Table 1 Immune checkpoint-based immunotherapies in EAE models

PD-1

PD-L1^high DC

Gene-modified DC: It reduced T-cell response to MOG, cell infiltration into the spinal cord, and EAE severity.

5-aza-treated DC: It inhibited CD4⁺ T cell proliferation and cytokine secretion, inflammatory cell infiltration, CNS demyelination, and EAE progression.

E3-treated DC: It protected against developing EAE through immune deviation to a Th2 response.

1,25(OH)₂D₃-treated DC: It enhanced PD-1 expression of spleen and lymph node T cells and alleviated the clinical symptoms of EAE.

[55, 58,59,60]

PD-L1-knocked out DC

The treatment enhanced the recruitment of regulatory CD8⁺ T cells to the CNS and EAE amelioration.

[61]

PD-L1 ^high Treg cell

The treatment inhibited EAE in a FoxA1-and PD-L1-dependent manner.

[62]

PD-L1 ^high Breg cell

The treatment protected against the development and severity of MOG-induced EAE and diminished the release of inflammatory cytokines IFN-γ and IL-17.

[63]

IL-12

The treatment inhibited EAE by upregulating PD-L1 on CD11b⁺ APCs via an IFN-γ-dependent manner.

[64]

MIS416

The treatment prevented EAE via IFN-γ-dependent expansion of PD-L1-expressing peripheral myeloid cells.

[65]

PD-L1 Ig fusion protein

The treatment led to long-lasting amelioration in the severity of EAE by inhibiting the development of Th17 cells and the ROR-γt as well as IRF4.

[67]

CTLA-4

CTLA-4-Fc

The treatment resulted in significant recovery after an acute episode, EAE relapses, and full clinical remission while having no notable impact on the rate of EAE relapse.

The treatment also protected against EAE through anti-inflammatory effects and prevented demyelination or axonal loss.

[68, 69]

dNP2-ctCTLA-4

The treatment led to decreased Th1 and Th17 cell infiltration to the CNS and demyelination.

The treatment also led to EAE remission with long-term control and prevention of relapse through expansion of Foxp3+ Tregs, Foxp3 expression during Th1 or Th17 cell differentiation, and CTLA-4 expression.

[70, 71]

B7-1 Ig

The treatment ameliorated EAE through the development of naïve MBP-specific Th precursor cells via the Th2 pathway.

[72]

CD40

Anti-CD40L Ab

The treatment at either the peak of acute EAE or during remission inhibited clinical disease progression and CNS inflammation by suppressing Th1 differentiation and effector function, IFN-γ release, myelin peptide-specific delayed-type hypersensitivity responses, as well as inducing encephalitogenic effector cells.

The treatment also mitigated EAE severity by regulating IL-10- and IL-35-producing Foxp3⁺ Treg cells.

[73, 74]

KGYY₆

The treatment prevented the progression of the disease and alleviated symptoms through binding to Th40 and memory T cells and upregulating the expression of CD69 and IL-10 in the CD4⁺ T cell compartment.

[75]

CD137

Agonistic anti-CD137 Ab

The treatment reduced EAE incidence and severity through suppression of IFN-γ-releasing CD8⁺ T cells, Th17 cells, and related pathogenic IL-17 release while raising Foxp3⁺ CD4⁺ Treg cell frequency in an IFN-γ-independent manner. Even though, this was only effective when administered during the disease induction phase.

[76, 77]

CD137L knockout

The treatment protected against demyelination and the development of EAE by restricting encephalitogenic T cell activation and inflammatory cytokine release, as well as their trafficking into the CNS by downregulating VCAM-1.

[78]