Potential therapeutic interventions at the cpPME
| Disease . | Pathophysiological issue at cpPME . | Potential CP-targeted therapeutic intervention . | Rationale/mechanism . |
|---|---|---|---|
| MS | Pro-inflammatory myelin antigens via CP to cervical LNs drive autoreactive T cell priming Local cpPME immunosuppression is insufficient to produce tolDCs | TolDC delivery intranasally (to reeducate T cell responses) Intranasal tolDC promotion (IL-10, vitamin D) + increase tolDC egress across CP (VEGF-C) | Reducing antigen efflux could limit autoimmune priming; conversely promoting tolDC efflux can suppress disease Delivery at CP could skew immune responses toward tolerance and increase tolDC in CLNs |
| CNS infection (e.g., meningitis, encephalitis) | Inflammatory debris clearance; waste, fibrin, pathogens Fluid clearance and prevention of edema | Intranasal fibrinolytics (e.g., tPA) to clear CP obstruction; local antimicrobial delivery via nasal route Intranasal VEGF-C, CLN stimulation | Keeps CP drainage pathways open, maintaining CSF clearance; direct drug delivery bypasses BBB Immunomodulation at CP can reduce destructive inflammation while still allowing pathogen clearance and surveillance |
| AD | Impaired clearance of Aβ/tau? Poor CSF outflow → poor immune surveillance of CNS | Enhance CP lymphatic clearance (VEGF-C, intranasal lymphatic activators); intranasally (Aβ-degrading enzymes, neprilysin); CSF-to-nasal dialysis devices (experimental) | Restores Aβ/tau clearance into nasal mucosal lymphatics; intranasal delivery avoids BBB limits; device-assisted clearance could reduce toxic protein accumulation |
| Stroke (ischemic/hemorrhagic) | Stroke triggers release of CNS antigens and DAMPs into CSF; immune activation in cervical LNs can worsen systemic immunosuppression or autoimmunity Clot aggregation at CSF efflux points and increased need of edema clearance | Modulate cpLV drainage (VEGFR-3 blockade/MAZ51) temporary reduction of antigen efflux to LNs during the acute phase Fibrinolytics at CP (in hemorrhagic stroke) to prevent clot-mediated CSF blockage. Targeted VEGF-C delivery | Limiting antigen, DAMP, and cytokine efflux may reduce harmful peripheral inflammation responses after stroke Tolerogenic approaches could prevent poststroke inflammation; fibrin clearance maintains CSF outflow and prevents hydrocephalus |
| Brain cancer (e.g., glioblastoma) | Impaired CSF outflow (edema)? Impaired tumor antigen drainage through CP? Local cpPME immune suppression? | Enhance CP lymphatic drainage (VEGF-C). Nanoparticle antigen delivery via intranasal route Intranasal checkpoint modulators (e.g., PD-L1/PD-1 blockade locally at CP); + TGF-β blockade | Restores or boosts tumor antigen access to cervical LNs → stronger antitumor immunity; improves fluid homeostasis Local immune checkpoint control and TGF-β could prevent tumor-induced tolerogenic niche formation at cpPME, generating pro-inflammatory DCs |
| Disease . | Pathophysiological issue at cpPME . | Potential CP-targeted therapeutic intervention . | Rationale/mechanism . |
|---|---|---|---|
| MS | Pro-inflammatory myelin antigens via CP to cervical LNs drive autoreactive T cell priming Local cpPME immunosuppression is insufficient to produce tolDCs | TolDC delivery intranasally (to reeducate T cell responses) Intranasal tolDC promotion (IL-10, vitamin D) + increase tolDC egress across CP (VEGF-C) | Reducing antigen efflux could limit autoimmune priming; conversely promoting tolDC efflux can suppress disease Delivery at CP could skew immune responses toward tolerance and increase tolDC in CLNs |
| CNS infection (e.g., meningitis, encephalitis) | Inflammatory debris clearance; waste, fibrin, pathogens Fluid clearance and prevention of edema | Intranasal fibrinolytics (e.g., tPA) to clear CP obstruction; local antimicrobial delivery via nasal route Intranasal VEGF-C, CLN stimulation | Keeps CP drainage pathways open, maintaining CSF clearance; direct drug delivery bypasses BBB Immunomodulation at CP can reduce destructive inflammation while still allowing pathogen clearance and surveillance |
| AD | Impaired clearance of Aβ/tau? Poor CSF outflow → poor immune surveillance of CNS | Enhance CP lymphatic clearance (VEGF-C, intranasal lymphatic activators); intranasally (Aβ-degrading enzymes, neprilysin); CSF-to-nasal dialysis devices (experimental) | Restores Aβ/tau clearance into nasal mucosal lymphatics; intranasal delivery avoids BBB limits; device-assisted clearance could reduce toxic protein accumulation |
| Stroke (ischemic/hemorrhagic) | Stroke triggers release of CNS antigens and DAMPs into CSF; immune activation in cervical LNs can worsen systemic immunosuppression or autoimmunity Clot aggregation at CSF efflux points and increased need of edema clearance | Modulate cpLV drainage (VEGFR-3 blockade/MAZ51) temporary reduction of antigen efflux to LNs during the acute phase Fibrinolytics at CP (in hemorrhagic stroke) to prevent clot-mediated CSF blockage. Targeted VEGF-C delivery | Limiting antigen, DAMP, and cytokine efflux may reduce harmful peripheral inflammation responses after stroke Tolerogenic approaches could prevent poststroke inflammation; fibrin clearance maintains CSF outflow and prevents hydrocephalus |
| Brain cancer (e.g., glioblastoma) | Impaired CSF outflow (edema)? Impaired tumor antigen drainage through CP? Local cpPME immune suppression? | Enhance CP lymphatic drainage (VEGF-C). Nanoparticle antigen delivery via intranasal route Intranasal checkpoint modulators (e.g., PD-L1/PD-1 blockade locally at CP); + TGF-β blockade | Restores or boosts tumor antigen access to cervical LNs → stronger antitumor immunity; improves fluid homeostasis Local immune checkpoint control and TGF-β could prevent tumor-induced tolerogenic niche formation at cpPME, generating pro-inflammatory DCs |