Kidney transplantation has improved life expectancy and quality of life for patients with end-stage renal failure. However, despite the impressive improvements in short-term outcome parameters due to better and more potent immunosuppressive drugs, the long-term survival of renal allografts has changed little during the past decades [1▪▪]. Clinical emphasis has shifted from the prevention of acute rejection towards reduction of chronic alloimmune injury and immune suppression-related side effects to optimize preservation of renal allograft function.
A number of factors, such as quality of the graft, ischemia/reperfusion injury, and/or (subclinical) acute rejection may adversely affect renal structure, causing early tubular atrophy and interstitial fibrosis (IF/TA). In recent years it has become clear that ongoing alloreactivity may play a central role in the functional prognosis of kidney allografts . True chronic allograft rejection, or ongoing immune injury to the graft may be caused by cellular and/or humoral mechanisms with de-novo donor-specific antibody formation [3–5]. Clinically, chronic renal transplant dysfunction is characterized by a gradual, but progressive loss of function with hypertension and a variable degree of proteinuria. Histologically, IF/TA may be accompanied by an influx of T cells, macrophages, and/or B cells, as well as complement (C4d) deposition in the peritubular capillaries, smooth-muscle proliferation, and obliterative vasculopathy. Several studies with early protocol biopsies have shown that especially the combination of inflammation and fibrosis has the worst outcome in term of graft function and survival [6–9]. Ongoing immune injury plays a crucial role to cause IF/TA in the graft [2,10,11]. Asymptomatic infiltrates in early protocol biopsies most likely represent a donor-specific immune response as they correlate with human leukocyte antigen (HLA)-DR mismatches; underscoring the fact that clinical immunosuppression is imperfect . In typical cases of chronic antibody-mediated rejection, antibodies deposit on the capillary endothelium causing transplant glomerulopathy .
In recent years it has become evident that mesenchymal stromal cells (MSCs) have potent immunomodulatory and reparative effects. MSCs are pluripotent cells that can be isolated from various tissue types including bone marrow, adipose tissue, and umbilical cord blood. At present no unique phenotype has been identified that allows the reproducible isolation of MSC precursors with a predictable differentiation potential. Functional characterization still relies primarily on their ability to adhere to plastic and their multilineage differentiation potential. The International Society of Cellular Therapy has stated that MSCs should bear at least the stromal markers CD73, CD90, and CD105, while negative for the hematopoietic markers CD14, CD34, and CD45 . MSC transplantation, both autologous and allogeneic, has been performed for the treatment of a wide variety of diseases in humans . Encouraging results have been obtained in patients with graft-versus-host and Crohn's disease [15,16]. Important for their clinical application is that MSCs can be easily isolated due to their adherence to plastic, proliferation potential, and expansion in cultures . In addition, MSCs can be cryopreserved without changes in phenotype or differentiation potential .
In solid organ transplantation (SOT), MSCs have been used in various preclinical studies and data are currently arising from clinical studies [19–23]. We hypothesize that infusion of MSCs may provide a novel treatment option to prevent or treat ongoing (chronic) rejection (Fig. 1) with less side effects as compared to existing immunosuppressive therapeutic interventions. The focus of the current review is on recent insights into MSC biology as well as preclinical and clinical data on their potential role in the prevention or treatment of chronic rejection.
IMMUNOMODULATORY PROPERTIES OF MESENCHYMAL STROMAL CELLS
Several studies have indicated that MSCs can modulate immune responses [24,25] and several reviews have discussed these topics in detail [21,26]. The mechanisms underlying their immunosuppressive effects are most likely a combination of direct cell–cell contact and paracrine factors, including indoleamine 2,3-dioxygenase (IDO), interferon (IFN)-γ, HLA-G, interleukin (IL)-10, and transforming growth factor (TGF)-β. Keys soluble factors have not been identified yet. Here, we will briefly describe the major mechanisms involved in MSC-induced immunomodulation in the context of SOT.
Mesenchymal stromal cells inhibit proliferative immune responses
Mesenchymal stromal cells are poor antigen-presenting cells and do not express major histocompatibility complex (MHC) class II or co-stimulatory molecules, such as CD80, CD86, and CD40L. In addition, MSCs strongly inhibit T-cell proliferation both in vitro and in vivo [25,27–30]. Furthermore, MSCs have been reported to induce T-cell division arrest , as well as to decrease the secretion of inflammatory cytokines by various immune cell populations . Recently, it was shown that MSCs not only suppress Th1 functions, but also the Th17-mediated activation and proliferation through soluble and cell-dependent factors [32,33]. Apart from their effects on T cells, MSCs have additional targets in the immune system. They inhibit the IL-2 and IL-15-driven natural killer (NK) cell proliferation and IFN-γ production [24,34–36] as well as the dendritic cell (DC) generation from peripheral blood monocytes in vitro [37–39]. Interestingly, intravenous injection of MSCs significantly affected the ability of DCs to prime T cells in vivo because of their inability to home to draining lymph nodes [40▪▪].
As antibodies play a crucial role in chronic rejection, future therapies should not only be focused on T-cell activation, but also on the direct control of B cells. Although data are scarce and remain controversial, there is evidence that MSCs affect B-cell functioning . Mouse and human MSCs inhibited B-cell proliferation and significantly reduced immunoglobulin production by plasma cells, with optimal results in high (1 : 1 or 1 : 4) MSC–B cell responder ratio [42,43]. At lower rations (1 : 10) it was reported that MSCs fail to inhibit B-cell proliferation and IgG production [42,44]. In vivo bone marrow-derived MSCs reduced intragraft IgG as well as IgM in a murine cardiac transplantation model . The suppression of plasma cell immunoglobulin secretion may be mediated by alternatively cleaved CCL2  and PD-1/PD-L1 interactions . In a murine model of systemic lupus erythematosus (SLE), human MSC treatment induced complete remission of the disease , whereas another study found no effect while using the same model . Clearly, more studies are needed to gain insight into the interaction of MSCs with B cells and their roles in organ transplantation.
Mesenchymal stromal cells induce regulatory immune cells
Apart from their effects on effector immune cells, MSCs have also been found to induce suppressor/regulatory cells [21,50]. They have the ability to induce regulatory FoxP3+ Tregs, T-regulatory 1 cells (Tr1), IL10+-producing cells, and Th3 TGF B+ regulatory T cells . In addition, MSCs mediated a switch to alternatively activated M2 macrophages . These macrophages induced by Th2 cytokines such as IL-4 and IL-13 possess anti-inflammatory activities and are considered the regulatory type macrophage subsets . In transplant recipients, a recent study reported regulation of the alloantibody response in tolerant recipients and the accumulation of B cells exhibiting an inhibited and regulatory profile . The relation between MSCs and Bregs has not been studied so far, but available data suggest that MSCs may increase Breg differentiation [41,42,44].
TISSUE REPAIR BY MESENCHYMAL STROMAL CELLS
Mesenchymal stromal cells have been shown to ameliorate tissue damage in response to injury and disease. In line with these findings, MSCs were originally evaluated for their capacity to repair skeletal defects in experimental models and subsequently in patients with osteogenesis imperfect [55,56]. Different studies have suggested that the capacity of MSCs to produce paracrine factors rather than their transdifferentiation, plays a prominent role in effecting tissue repair [26,57].
Mesenchymal stromal cells exert antifibrotic properties
In animal models, MSC transplantation decreased fibrosis in the heart , and other organs such as the lung, liver, and kidney [59–61]. Different cytokines have been shown to mediate the antifibrotic properties, including BMP-7 . In addition, it was recently shown that exosomes play a major role in amelioration of liver fibrosis, by down-regulation of collagen type I and III, TGF-β, and Smad2 expression . After kidney transplantation, Franquesa et al. [63▪▪] observed a therapeutic effect of MSCs attenuating the progression of IF/TA when this process is already in progress. MSC-treated animals demonstrated also less macrophages infiltrating the parenchyma and a lowered expression of inflammatory cytokines [63▪▪]. These results suggest that the beneficial effect is attributable to the reduction of immunomodulation by MSCs, rather than promoting tissue regeneration. However, as fibrosis and inflammation are interconnected it remains difficult to dissect the different mechanisms involved.
Mesenchymal stromal cells exert angiogeneic properties
The process of transplantation results in several insults to the donor endothelium that will require repair. Microvascular endothelial cells are very susceptible to injury, including ischemia/reperfusion injury, as well as ongoing immune injury . Graft microvascular injury has been documented in association with progressive IF/TA and graft dysfunction, and replacement of endothelial cells correlates with degrees of injury in human allografts [65–67]. Previous studies have shown that MSCs can differentiate toward endothelial cell lineage and contribute to angiogenesis and endothelial repair in vitro and in vivo [19,68]. Murine bone marrow MSC-conditioned media have been shown to consist of vascular endothelial growth factor, basic fibroblast growth factor, and placental growth factor which enhance proliferation of endothelial cells and smooth muscle cells. In renal ischemia, the process of microvascular rarefaction was reduced in postischemic kidneys after the injection of MSCs . The protection of loss of peritubular capillaries attributed to MSC therapy implicates important indications in the context of transplantation.
PRECLINICAL STUDIES OF MESENCHYMAL STROMAL CELL THERAPY IN ALLOGRAFT REJECTION AFTER SOLID ORGAN TRANSPLANTATION
In line with their immunosuppressive capacities in vitro, MSCs also display immunosuppressive capacities in experimental animal models of transplantation. In a study on baboon MSCs, Bartholomew et al.  observed MSCs to suppress the proliferative activity of allogeneic peripheral blood lymphocytes in vitro. In addition, the in-vivo effects of baboon MSCs were tested by intravenous administration of donor MSCs to MHC-mismatched recipient baboons prior to autologous, donor, and third-party skin transplants. They found prolonged skin graft survival after MSC administration as compared to the control animals. In a rat heart transplantation model, donor MSCs suppressed the allogeneic T-cell responses both in vitro and in vivo, and intravenous administration of MSCs prolonged the survival of transplanted hearts . MSCs vigorously migrated to the site of allograft rejection during chronic rejection, suggesting that they may be (chemo)attracted to this site of inflammation to participate in the process of active tissue repair. Moreover, MSC differentiation towards a fibroblast progeny was inhibited and deviated towards the myocyte lineage, suggesting a potential as a new strategy to treat of chronic or ongoing rejection [72,73]. In another model, the pretransplant infusion of MSCs prolonged the survival of semi-allogeneic (B6C3 in B6) murine heart transplants through the generation of regulatory T cells . Pretransplant infusion of recipient MSCs appeared to be more effective as compared with peri-transplant, suggesting that the appropriate timing is also an important factor . Interestingly, the same group investigated the optimal timing for MSC infusion to promote immune tolerance in a murine kidney transplant model [75▪▪]. Post-transplant MSC infusion caused premature graft dysfunction and failed to prolong graft survival. In contrast, pretransplant MSC infusion induced a significant prolongation of kidney graft survival by inducing regulatory T cells [75▪▪]. These results indicate that the inflammatory ‘milieu’ is of importance in the mechanistic function of MSCs.
Of relevance for the clinical setting may also be the optimal concurrent immunosuppressive regimen in that MSCs and drugs do not negatively impact each other. A few preclinical studies have addressed this interaction in vivo. Eggenhofer et al. [76,77] found a potent synergistic effect of MSCs with mycophenolate mofetil. In addition, MSCs combined with low-dose cyclosporin A (CsA) better protected graft function, but could not prolong animal survival compared with CsA monotherapy . This lack of beneficial effect of the MSC-treated group over CsA monotherapy is related to direct effects of CsA on MSC function while allowing reduced CsA doses. In a study by Ge et al. , infusion of MSCs and rapamycin synergized to attenuate alloimmune responses and to promote cardiac allograft tolerance. In the MSC-treated animals a high frequency of Tol-DCs and CD4+CD25+Foxp3+ T cells was accompanied by the absence of antidonor antibodies. These results support combination of MSCs with a mammalian target of rapamycin inhibitor in clinical transplantation.
CLINICAL TRIALS WITH MESENCHYMAL STROMAL CELL IN SOLID ORGAN TRANSPLANTATION
The in-vitro immunosuppressive and reparative properties of MSCs and the positive results in experimental studies have led to the start of a number of clinical trials in SOT. In addition, safety and feasibility data from different trials including GvHD, Crohn's disease, neurologic diseases (including multiple sclerosis and Parkinson's disease) trials in cardiac disease (heart failure, myocardial ischemia) and limb ischemia have not opposed trials in SOT. Currently six trials are registered (www.clinicaltrials.gov), of which three trials in kidney recipients are (nearly) completed. In a pilot study by Perico et al.  safety and clinical feasibility autologous MSCs were tested in two recipients of kidneys. MSC infusion was shown to be feasible, allowing enlarging of Tregs in the peripheral blood and control of memory CD8+ T-cell function. However, patients given autologous bone marrow MSCs and kidney transplantation both developed renal insufficiency 7–14 days after cell infusion, probably related to the post-transplant infusion of MSCs. In a recent trial among 159 patients undergoing renal transplantation, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infections, and better estimated renal function at 1 year . In our phase 1 clinical study (clinical trials NCT00734396), safety and feasibility data of autologous MSC therapy in HLA-DR-mismatched patients with subclinical rejection in their renal biopsy at 4 or 24 weeks after renal transplantation are expected soon. Our study will reveal the first data of MSC therapy at the time of a rejection episode. A study in kidney transplant recipients evaluating the effect of MSCs in chronic allograft nephropathy is registered by the Fuzhou Institute of China. Additionally, a recent study aimed at evaluating safety and tolerability of third party MSCs after liver and kidney transplantation with standard immunosuppressive therapy is registered recently. In liver transplantation, a safety and feasibility study of commercial available third-party multipotent adult progenitor cells for immunomodulation given during and 3 days after liver transplantation therapy is planned . In lung transplantation, safety of infusions from related or unrelated HLA-identical or HLA-mismatched donors are currently analysed in the management of bronchiolitis obliterans. More focused research is needed to get information about MSC-mediated amelioration of chronic rejection in clinical trials.
Mesenchymal stromal cells could potentially play an important role in the prevention and treatment of chronic rejection due to control of lymphocytes, antibodies, and other players in the immune system and due to tissue remodelling. Although MSCs may be functional in targeting microenvironment and the process of chronic rejection, the overall mechanistic role of MSCs in chronic alloimmune injury needs to be elucidated. Furthermore future studies need to elucidate issues of clinical importance in transplant recipients which include dosing, number of MSC infusions and interactions with immune suppression. In addition, due to the possible interaction with the microenvironment in the graft, timing of MSC treatment seems crucial. Finally, long-term follow-up for unwanted side effects is of greatest importance, especially since transplant recipients are already at increased risk for (opportunistic) infections and malignancies.
Conflicts of interest
There are no conflicts of interest.
The study was sponsored by the Dutch Organization for Sciences (NWO/ZonMW; TAS and Veni), the Nefrosearch grant and the European Community's Seventh Framework Programme (FP7/2007–13, HEALTH-F5-2008-223007 STAR-T REK).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 115–116).
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