ena-STUDY-EMBL-08-03-2018-08:37:34:472-74
Myeloid-derived suppressor cell exosomes have significant immunoregulatory effects in autoimmune disease as exemplified in mouse alopecia areata
The therapy of autoimmune diseases still poses a major challenge, frequently relying on non-specific immunosuppressive drugs. Ongoing efforts aim reestablishing self tolerance by har-nessing immune cells with suppressive activity as regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). We described in a mouse Alopecia Areata (AA) model therapeutic efficacy of MDSC. Keeping the AA model, we now asked whether MDSC exosomes (MDSC-Exo) can replace MDSC. MDSC-Exo from bone marrow cells (BMC)-derived MDSC of healthy donors could substantially facilitate treatment. Knowledge on MDSC-Exo being limited, the question on their suitability had to be answered in advance.Protein marker profiles pointed towards comparability of BMC- to ex vivo collected inflam-matory MDSC / MDSC-Exo of mice with a chronic contact dermatitis. Proteome analyses substantiated a large overlap of function-relevant molecules in MDSC versus MDSC-Exo. Furthermore, MDSC-Exo are uptaken by T cells, macrophages, NK and most avidly Treg, MDSC-Exo uptake exceeding binding of MDSC. In AA mice, MDSC-Exo preferentially tar-get skin-draining lymph nodes and cells in the vicinity of remnant hair follicles. MDSC-Exo uptake is accompanied by a strong increase in Treg, reduced T helper proliferation, mitigated cytotoxic activity and slightly increased lymphocyte apoptosis. Repeated MDSC-Exo appli-cation in florid AA prevented progression and sufficed for partial hair regrowth. Deep sequencing of lymphocyte mRNA from these mice showed a significant increase in immu-noregulatory mRNA, including FoxP3 and arginase 1. Downregulated mRNA preferentially was engaged in prohibiting T cell hyperreactivity.Taken together, proteome analysis provided important insights into potential MDSC-Exo activities that with high preference home to AA-affected organs. Most importantly, changes in leukocyte mRNA after repeated treatment of AA mice with MDSC-Exo sustainably supported the strong impact on the adaptive and the non-adaptive immune system, with Treg expansion being a dominant feature. Thus, MDSC-Exo could well serve as therapeutic in AA and other autoimmune diseases.
The therapy of autoimmune diseases still poses a major challenge, frequently relying on non-specific immunosuppressive drugs. Ongoing efforts aim reestablishing self tolerance by har-nessing immune cells with suppressive activity as regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). We described in a mouse Alopecia Areata (AA) model therapeutic efficacy of MDSC. Keeping the AA model, we now asked whether MDSC exosomes (MDSC-Exo) can replace MDSC. MDSC-Exo from bone marrow cells (BMC)-derived MDSC of healthy donors could substantially facilitate treatment. Knowledge on MDSC-Exo being limited, the question on their suitability had to be answered in advance.Protein marker profiles pointed towards comparability of BMC- to ex vivo collected inflam-matory MDSC / MDSC-Exo of mice with a chronic contact dermatitis. Proteome analyses substantiated a large overlap of function-relevant molecules in MDSC versus MDSC-Exo. Furthermore, MDSC-Exo are uptaken by T cells, macrophages, NK and most avidly Treg, MDSC-Exo uptake exceeding binding of MDSC. In AA mice, MDSC-Exo preferentially tar-get skin-draining lymph nodes and cells in the vicinity of remnant hair follicles. MDSC-Exo uptake is accompanied by a strong increase in Treg, reduced T helper proliferation, mitigated cytotoxic activity and slightly increased lymphocyte apoptosis. Repeated MDSC-Exo appli-cation in florid AA prevented progression and sufficed for partial hair regrowth. Deep sequencing of lymphocyte mRNA from these mice showed a significant increase in immu-noregulatory mRNA, including FoxP3 and arginase 1. Downregulated mRNA preferentially was engaged in prohibiting T cell hyperreactivity.Taken together, proteome analysis provided important insights into potential MDSC-Exo activities that with high preference home to AA-affected organs. Most importantly, changes in leukocyte mRNA after repeated treatment of AA mice with MDSC-Exo sustainably supported the strong impact on the adaptive and the non-adaptive immune system, with Treg expansion being a dominant feature. Thus, MDSC-Exo could well serve as therapeutic in AA and other autoimmune diseases.