Allogeneic mesenchymal stem cells: Agents of immune modulation

Abstract

Adult mesenchymal stem cells possess a remarkably diverse array of immunosuppressive characteristics. The capacity to suppress the regular processes of allogeneic rejection, have allowed the use of tissue mismatched cells as therapeutic approaches in regenerative medicine and as agents of immune deviation. This review describes recent advances in understanding the mechanistic basis of mesenchymal stromal or stem cells (MSC) interaction with innate immunity. Particular emphasis is placed on the effect of Toll-like receptor signalling on MSC and a hypothesis that innate immune signals induce a 'licensing switch' in MSC is put forward. The mechanisms underlying MSC suppression of T cell responses and induction of regulatory populations are surveyed. Conflicting data regarding the influence of MSC on B cell function are outlined and discussed. Finally the limits to MSC mediated immune modulation are discussed with reference to the future clinical application of novel cell therapies. J. Cell. 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. To the fore of these novel approaches is the use of adult mesenchymal stromal or stem cells (MSC). The term 'mesenchymal stem cell' was coined by Caplan in 1991 [Caplan, 1991] to describe the rare population of bone marrow derived, plastic adherent cells discovered by Friedenstein and Petrokova [1966]. Originally these stromal cells were assumed to directly repair degenerative disease by differentiation; however, it is now appreciated that MSC also release soluble factors that act in a paracrine manner to promote repair [Caplan, 2009]. However, while MSC might be considered as trophic agents that guide the processes of tissue repair, the nature of the trophic activities remain ill defined.The beneficial actions of MSC encompass anti-apoptotic, cytoprotective effects and the promotion of angiogenesis [Caplan, 2009] and it is the multifactorial, coordinated and targeted features of MSC that make the cell therapy approach superior to small molecule modalities. Angiogenic action is likely to be an important component of tissue repair; pericyte mediated vascular stability contributes to wound healing and tissue resident MSC may be derived from a perivascular precursor [Bianco et al., 2010], and may be intimately involved in neovascularisation of wounds and therefore regeneration.Whilst the above features are important attributes of MSC biology, one trophic function has become the subject of intense scrutiny in the last 7 years. It is now apparent that MSC are powerful modulators of the mammalian immune response. These findings date back to studies which demonstrated that tissue mismatched (allogeneic) and even species mismatched (xenogeneic) MSC were effective cell therapies [Bartholomew et al., 2002;Grinnemo et al., 2004]. The implications were that MSC would disobey the regular rules of tissue transplantation and enjoy a degree of immune privilege,...

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

“…The anti-inflammatory and immunomodulatory MSCs could allow for allogeneic transplantation (14,15). There is some evidence, however, that MSCs may have both cellular and humoral alloreactivity, such as activation of T-cells that may reduce the capacity of allogeneic MSC transplantation (16,17). Yet MSC immunogenicity is still considerably attenuated compared with other allogeneic cell types because of their intrinsic antiinflammatory and immunomodulatory properties and absent to low major histocompatibility class II antigen expression (16,18).…”

Local Inhibition of Complement Improves Mesenchymal Stem Cell Viability and Function After Administration

“…2 It has therefore been assumed that MSCs expanded from one donor could be used to treat other patients without being rejected. 3,4 Because of the convenience of preparation, timing, cost effectiveness, and lack of need for human leukocyte antigen (HLA) matching, many clinical trials on MSCs have used alloMSCs. 5 Infusion of MSCs by intravenous injection is the most common delivery route in both humans and animals.…”

Study of the Quantitative, Functional, Cytogenetic, and Immunoregulatory Properties of Bone Marrow Mesenchymal Stem Cells in Patients with B-Cell Chronic Lymphocytic Leukemia

“…The nonhematopoietic components of the BM microenvironment are thought to derive from MSCs [15][16][17]. This population has been shown to support hematopoiesis [15] and to affect B-cell proliferation and differentiation either positively or negatively [18,19], thereby providing the theoretical background for studying the MSC putative role in CLL pathogenesis. Notably, this particular field of research has not been extensively explored.…”

“…Given that MSCs have been shown to modulate not only normal B-cell proliferation and differentiation [18,19] but also the tumor growth [20], one could speculate that potential abnormalities in patient MSCs might contribute to the pathophysiology of CLL by providing malignant cells with aberrant growth/survival signals. Likewise, in view of the well-established immunoregulatory potential of BM MSCs on T-cells [18,19], it could be hypothesized that the common T-cell dysfunction in CLL [21,22] might be attributed to deregulated immunomodulatory effects exerted by BM MSCs.…”

“…BM-MSCs have also been reported to influence B-cell function, proliferation, and differentiation [18,19]. In this regard, we further examined the immuroregulatory effects on B-cells of CLL-derived MSCs as compared with their normal counterparts.…”