Exo-D-Mapps Attenuates Production of Inflammatory Cytokines and Promoted Generation of Immunosuppressive Phenotype in Peripheral Blood Mononuclear Cells

Abstract

Mesenchymal stem cells (MSCs) produce immunomodulatory factors that regulate production of cytokines and chemokines in immune cells affecting their functional properties. Administration of MSCs-sourced secretome, including MSC-derived conditioned medium (MSC-CM) and MSC-derived exosomes (MSC-Exos), showed beneficial effects similar to those observed after transplantation of MSCs. Due to their nano-size dimension, MSC-Exos easily penetrate through the tissue and in paracrine and endocrine manner, may deliver MSC-sourced factors to the target immune cells modulating their function. MSCs derived from amniotic fluid (AF-MSCs) had superior cell biological properties than MSCs derived from bone marrow. We recently developed “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling (Exo-d-MAPPS)”, a biological product in which the activity is based on AF-MSC-derived Exos capable to deliver immunomodulatory molecules and growth factors to the target cells. Herewith, we analyzed immunosuppressive capacity of Exo-d-MAPPS against human peripheral blood mononuclear cells (pbMNCs) and demonstrated that Exo-d-MAPPS efficiently suppressed generation of inflammatory phenotype in activated pbMNCs. Exo-d-MAPPS attenuated production of inflammatory cytokines and promoted generation of immunosuppressive phenotype in Lipopolysaccharide-primed pbMNCs. Exo-d-MAPPS treatment reduced expansion of inflammatory Th1 and Th17 cells and promoted generation of immunosuppressive T regulatory cells in the population of Concanavalin A-primed pbMNCs. Similarly, Exod-MAPPS treatment suppressed pro-inflammatory and promoted anti-inflammatory properties of α-GalCer-primed pbMNCs. In summing up, due to its capacity for suppression of activated pbMNCs, Exo-d-MAPPS should be further explored in animal models of acute and chronic inflammatory diseases as a poten-tially new remedy for the attenuation of detrimental immune response.

Therapeutic Potential of „Derived-Multiple Allogeneic Proteins Paracrine Signaling-D-Mapps” in the Treatment of Dry Eye Disease

“…In similar manner as Th1 cells, effector Th17 cells promote corneal epithelial barrier disruption through the enhanced production of IL-17 [15]. Since d-MAPPS efficiently attenuated production of IL-17 in activated CD4+ T helper cells [19], we assume that d-MAPPSinduced suppression of Th17 cell-driven inflammation in the eye was, at least partially, responsible for beneficial effects of d-MAPPS eye drops in DED patients.…”

“…Th1 cell-derived IFN-γ promote apoptosis and squamous metaplasia of the ocular surface epithelia while M1 macrophage-derived matrix metalloproteinases (MMPs) and inflammatory mediators (tumor necrosis factor alpha (TNF-α) and nitric oxide) disrupt epithelial cell barriers [15,18]. We recently demonstrated that d-MAPPS significantly attenuated concentration of IL-12 in the supernatants of activated human peripheral blood mononuclear cells (pbMNCs) and alleviate production of IFN-γ in activated lymphocytes [19]. d-MAPPS contains large number of immunoregulatory factors which are capable to suppress detrimental T cell-driven immune response [10].…”

Therapeutic Potential of d-MAPPS™ for Ocular Inflammatory Diseases and Regeneration of Injured Corneal and Retinal Tissue

“…d-MAPPS™ containing sTNFRI and sTNFRII binds to the TNF-α and prevent the TNF-α-dependent over-expression of E and P selectins on EC, crucially contributing to the reduced recruitment of circulating monocytes and lymphocytes in the uvea of d-MAPPS™-treated eyes [ 11 , 16 ]. Significantly attenuated concentrations of IL-12 and IFN-γ were observed in the supernatants of d-MAPPS™-treated monocytes and lymphocytes [ 12 ]. d-MAPPS™ containing GRO-γ is able to suppress DCs:T cell cross-talk and efficiently inhibits the DC-dependent generation of inflammatory Th1 cells [ 12 ].…”

“…Significantly attenuated concentrations of IL-12 and IFN-γ were observed in the supernatants of d-MAPPS™-treated monocytes and lymphocytes [ 12 ]. d-MAPPS™ containing GRO-γ is able to suppress DCs:T cell cross-talk and efficiently inhibits the DC-dependent generation of inflammatory Th1 cells [ 12 ]. GRO-γ-treated DCs had a tolerogenic phenotype characterized by the increased secretion of immunosuppressive IL-10, and reduced the production of inflammatory cytokines IL-12, IL-23, IFN-γ, and TNF-α [ 12 ].…”

“…In line with these observations, we recently developed “derived- Multiple Allogeneic Proteins Paracrine Signaling d-MAPPS™ regenerative biologics platform technology”, which is a bioengineered biological product derived from human amniotic fluid (AF), manufactured under current Good Manufacturing Practices (cGMP), regulated and reviewed by the Food and Drug Administration (FDA) [ 11 ]. The therapeutic potential of d-MAPPS™ in the treatment of inflammatory eye diseases and in corneal regeneration has been documented in several in vitro studies and pilot clinical trials, indicating that it could be considered a new therapeutic agent in regenerative ophthalmology [ 11 , 12 , 13 , 14 , 15 , 16 ]. Herewith, we emphasized the molecular mechanisms responsible for the therapeutic efficacy of d-MAPPS™ and present the main beneficial effects of d-MAPPS™ which have been observed in clinical settings.…”