Article

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

Department of Immunobiology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom
The Journal of Immunology (Impact Factor: 5.36). 04/2013; 190(9). DOI: 10.4049/jimmunol.1202710
Source: PubMed

ABSTRACT A major goal of immunotherapy remains the control of pathogenic T cell responses that drive autoimmunity and allograft rejection. Adherent progenitor cells, including mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs), represent attractive immunomodulatory cell therapy candidates currently active in clinical trials. MAPCs can be distinguished from MSCs on the basis of cellular phenotype, size, transcriptional profile, and expansion capacity. However, despite their ongoing evaluation in autoimmune and allogeneic solid organ transplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited. In this study, we used allogeneic islet transplantation as a model indication to assess the ability of clinical-grade MAPCs to control T cell responses that drive immunopathology in human autoimmune disease and allograft rejection. MAPCs suppressed T cell proliferation and Th1 and Th17 cytokine production while increasing secretion of IL-10 and were able to suppress effector functions of bona fide autoreactive T cells from individuals with type 1 diabetes mellitus, including killing of human islets. Furthermore, MAPCs favored the proliferation of regulatory T cells during homeostatic expansion driven by γ-chain cytokines and exerted a durable, yet reversible, control of T cell function. MAPC suppression required licensing and proceeded via IDO-mediated tryptophan catabolism. Therefore, the common immune modulatory characteristics of clinical-grade MAPCs shown in this study suggest that they can be regarded as an alternative source of adult progenitor cells with similar clinical usefulness to MSCs. Taken collectively, these findings may guide the successful deployment of both MSCs and MAPCs for the amelioration of human autoimmunity and allograft rejection.

Full-text

Available from: Ania Skowera, Feb 17, 2015

Click to see the full-text of:

Article: Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

2.14 MB

See full-text
0 Bookmarks
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ongoing research is constantly looking for means to modulate the immune system for long-lasting engraftment of pluripotent stem cells (PSC) during stem cell-based therapies. This study reviews data on in-vitro and in-vivo immunogenicity of embryonic and induced-PSC and describes how their immunological properties can be harnessed for tolerance induction in organ transplantation. Although PSC display immunomodulatory properties in vitro, they are capable of eliciting an immune response that leads to cell rejection when transplanted into immune-competent recipients. Nevertheless, long-term acceptance of PSC-derived cells/tissues in an allogeneic environment can be achieved using minimal host conditioning. Protocols for differentiating PSC towards haematopoietic stem cells, thymic epithelial precursors, dendritic cells, regulatory T cells and myeloid-derived suppressor cells are being developed, suggesting the possibility to use PSC-derived immunomodulatory cells to induce tolerance to a solid organ transplant. PSC and/or their derivatives possess unique immunological properties that allow for acceptance of PSC-derived tissue with minimal host conditioning. Investigators involved either in regenerative or in transplant medicine must join their efforts with the ultimate aim of using PSC as a source of donor-specific cells that would create a protolerogenic environment to achieve tolerance in solid organ transplantation.
    Current Opinion in Organ Transplantation 12/2014; 20(1). DOI:10.1097/MOT.0000000000000144 · 2.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Our laboratory utilized biomimicry to develop a synthetic bone scaffold based on hydroxyapatite-gelatin-calcium silicate (HGCS). Here, we evaluated the potential of HGCS scaffold in bone formation in vivo using the rat calvarial critical-sized defect (CSD). Twelve Sprague-Dawley rats were randomized to four groups: control (defect only), decellularized bone matrix (DECBM), and HGCS with and without multipotent adult progenitor cells (MAPCs). DECBM was prepared by removing all the cells using SDS and NH4OH. After 12 weeks, the CSD specimens were harvested to evaluate radiographical, histological, and histomorphometrical outcomes. The in vitro osteogenic effects of the materials were studied by focal adhesion, MTS, and alizarin red. Micro-CT analysis indicated that the DECBM and the HGCS scaffold groups developed greater radiopaque areas than the other groups. Bone regeneration, assessed using histological analysis and fluorochrome labeling, was the highest in the HGCS scaffold seeded with MAPCs. The DECBM group showed limited osteoinductivity, causing a gap between the implant and host tissue. The group grafted with HGCS+MAPCs resulting in twice as much new bone formation seems to indicate a role for effective bone regeneration. In conclusion, the novel HGCS scaffold could improve bone regeneration and is a promising carrier for stem cell-mediated bone regeneration.
    BioMed Research International 06/2014; 2014:837524. DOI:10.1155/2014/837524 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims/hypothesis Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes. Methods MVs were purified from heterologous human MSCs by differential centrifugation. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with type 1 diabetes at disease onset, and responses to GAD65 stimulation were assessed by IFN-gamma enzyme-linked immunosorbent spot analysis. Levels of cytokines and prostaglandin E-2 (PGE(2)) were measured in the supernatant fraction, and T helper 17 (Th17) and regulatory T cell analysis was performed. Results MVs were internalised by PBMCs, as assessed by confocal microscopy and flow cytometry analyses. MVs significantly decreased IFN-gamma spots and levels in GAD65-stimulated PBMCs, and significantly increased transforming growth factor-beta (TGF-beta), IL-10, IL-6 and PGE(2) levels. Furthermore, MVs decreased the number of Th17 cells and the levels of IL-17, and increased FoxP3(+) regulatory T cells in GAD65-stimulated PBMCs. Conclusions/interpretation These results provide evidence that MSC-derived MVs can inhibit in vitro a proinflammatory response to an islet antigenic stimulus in type 1 diabetes. The action of MVs involves PGE(2) and TGF-beta signalling pathways and IL-10 secretion, suggesting a switch to an anti-inflammatory response of T cells.
    Diabetologia 05/2014; 57(8). DOI:10.1007/s00125-014-3262-4 · 6.88 Impact Factor