The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy

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Abstract

There is growing interest in the use of mesenchymal stem cells (MSC) for immune therapy. Clinical trials that use MSC for treatment of therapy resistant graft versus host disease, Crohn's disease and organ transplantation have initiated. Nevertheless, the immunomodulatory effects of MSC are only partly understood. Clinical trials that are supported by basic research will lead to better understanding of the potential of MSC for immunomodulatory applications and to optimization of such therapies. In this manuscript we review some recent literature on the mechanisms of immunomodulation by MSC in vitro and animal models, present new data on the secretion of pro-inflammatory and anti-inflammatory cytokines, chemokines and prostaglandins by MSC under resting and inflammatory conditions and discuss the hopes and expectations of MSC-based immune therapy.

Section snippets

Mesenchymal stem cells

Mesenchymal stem cells (MSC) are the current focus of a growing number of research laboratories for their potential use for immune therapy. They are found in the bone marrow and at multiple other sites including adipose tissue [1], skin [2], spleen, and heart [3]. In vitro, MSC are characterized by plastic adherence, colony forming capacity and rapid proliferation. The immunophenotype of MSC, CD45, CD34, CD13+, CD44+, CD73+, CD90+, CD166+, CD80, CD86, HLA class Ilow, HLA class II,

The immunomodulatory properties of MSC

MSC have potent immunosuppressive capacity. This is demonstrated in vitro by the inhibition of T lymphocyte proliferation and pro-inflammatory cytokine production after mitogen or cellular stimulation by MSC [7], [8]. MSC furthermore inhibit the antibody production of B cells [9] and inhibit the generation and function of antigen presenting cells [10]. The immunosuppressive effects of MSC have been further evidenced in a number of in vivo models, where MSC were demonstrated to alleviate

Mechanisms of immunomodulation by MSC

The immunosuppressive effect of MSC is for a large extent mediated via soluble factors. Separation of MSC by a transwell membrane does not prevent inhibition of activated immune cell proliferation. Several factors have been proposed to play a role in the immunosuppressive effect of MSC, including TGF-β, hepatocyte growth factor (HGF) [7], nitric oxide [17] and HLA-G [18]. Furthermore, the tryptophan depleting enzyme indoleamine 2,3-dioxygenase (IDO) plays a crucial role in the immunosuppressive

The secretion of cytokines and chemokines by MSC

In addition to anti-inflammatory factors, MSC produce and secrete pro-inflammatory cytokines and chemokines. We analyzed the secretion of 40 soluble factors by MSC after 48 h of culture in serum-free MEM-α using Raybio® arrays (Raybiotech, Norcross, GA). MSC constitutively secreted large amounts of the cytokines IL6 and IL8, the chemokine CCL2, and of TIMP-2, known for long to have tumor cell invasion inhibitory capacity [23] (Fig. 1A). When IFN-γ (50 ng/ml) was added to the MSC for 48 h, there

The secretion of prostaglandins by MSC

In addition to cytokines and chemokines, MSC secrete prostaglandins, of which PGE2 has earlier been associated with the immunosuppressive effect of MSC [29]. We recently analyzed the secretion of prostaglandins by human heart-derived MSC in more detail. MSC were isolated from atrial tissue that became available after heart transplantation, as described before [30]. After expansion for 3 up to 5 passages, MSC were kept in serum-free medium for 48 h. Levels of prostaglandins were measured in the

Immunological response to MSC infusion

While the proactive effects of MSC on immune cells, such as the secretion of anti-inflammatory factors, are subject of intense research, there is little attention for potential passive immunomodulatory effects of MSC. It is for instance possible that infusion of MSC elicits an immune response, as cultured MSC have a phenotype that is different to the phenotype of MSC in tissues. MSC may therefore be recognized by the immune system and induce an immunomodulatory effect that is independent on

Immunogenicity of MSC

MSC have a low immunogeneic phenotype as they express low levels of HLA and co-stimulatory molecules and they do not elicit alloreactive T lymphocyte responses in vitro [4]. Nevertheless, there is now convincing evidence that MSC are immunogeneic after in vivo infusion. Nauta et al. demonstrated some years ago that infusion of donor, but not host-derived, MSC can promote rejection of donor bone marrow transplants in sublethally irradiated mice [34]. A similar finding was observed in a skin

Interaction between MSC and immunosuppressive drugs

There is hope that MSC may be capable of complementing or even replacing immunosuppressive drugs in the future. As this therapy emerges, there is no doubt that MSC will be administered in combination with immunosuppressive drugs. As these drugs and MSC have common targets (the proliferating T cell pool), there is a possibility that MSC and immunosuppressive drugs have a reciprocal effect on each other's efficacy. In vitro data demonstrates that the immunosuppressive capacity of MSC is reduced

MSC immunotherapy in animal studies

Data from animal models of immunotherapy with MSC must still be considered heterogenous. In the first promising studies, MSC were able to control lethal GvHD after allogeneic bone marrow transplantation [39] whereas in a different mouse model MSC failed to prevent GvHD [40]. These findings clearly reflect that MSC biology is complex in living organisms and that results depend on a multitude of factors, one of which are non-standardized culture conditions used in different laboratories. More and

MSC as immune therapy in the clinic

MSC have been successfully applied for the treatment of steroid-resistant GvHD in a multicenter, clinical phase II study that was recently published [44]. This study represents the most successful clinical application of MSC so far reported and was considered a breakthrough within this field. However, grade IV GvHD must be considered a unique clinical situation, as overall the treatment options are very limited, which makes the decision to commit to experimental therapies relatively easy.

Conclusions

MSC are a promising cell population that is currently investigated on the preclinical and clinical level by a growing number of laboratories around the globe. In the recent years this has led to a significant increase in the knowledge about MSC immunobiology and first clinical therapies are evolving.

However, failure will follow the first “MSC-hype” and further thorough analysis and discussion needs to be undertaken by dedicated MSC immunobiologists to achieve a real future clinical benefit.

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