Immune Checkpoint Ligand Bioengineered Schwann Cells as Antigen‐Specific Therapy for Experimental Autoimmune Encephalomyelitis

Abstract

disorder multiple sclerosis (MS), which disrupts communication between the brain and peripheral system. [4,6] At least 2.5 million people worldwide are affected by MS. Most patients initially experience episodes of reversible neurological deficits, followed by remission, before chronic neurological deterioration leads to severe, irreversible disabilities. [6] Unfortunately, MS cannot be completely cured, although available immunomodulatory therapies reduce the frequency and severity of MS relapses by inducing antigen-specific immunotolerance, [7] thus delaying the accumulation of disabilities. New treatment strategies involve the induction of antigen-specific T reg cells [8,9] that suppress inflammatory pathogens and restore peripheral immunotolerance without causing systemic immunosuppression.Immune checkpoints play key roles in maintaining immunotolerance. [10] For example, studies have found that coinhibitory immune checkpoint pathways such as programmed death 1 (PD-1)-PD ligand 1 (PD-L1), [10,11] and cytotoxic T lymphocyte associated protein 4 (CTLA-4)-cluster of differentiation 86 (CD86) [10,12] directly regulate the development and maintenance of myelin-specific induced T reg cells. [13] Here, we aimed to determine whether the intravenous (i.v.) administration of coinhibitory immune checkpoint ligand-bioengineered glia can be used as a prophylactic treatment to prevent the development of MS or use in therapeutic Failure to establish immune tolerance leads to the development of autoimmune disease. The ability to regulate autoreactive T cells without inducing systemic immunosuppression represents a major challenge in the development of new strategies to treat autoimmune disease. Here, a translational method for bioengineering programmed death-ligand 1 (PD-L1)-and cluster of differentiation 86 (CD86)-functionalized mouse Schwann cells (SCs) to prevent and ameliorate multiple sclerosis (MS) in established mouse models of chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is described. It is shown that the intravenous (i.v.) administration of immune checkpoint ligand functionalized mouse SCs modifies the course of disease and ameliorates EAE. Further, it is found that such bioengineered mouse SCs inhibit the differentiation of myelin-specific helper T cells into pathogenic T helper type-1 (T h 1) and type-17 (T h 17) cells, promote the development of tolerogenic myelin-specific regulatory T (T reg ) cells, and resolve inflammatory central nervous system microenvironments without inducing systemic immunosuppression.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.202107392.

An injectable subcutaneous colon-specific immune niche for the treatment of ulcerative colitis

“…Immunosuppressive molecule-functionalized nanofibers were engineered to simultaneously anergize autoreactive T cells and polarize macrophages through multiple immunosuppressive signaling pathways by incorporating immune checkpoint molecules and other immunosuppressants. These included programmed death-ligand 1 (PD-L1), which triggers the suppressive PD-1/PD-L1 immune checkpoint pathway [24][25][26] and induces the polarization of classically-activated M1 macrophages into alternatively-activated M2 macrophages 27 ; cluster of differentiation 86 (CD86), which triggers the immunosuppressive cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway in activated CD8 + T cells 25,26,28 ; immunomodulatory drug leflunomide which inhibits activated T cell and macrophage proliferation 29,30 ; and a pro-regulatory cytokine transforming growth factor-beta 1 (TGF-β1) mimetic peptide, which binds to the transforming growth factor-beta receptor II receptor to suppress the activation of CD8 + T cells 31,32 and polarize classically-activated M1 macrophages to alternatively-activated M2 macrophages 33,34 .…”

“…PD-L1 and CD86 mono-and dualfunctionalized nanofibers and leflunomide encapsulated nanofibers were prepared from dibenzocyclooctyne functionalized nanofibers by strain-promoted azide-alkyne cycloaddition with the corresponding azide-functionalized immune checkpoint ligands (Supplementary Fig. 7-9) and azide-functionalized leflunomide-encapsulated poly(ethylene glycol)-poly(lactide-co-glycolide) nanoparticles 25,26 (Supplementary Fig. 10).…”

An Injectable Subcutaneous Colon-Specific Immune Niche For The Treatment Of Ulcerative Colitis

“…PD-L1 and CD86 mono- and dual-functionalized nanofibers and leflunomide encapsulated nanofibers were prepared from dibenzocyclooctyne functionalized nanofibers by strain-promoted azide-alkyne cycloaddition with the corresponding azide-functionalized immune checkpoint ligands (Supplementary Fig. 7-9) and azide-functionalized leflunomide-encapsulated poly(ethylene glycol)-poly(lactide-co-glycolide) nanoparticles 25, 26 (Supplementary Fig. 10).…”

“…PD-L1-, CD86-, and PD-L1/CD86- functionalized nanofibers (PD-L1 NFs, CD86 NFs, and PD-L1/CD86 NFs) were prepared via stain-promoted 1,3-dipolar cycloaddition as previously reported 26 . The target degree of functionalization for mono-functionalized NFs was 10 μg of azide-functionalized PD-L1-Ig or CD86-Ig (mono-functionalized nanofibers) per 1 mg of DBCO-functionalized nanofibers.…”

“…Leflunomide-encapsulated nanofibers (LEF NFs) were fabricated via stain-promoted 1,3-dipolar cycloaddition as previously reported 26 . The target degree of functionalization was 200 µg of azide-functionalized leflunomide-encapsulated nanoparticles per milligram of dibenzocyclooctyne-functionalized NFs.…”