Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate

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Abstract

The induction of tolerance towards allogeneic solid organ grafts is one of the major goals in transplantation medicine. Mesenchymal stem cells (MSC) inhibit the immune response in vitro, and thus are promising candidate cells to promote acceptance of transplanted organs in vivo. Such novel approaches of tolerance induction are needed since, to date, graft acceptance can only be maintained through life-long treatment with unspecific immunosuppressants that are associated with toxic injury, opportunistic infections and malignancies.

We demonstrate that donor-derived MSC induce long-term allograft acceptance in a rat heart transplantation model, when concurrently applied with a short course of low-dose mycophenolate. This tolerogenic effect of MSC is at least partially mediated by the expression of indoleamine 2,3-dioxygenase (IDO), demonstrated by the fact that blocking of IDO with 1-methyl tryptophan (1-MT) abrogates graft acceptance. Moreover we hypothesize that MSC interact with dendritic cells (DC) in vivo, because allogeneic MSC are rejected in the long-term but DC acquire a tolerogenic phenotype after applying MSC.

In summary, we demonstrate that MSC constitute a promising tool for induction of non-responsiveness in solid organ transplantation that warrants further investigation in clinical trials.

Introduction

Mesenchymal stem cells reside in the bone marrow and other tissues and give rise to osteoblasts, chondrocytes and adipocytes [1]. MSC can be cultured from bone marrow aspirates and can be expanded to large quantities appropriate for clinical application. Moreover, MSC are promising candidates for immunosuppressive cell therapy since they have been shown to suppress the immune response in vitro [2], [3]. In this context we and others have demonstrated that MSC inhibit responder cell proliferation in mixed lymphocyte cultures (MLC) with and without interleukin 2 [4]. Recent data also suggest that MSC can mediate this suppressive effect in numerous ways [2]. On the one hand, MSC activate regulatory T cells [5], which in turn are powerful modulators of the immune response [6]. On the other hand, MSC can interact with antigen-presenting cells (APC) [7] and inhibit DC differentiation and proliferation by locking DC in an immature state that promotes tolerance [8], [9]. Moreover, it has been described that MSC express indoleamine 2,3-dioxygenase (IDO) upon stimulation with interferon-γ (IFN-γ), thereby leading to T cell suppression in MLC [10]. IDO catalyzes the conversion from tryptophan to kynurenine and is also expressed by APC, especially DC. Activation of IDO has been described as a major T cell inhibitory mechanism in the APC/T cell interaction [11], [12], [13] and has been identified as the controlling mechanism for the acceptance of the fetus during pregnancy [14]. These in vitro properties of MSC suggest that they might as well have immunosuppressive effects in vivo. Recent reports indeed show that MSC prolong skin graft survival and attenuate graft-versus-host disease [15], [16].

In our current study, we demonstrate that MSC induce long-term allograft acceptance in a fully MHC-mismatched rat heart transplantation model when injected prior to transplantation with a short course of low-dose mycophenolate mofetil (MMF) that acts synergistically with MSC. MMF is an anti-proliferative drug that inhibits predominantly lymphocyte proliferation [17]. MSC-induced tolerance is, in least partially, mediated by the expression of IDO and the emergence of tolerogenic DC.

Section snippets

Animals and experimental groups

LEW (MHC haplotype: RT1l, Charles River, Sulzfeld, Germany, http://www.criver.com/), ACI (MHC haplotype: RT1a) and BN (MHC haplotype: RT1n, Charles River, Sulzfeld) rats weighing approximately 250 g were maintained in the animal center at the University of Regensburg. All animal procedures were approved by regional authorities and conducted under appropriate anesthesia.

LEW rats were used as heart transplant donors and ACI rats served as recipients. Heterotopic heart transplantation was

MSC elicit an immune response and are rejected from allogeneic recipients

We transplanted hearts from LEW rats (RT1l) into the abdominal cavity of ACI recipient rats (RT1a) to determine whether MSC can induce long-term graft survival in a completely MHC-mismatched allotransplantation model with clinical relevance. MSC were purified from LEW rats by plastic adherence and differentiated into osteoblasts, chondrocytes and adipocytes applying appropriate culture conditions. Using flow cytometry, MSC expressed the characteristic surface marker profile reported for MSC:

Discussion

We introduce the finding that MSC induce long-term allograft acceptance, when concurrently applied with mycophenolate. This observation opens up the principal possibility for a clinical application of MSC for immunomodulation in solid organ transplantation.

Importantly, the time point of MSC injection is crucial. MSC treatment after heart transplantation did not mediate prolonged graft survival in the present setting. This observation is in accordance with our previous results, showing that MSC

Acknowledgements

We thank Irina Kucuk and Friederike Thamm for her excellent technical assistance. This study was supported by a grant from Roche Pharmaceuticals, Grenzach-Wyhlen. MHD was supported by the Junior Basic Science Grant of the European Society of Organ Transplantation.

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Popp F.C.: conception and design, data analysis and interpretation, collection and/or assembly of data, manuscript writing, final approval of manuscript; Eggenhofer E.: conception and design, data analysis and interpretation, collection and/or assembly of data, manuscript writing, final approval of manuscript; Renner P.: data analysis and interpretation, collection and/or assembly of data; Slowik P.: data analysis and interpretation, collection and/or assembly of data; Lang S.A.: data analysis and interpretation, collection and/or assembly of data; Kaspar H.: collection and/or assembly of data; Geissler E.K.: conception and design, financial support, final approval of manuscript; Piso P.: conception and design, financial support, final approval of manuscript; Schlitt H.J.: conception and design, financial support, administrative support, final approval of manuscript; Dahlke M.H.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript

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These authors contributed equally to this work.

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