Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase.
Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.
Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany. meisel@med.uni-duesseldorf.de
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R
Meisel
S
S
Brockers
K
K
Heseler
O
O
Degistirici
H
H
Bülle
C
C
Woite
S
S
Stuhlsatz
W
W
Schwippert
M
M
Jäger
R
R
Sorg
R
R
Henschler
J
J
Seissler
D
D
Dilloo
W
W
Däubener
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology*; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development*; D014123:Toxoplasmosis / Q000276:immunology / Q000378:metabolism / Q000469:parasitology
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II