title: Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses.
abstract: Infusion of human third-party mesenchymal stromal cells (MSCs) appears to be a promising therapy for acute graft-versus-host disease (aGvHD). To date, little is known about how MSCs interact with the body's innate immune system after clinical infusion. This study shows, that exposure of MSCs to blood type ABO-matched human blood activates the complement system, which triggers complement-mediated lymphoid and myeloid effector cell activation in blood. We found deposition of complement component C3-derived fragments iC3b and C3dg on MSCs and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. MSCs bound low amounts of immunoglobulins and lacked expression of complement regulatory proteins MCP (CD46) and DAF (CD55), but were protected from complement lysis via expression of protectin (CD59). Cell-surface-opsonization and anaphylatoxin-formation triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation in blood. The complement-activating properties of individual MSCs were furthermore correlated with their potency to inhibit PBMC-proliferation in vitro, and both effector cell activation and the immunosuppressive effect could be blocked either by using complement inhibitor Compstatin or by depletion of CD14/CD11b-high myeloid effector cells from mixed lymphocyte reactions. Our study demonstrates for the first time a major role of the complement system in governing the immunomodulatory activity of MSCs and elucidates how complement activation mediates the interaction with other immune cells.
authors: Department of Laboratory Medicine, Clinical Immunology and Transfusion Medicine, Karolinska Institutet and Hematology Center at Karolinska University Hospital Huddinge, Stockholm, Sweden. guido.moll@ki.se
authors: Guido
authors: G
authors: Moll
authors: Regina
authors: R
authors: Jitschin
authors: Lena
authors: L
authors: von Bahr
authors: Ida
authors: I
authors: Rasmusson-Duprez
authors: Berit
authors: B
authors: Sundberg
authors: Lena
authors: L
authors: Lönnies
authors: Graciela
authors: G
authors: Elgue
authors: Kristina
authors: K
authors: Nilsson-Ekdahl
authors: Dimitrios
authors: D
authors: Mougiakakos
authors: John D
authors: JD
authors: Lambris
authors: Olle
authors: O
authors: Ringdén
authors: Katarina
authors: K
authors: Le Blanc
authors: Bo
authors: B
authors: Nilsson
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008648:Mesoderm / Q000166:cytology*; D011951:Receptors, Complement / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D011951:Receptors, Complement; D003165:Complement System Proteins