antibiotic against Gram-positive bacteria. Inhibits cell wall biosynthesis |
| [68] | Doxycycline | Yes/yes | A tetracycline antibiotic that inhibits bacterial protein synthesis |
| Methylxanthines | |||
| [58] | Pentoxifylline | Yes/yes | A methylxanthine derivative that lowers blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation |
| NF-kB inhibitors | |||
| [59] | Tat-NBD peptide | No/no | A 22 amino acid peptide that inhibits NF-κB signalling by penetrating the cell and blocking the NF-κB essential modifier (NEMO) |
| Fingolimod | |||
| [37, 47, 48, 70] | Fingolimod (FTY720) | Yes/yes | A sphingosine 1-phosphate (S1P) receptor agonist that causes lymphocytes to be sequestered to the lymph nodes |
| GSK3β inhibitor | |||
| [71] | SB216763 | No/no | Selectively inhibits the activity of GSK-3α and GSK-3β, preventing PI3-kinase induced cell death |
| Innate defence regulator proteins | |||
| [60] | IDR-1018 | No/no | A synthetic 12 amino acid antibiofilm peptide that selectively binds to the nucleotide (p)ppGpp inhibiting bacterial function |
| Lipoxin A4 | |||
| [72] | LXA4 | No/no | A metabolite of arachidonic acid that stimulates the bacteria-killing capacity of leukocytes, inhibit neutrophil infiltration and pro-inflammatory cytokine and chemokine production via inhibition of NF-κB and activator protein 1 |
| Cytokine IL-35 targeted therapies | |||
| [73] | Recombinant human IL-35 | No/no | An anti-inflammatory cytokine that induces regulatory T and B lymphocytes |
| Melanocortin 1 receptor agonists | |||
| [74] | BMS-470539 | No/no | A small molecule that acts as a selective agonist of the melanocortin 1 receptor promoting downstream signalling |
| COX2 inhibitors | |||
| [45, 75] | Ibuprofen | Yes/yes | A non-steroidal anti-inflammatory that non selectively inhibits COX1 and COX2 to reduce prostaglandin synthesis |
| [53] | Celecoxib | Yes/yes | A non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits COX2 and decreases prostaglandin synthesis |
| Granulocyte colony-stimulating factor | |||
| [76] | Human G-CSF produced by recombinant DNA technology | No/no | An endogenous lipoxygenase-derived eicosanoid mediator that suppresses leukocytes and inhibits production of pro-inflammatory cytokines |
| Colony stimulating factor 1 | |||
| [77] | Rh-CSF1 | No/no | Recombinant human growth factor of CSF1 that leads to the recruitment of CSF1R expressing cells including macrophages, monocytes and dendritic cells |
| Cytokine TNF targeted therapies | |||
| [40, 52, 56] | Etanercept | Yes/yes | A soluble TNF receptor that sequesters TNF to prevent it from interacting with endogenous TNF receptors |
| Cytokine IL-1 targeted therapies | |||
| [38, 39] | Mouse anti- ovine-IL-1β, monoclonal antibodies | No/no | A mouse-anti-ovine IL-1β monoclonal antibody that binds to ovine IL-1β and neutralises inflammation by blocking IL-1β from interacting with the IL-1β receptors |
| [46, 49–51, 55] | Anakinra | Yes/yes | A recombinant human IL-1 receptor antagonist that competitively binds to the IL-1 receptor inhibiting the activity of IL-1α and IL-1β |
| [46] | 101.10 (Rytvela) | No/no | An allosteric IL-1 receptor peptide antagonist that selectively binds to the IL-1 receptor inhibiting the activity of IL-1α and IL-1β |