Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells

Abstract

To cite this article: Kavanagh H, Mahon BP. Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy 2011; 66: 523–531. Abstract Background: Adult bone marrow‐derived mesenchymal stem cells (MSC) possess potent immune modulatory effects which support their possible use as a therapy for immune‐mediated disease. MSC induce regulatory T cells (Treg) in vitro although the in vivo relevance of this is not clear. Objective: This study addressed the hypothesis that adult bone marrow derived‐MSC would prevent the pathology associated with allergen‐driven airway inflammation, and sought to define the effector mechanism. Methods: The influence of allogeneic MSC was examined in a model system where Treg induction is essential to prevent pathology. This was tested using a combination of a model of ovalbumin‐driven inflammation with allogeneic MSC cell therapy. Results: Systemic administration of allogeneic MSC protected the airways from allergen‐induced pathology, reducing airway inflammation and allergen‐specific IgE. MSC were not globally suppressive but induced CD4+FoxP3+ T cells and modulated cell‐mediated responses at a local and systemic level, decreasing IL‐4 but increasing IL‐10 in bronchial fluid and from allergen re‐stimulated splenocytes. Moderate dose cyclophosphamide protocols were used to differentially ablate Treg responses; under these conditions the major beneficial effect of MSC therapy was lost, suggesting induction of Treg as the key mechanism of action by MSC in this model. In spite of the elimination of Treg, a significant reduction in airway eosinophilia persisted in those treated with MSC. Conclusion: These data demonstrate that MSC induce Tregin vivo and reduce allergen‐driven pathology. Multiple Treg dependent and independent mechanisms of therapeutic action are employed by MSC.

Allogeneic mesenchymal stem cells: Agents of immune modulation

“…The differentiation of CD4 þ T cells to specific subsets is also influenced by MSC; with the mesenchymal cell skewing T cell responses towards regulatory patterns of cytokine secretion and concurrent suppression of Th1, Th2 or Th17 responses [Nemeth et al, 2009;Rafei et al, 2009;Ghannam et al, 2010]. These data are supported by elegant in vivo models of transplantation and autoimmune disease where MSC alter T cell polarisation away from the typical effector responses [Casiraghi et al, 2008;Ge et al, 2009;Rafei et al, 2009;Kavanagh and Mahon, 2011]. Treg themselves are candidate cell therapeutics but the ability of MSC to induce these cells and also mediate repair suggests cell therapy directed at the induction of tolerance in organ transplantation, GvHD, and autoimmune disorders.…”

“…Likewise, MSC block neutrophil function by suppressing the oxidative burst of resting and activated neutrophils while preserving their phagocytic and chemotactic functions . Furthermore, recent in vivo data suggest that MSC also suppress inflammatory eosinophil localisation in vivo [Kavanagh and Mahon, 2011]. Thus MSC appear to be recruited by, but protected from, the principle innate deletional mechanisms and suppress a range of inflammatory pathways consistent with functions in co-ordinating the resolution of inflammation and a transition to reparative processes.…”

“…It also implied that allogeneic MSC could be used as agents of immune deviation in conditions such as graft versus host disease (GvHD), type I diabetes or autoimmune diseases, in addition to regenerative applications for myocardial infarction or joint damage. Journal of Cellular Biochemistry 112:1963-1968(2011 The intervening years have seen a rapid delineation of the mechanisms by which MSC modulate different aspects of both the innate and adaptive immune response. This has been accompanied by a large number of clinical trials in which allogeneic MSC have been safely deployed against a wide range of human diseases.…”

“…Biochem. 112: 1963-1968, 2011. ß 2011 KEY WORDS: MESENCHYMAL STEM CELLS; IMMUNOLOGY; CELL THERAPY C ell-based therapies to treat human disease are set to become clinical reality.…”

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

“…Recent reports have demonstrated the anti-inflammatory potential of MSCs in several murine asthma models induced by high-molecular-weight allergens (ovalbumin, ragweed, and aspergillus hyphal extract) [11,13,[22][23][24][25][26][27][28] and in a low-molecular-weight, toluene diisocyanate (TDI)-induced asthma model [14]. However, in most of these models, the MSCs were administered preventively, that is, during the immunization phase or concomitantly with the induction of asthma.…”