Treatment of Experimental Autoimmune Encephalomyelitis by Codelivery of Disease Associated Peptide and Dexamethasone in Acetalated Dextran Microparticles

Abstract

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that can cause loss of motor function and is thought to result, in part, from chronic inflammation due to an antigen-specific T cell immune response. Current treatments suppress the immune system without antigen specificity, increasing the risks of cancer, chronic infection, and other long-term side effects. In this study, we show treatment of experimental autoimmune encephalomyelitis (EAE), a model of MS, by coencapsulating the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) with dexamethasone (DXM) into acetalated dextran (Ac-DEX) microparticles (DXM/MOG/MPs) and administering the microparticles subcutaneously. The clinical score of the mice was reduced from 3.4 to 1.6 after 3 injections 3 days apart with the coencapsulated microparticulate formulation (MOG 17.6 μg and DXM 8 μg). This change in clinical score was significantly greater than observed with phosphate-buffered saline (PBS), empty MPs, free DXM and MOG, DXM/MPs, and MOG/MPs. Additionally, treatment with DXM/MOG/MPs significantly inhibited disease-associated cytokine (e.g., IL-17, GM-CSF) expression in splenocytes isolated in treated mice. Here we show a promising approach for the therapeutic treatment of MS using a polymer-based microparticle delivery platform.

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

“…Moreover, IL10-PLGA had no protective effect in any protocol, which is in accordance with previous data from Cannella et al showing that treatment with IL-10 does not protect from EAE [33]. These results are in line with those recently reported by Peine et al showing effectiveness of EAE treatment by codelivery of MOG and dexamethasone in acetalated dextran microparticles [34]. Therefore, delivery of the autoantigen together with immunosuppressive agents, such as IL-10 or dexamethasone, is crucial to suppress the autoimmune response.…”

“…Our data do not support the possibility that the protective effect was mediated by CD4 + CD25 + FoxP3 + T REG cells since their numbers were similar in the spleens of mice treated with blank-PLGA and those treated with IL-10-PLGA plus MOG-PLGA (data not shown). This is in line with other reports [34], but it does not rule out the involvement of other populations of regulatory cells or CD4 + CD25 + FoxP3 + T REG cells compartimentalized in other tissues [36,37].…”

Co-delivery of autoantigen and dexamethasone in incomplete Freund's adjuvant ameliorates experimental autoimmune encephalomyelitis

“…Our lab has verified these results in a screen of eleven immunomodulators in antigen-specific splenocytes obtained from EAE mice, and determined that DEX was capable of suppressing pro-inflammatory Th1-related cytokines, increasing regulatory cytokines, and decreasing the overall T-cell response [31]. Other groups have tested the co-administration or co-delivery of DEX and autoantigen in animal models of autoimmunity with successful outcomes [9, 37]. …”

Engineering Biomaterials to Direct Innate Immunity

“…[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance. [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance.…”

“…[90,91] DCs isolated from mice and treated with these particles after stimulation with LPS in culture expressed lower levels of inflammatory cytokines IL-6 and IL-12, increased regulatory cytokine IL-10, and induced less proliferation and inflammatory cytokine secretion by antigen-specific mouse T cells. Other studies have employed polymeric carriers, such as PLGA and dextran, to co-deliver disease relevant antigen with known regulatory signals such as rapamycin, [92,96,97,101,105] IL-10, [89] dexamethasone, [93] and TGF-β. [91] When these particles were tested in cells from human patients, particle treated DCs similarly expressed lower levels of activation markers and reduced polarization of T cells toward inflammation.…”