Autoantigen-specific immunosuppression with tolerogenic peripheral blood cells prevents relapses in a mouse model of relapsing-remitting multiple sclerosis

Abstract

BackgroundDendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease.MethodsWe replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone®), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone®, incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of 111Indium-labelled MICCop. The number and inhibitory activity of CD4+CD25+FoxP3+ regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay.ResultsMICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4+CD25+FoxP3+ cells displaying a suppressive cytokine profile and inhibiting T-cell responses.ConclusionWe describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response.

A Tolerogenic Artificial APC Durably Ameliorates Experimental Autoimmune Encephalomyelitis by Directly and Selectively Modulating Myelin Peptide–Autoreactive CD4+ and CD8+ T Cells

“…Thus, recently, increasing attentions have shifted toward the autoantigen-specific immunotherapy. Numerous strategies have been demonstrated in the treatment of EAE or MS, such as the soluble myelin peptide immunotherapy including glatiramer acetate, mixture of MBP 85-99 , PLP 139-151 and myelin oligodendrocyte glycoprotein (MOG) (17), and altered peptide ligand (18); soluble autoantigen arrays (SAgAs) like codelivery of PLP 139-151 and regulatory molecules by hyaluronic acid polymer chain (19,20); myelin Ag-decorated apoptotic dendritic cells (DCs) (21) or spleen cells (22); myelin protein or peptide-decorated or encapsulated polystyrene or polylactic-coglycolic acid (PLGA) particles (23)(24)(25); and recombinant TCR ligand-like RTL1000, a recombinant fusion protein of HLA-DR2-ɑ1b1-hMOG used in MS clinical trials (26). However, most of these modulators act in a semi or indirect Ag-specific manner to induce autoantigen-specific suppression and tolerance.…”

Immunsuppressive Wirkung von Mitomycin-C-behandelten mononukleären Zellen des peripheren Blutes (MICs) in der Vaskularisierten Composite Allotransplantation

“…In vorherigen Tierversuchen hat sich dies jedoch nicht bestätigt. Werden PBMCs beispielsweise über UV-Bestrahlung apoptotisch gemacht, üben sie keine immunsuppressive Wirkung aus [32]. Des Weiteren führt die Inkubation mit MMC zu einer verminderten Expression der ko-stimulatorischen Moleküle CD80, CD86 und ICAM-1 [26].…”

Vitamin D Deficiency and Rheumatoid Arthritis

“…Background RA treatment usually consists of combined therapies that suppress the entire immune response, leading to increased susceptibility to a plethora of infections. In this sense, many efforts are made to develop more specific immunomodulatory strategies as, for example, the induction of antigen-specific tolerance [86][87][88]. Self-tolerance can be induced by different procedures such as self-antigen administration via tolerogenic routes (oral mucosa, for example), concomitant blocking of co-stimulatory molecules, or self-antigen targeting to resting antigen-presenting cells, such as DCs [89].…”