ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/metabolism , Bacteria/growth & development , Cytomegalovirus/growth & development , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mesenchymal Stem Cells/physiology , Multipotent Stem Cells/physiology , Stromal Cells/physiology , Toxoplasma/growth & development , Animals , Antiviral Agents/pharmacology , Bacteria/drug effects , Cells, Cultured , Cytokines/immunology , Cytokines/metabolism , Cytomegalovirus/drug effects , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/metabolism , Cytomegalovirus Infections/virology , Humans , Immune Tolerance , Immunosuppression Therapy , Interferon-gamma/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Toxoplasma/drug effects , Toxoplasmosis/immunology , Toxoplasmosis/metabolism , Toxoplasmosis/parasitologyABSTRACT
BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein (IAP) family is transiently expressed at low levels during normal hematopoesis but profoundly overexpressed in adult leukemia potentially contributing to leukemogenesis due to deregulated apoptosis and defective cell cycle control. Alternative splicing results in four different mRNA variants survivin, survivin2B, survivin-DeltaExon3 and survivin-3B, with distinct cellular localization patterns and anti-apoptotic potential. Due to co-localization of survivin and survivin-2B in the cytoplasm survivin-2B may permit interactive fine-tuning of survivin actions and moreover play an attenuating role in its anti-apoptotic function. Lack of survivin-2B is associated with disease progression of malignomas suggesting a differential role of these isoforms in tumorigenesis. PATIENTS AND METHODS: We therefore determined the expression of the functional survivin splice variants performing RT- and real-time PCR in a purely pediatric cohort of 20 patients suffering from precursor B-ALL (BCP-ALL). RESULTS: Here, we demonstrate for the first time in pediatric patients with precursor B-ALL an association between lower survivin-2B expression and affiliation to the high risk group. CONCLUSION: The idea that survivin-2B may act as natural antagonist of survivin could potentially be used in novel approaches of anti-cancer treatment by influencing the proportional expression of the different splice variants.
