Several recent in vivo and in vitro studies indicate that Treg activation, expansion, and/or induction from conventional CD4 + T cells are important components of the MSC-mediated immunomodulation. 19 To date, several phenotypically and functionally distinct induced Treg subsets have been described with the most delineated cell populations, including IL-10 + T regulatory (Tr) 1, TGF-β + T helper (Th) 3, and CD25 +FOXP3 + nTreg-like CD4 + cells. 18 Naturally occurring Tregs are of thymic origin, but it has become apparent that, under various conditions, induced or adaptive forms can be generated extrathymically. 17 Similar to the adoptive transfer of MSCs, administration of Tregs in GVHD patients is currently evaluated within clinical trials. 16 On successful engraftment, frequency of circulating Tregs has been shown to be of diagnostic as well as of prognostic value in GVHD. 11, 13, 15 Tregs are pivotal for the maintenance of self-tolerance and of extraordinary interest for transplantation research because of their capability of controlling autoreactive immune cells. 14, 15 Treg induction is one of the proposed pathways how HO-1 exerts its tolerogenic effects. 12, 13 There are various preclinical transplantation models evaluating HO-1, altogether suggesting beneficial effects with regards to transplantation tolerance and tissue regeneration. 10, 11 This versatility, coupling direct tissue protection with immunosuppression, is of substantial relevance for transplantation immunology, where several aggressive pathologic processes have to be faced simultaneously. 8, 9 Furthermore, HO-1 is a potent cytoprotective enzyme that exerts strong anti-inflammatory, antioxidative, and antiapoptotic activities through its products, especially carbon monoxide and biliverdin. 8 The stress-inducible enzyme heme-oxygenase-1 (HO-1), which catalyzes the rate-limiting step of the heme degradation to biliverdin, has a suppressive effect on T-cell proliferation in human and rat MSCs, which is similar to previous findings in regulatory T cells (Tregs). Recently, a stress-responsive pathway was found to be strongly involved in MSC-mediated T-cell suppression. 1, 3-5 To some degree, it has been implicated that full suppressive activity depends on a so-called proinflammatory “licensing” of MSCs composed of interferon-γ (IFN-γ) in concert with IL-1α, IL-1β, or tumor necrosis factor-α. These multifactorial processes require various contact as well as contact-independent signals, among them prostaglandin E 2 (PGE 2), IL-6, IL-10, indoleamine 2,3 dioxygenase (IDO), and transforming growth factor-β (TGF-β). 2 As yet, several key mechanisms have been described contributing to their direct or indirect alteration of T-, NK-, B-, and dendritic-cell functions. 1 Their regulatory impact on allogeneic immune reactions, such as graft-versus-host disease (GVHD), occurring after bone marrow transplantation makes MSCs an attractive tool of low toxicity for cell-based therapies. Nowadays, it is well established that human MSCs possess a plethora of immunomodulatory properties. Mesenchymal stem cells (MSCs) are a heterogeneous population of fibroblast-like, multipotent cells characterized by their ability to differentiate in vitro and in vivo into tissues of the mesodermal lineage. Taken together, we show that HO-1 produced by human MSCs beyond its direct suppressive function promotes formation of Tr1 and Th3 Tregs and IL-10 production, functions, which are taken over by other molecules, among them COX-2, after an alloreactive priming. Interestingly, HO-1 lost its impact regarding suppressiveness, Treg induction, and promotion of IL-10 production for MSCs, which were prelicensed in an MLR environment. We observed a substantial down-regulation of HO-1 facilitated by yet unidentified soluble factor(s) produced in an MLR, and most probably occurring at the level of its major transcription-factor NF-E2–related factor 2. Because inflammatory stimuli modulate (“license”) human MSCs, we were interested in whether an in vitro alloreactive micro-milieu within mixed lymphocyte reactions (MLRs) alters the HO-1 expression. Human MSCs were shown to induce, in a HO-1–dependent fashion, IL-10 + Tr1 and transforming growth factor-β + Th3 Treg-subsets in allo- and T-cell receptor-activated lymphocytes. As HO-1 has also been implicated in the induction of regulatory T cells (Tregs), we sought to examine its impact on MSC-driven promotion of Tregs. The stress-responsive, cytoprotective, and immunoregulatory molecule heme oxygenase-1 (HO-1) was recently identified as a key contributor for MSC-mediated suppression of alloactivated T cells. Mesenchymal stem cells (MSCs) are characterized by their manifold immunomodulatory and regenerative properties.
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