Analysis of the Application of Regulatory Dendritic Cells in Kidney Transplantation

After kidney transplantation (KT_x), recipients need to take immunosuppressive agents to prevent rejection. However, the toxicities and side effects of long-term usage of immunosuppressive agents should not be overlooked. How to reduce the dosages of immunoinhibitory agents has become a major problem that desperately needs to be solved. Currently, new immunosuppressive strategies, new immunosuppressive reagents and cell therapies are all being researched and developed [1]. Cell therapy has drawn increasing attention, and further investigation will not only provide potential targets of immunosuppressive reagents but also have very important clinical value. Dendritic cells (DCs) are heterogenous professional antigen-presenting cells that play central roles in innate immunity and adoptive immunity, including roles in immune tolerance induction and immune stabilization [2]. A group of DCs with the capability of immune tolerance induction was named tolerogenic DCs [3] or regulatory DCs (DC_reg). DC_reg have been applied as a cell therapy-based alternative to immunosuppressive agents. In addition, phase II clinical trials assessing the treatment of diabetes and autoimmune diseases with DC_reg have been carried out [4]. The kidneys, which have a special structure and function, are an important organ for ensuring a stable internal environment and normal metabolism. Before and after KT_x, does DC_reg infusion function to induce immune tolerance as expected? This is the focus of DC_reg-based cell therapy. In this manuscript, we review the application of DC_reg in KT_x recipients in regard to kidney immunology.

Characteristics of DC_reg

There are few natural DC_reg in vivo, and these cells are small and round [5] and greatly differ from DC_reg obtained in vitro. DC_reg induced in vitro are always smaller than normal mature DCs, with few short dendrites, and DC_reg cell phenotypes are also different from mature DC phenotypes [6]. Without inflammatory stimulation, immature DCs participate in peripheral immune tolerance induction, showing a DC_reg phenotype and functional characteristics. Under normal conditions, DC_reg express low levels of major histocompatibility complex II molecules and costimulatory molecules such as CD80 and CD86 [7]. Nevertheless, the expression of inhibitory molecules, such as human leukocyte differentiation antigen-G (HLA-G) [8], programmed death-ligand (PD-L)-1 and 2 [9], and galectin [10], increases. An increased PD-L1/CD86 ratio and enhanced IL-10 secretion are thought to be characteristics of DC_reg [11]. DC_reg may have relatively specific phenotypes in different tissues and organs; for instance, DC_reg are likely to have a CD141+CD14+ phenotype in the skin [12], and DC_reg may be DC-10 in the blood [13,14]. At present, genetic modification, drug intervention, cytokine exposure and so on are used to induce DC_reg, and precursor cells can be isolated from bone marrow cells, peripheral blood mononuclear cells or lymph node cells [15-17]. DC_reg can produce TGF-β1 [18,19], IL-10 [20,21], 2,3-IDO [22-24], IFN-γ and the Epstein-Barr virus (EBV) induction gene [25] or induce regulatory T cells (Tregs) [26,27] to exert their immune tolerance induction function.

Effects of the internal environment on DCs in KT_x recipients

Under normal conditions, KT_x recipients receive immune induction therapy before surgery and routine immunosuppressant administration after surgery to suppress potential immune rejection. Specific and nonspecific immunosuppressants severely weaken recipient immune function, and DCs are significantly affected. Studies have shown that immunosuppressive agents have different effects on different DC subsets. After KT_x, the numbers of recipient myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) are dramatically decreased, and the number of mDCs does not recover within 3 months after surgery [28]. If recipients receive immunosuppressive therapy in addition to conventional immunosuppressive therapy, DC numbers, including the numbers of mDCs and pDCs, decline more significantly early post operation; CD62L expression significantly increases on mDCs, but CD86 expression significantly decreases [29]. CD62L, an adhesion molecule, can mediate the initial retention related to DC rolling on endothelial cells. If recipients have taken immunosuppressive agents for over 1 year, the number of peripheral blood DCs (mDC1, mDC2 and pDCs) is decreased [30,31]. In other words, immunosuppressive agents result in maturation arrest in peripheral m DCs [32]. Some studies have reported that DC_reg numbers increase after usage of immunosuppressive agents. Rapamycin application can induce the production of ILT3highILT4high DCs [33], which have the ability to induce immune tolerance. Specific anti-CD52 monoclonal antibody (alemtuzumab, also called Campath-1H) induction therapy dramatically decreases the number of peripheral blood DCs, and after one month, mDCs will transform into pDCs (the mDCs/pDCs ratio declines) [34]. CTLA-4-Ig (belatacept) application can induce DCs to express HLA-G [35], which interferes with the activation of T cells. In recipients treated with belatacept, the numbers of regulatory cells (Tregs/regulatory B cells (Bregs)/plasmacytoid dendritic cells (pDCs)) markedly increase in renal allograft tissues, but the proportions of apoptotic cells and aged cells significantly decrease, and proliferation marker expression increases [36]. All of the published research indicates that immunosuppressive agents can interfere with DC growth and differentiation or the induction of DC_reg, and the results also emphasize the key role of DC_reg in inhibiting alloantigen-mediated rejection. The effects of different immunosuppressive agents may overlap. Thus, the following aspects, including DC_reg preparation, infusion frequency, pathways and cell numbers, all need to be considered to evaluate the similar and unique effects of immunosuppressive agents when DC_reg are applied as a cell therapy.

Specific microenvironment of renal allograft tissue

CX3CR1+ DCs can be found in the renal mesenchyme and glomerular mesangium by confocal laser scanning microscopy. These DCs highly express CD11c, F4/80, MHCII, FcR and inhibitory costimulatory molecules. Among these cells, at least one subgroup has the ability to perform phagocytosis, which means that the cells in this subgroup are tissue-resident immature DCs, and this subgroup forms a monitoring network for the microenvironment [37]. During the process of removal from the donor, transfer into an organ-preservation fluid, and implantation into the recipient, a renal allograft will undergo ischemia-reperfusion injury, which causes the release of endogenous molecules. Pattern recognition receptors can recognize these molecules as danger signals and induce inflammatory cell recruitment and mediator activation. As one of the sentinels in the kidneys, DCs will mature in the microenvironment and drain into the lymph nodes, presenting and activating T cells. Under this condition, T cells can differentiate into Th1 and Th17 effector cells or Th2 cells and Tregs [38,39]. Animal experiment results suggest that donor DCs in renal allograft tissue are rapidly replaced by recipient DCs after the donor kidney is implanted into the recipient [40]. Infiltrated recipient DCs and T cells in tissues are associated with shortened graft survival [41]. Clearance of recipient DCs can reduce the proliferation and survival of infiltrating T cells in a graft and inhibit effector T cell-mediated rejection [40,42]. Renal tubular epithelial cells are thought to be the main cell type that attracts white blood cells during the inflammatory response in the kidneys. They release MIP3α/CCL20, attracting immature DCs [43]. Renal tubular epithelial cells produce GM-CSF, inducing pDCs to perform phagocytosis and enhancing the alloantigen responsiveness of CD4+ and CD8+ T cells, which may act in the indirect alloantigen-presentation process [44]. Studies also showed the importance of pDCs in the induction of tolerance via the special mechanisms [45]. A recent study indicated that Tregs could also induce DC_reg generation, which was probably due to the contents of extracellular vesicles (such as miR-150-5p and miR-142-3p) released by Tregs, and that these DC_reg could secrete increased amounts of IL-10 and decreased amounts of IL-6 when stimulated with LPS [46].

The renal parenchyma consists of the renal cortex and medulla. The renal cortex is rich in blood vessels, and the renal medulla shows a significant osmotic gradient. Microarray analysis suggested that the hypertonic environment of the renal medulla could induce medulla DCs to dramatically increase the expression of transcripts with anti-inflammatory functions while reducing the expression of alloantigen-recognition transcripts, reducing the risk of local alloantigen rejection. The results indicated that the renal medulla environment might inhibit alloantigen responsiveness by regulating DCs [47,48]. Study results for a large-sample phenotypic detection and transcriptomic analysis of three kinds of DCs (mDC1, mDC2, and pDCs) from mice and humans showed that the functions of DC subtypes from different lymphatic hematopoietic systems due to the cell origin rather than the microenvironment. In comparison, DC subtypes from human lungs and skin were affected by the tissue microenvironment [49]. Currently, no reports on the origin of renal DCs have been published, but renal DCs perhaps have relatively special phenotypes and functions in inflammatory responses and noninflamed tissue. After infusion into recipients, the ideal prognosis for DC_reg is the following progression: binding to endothelial cells, infiltrating allograft tissues, migrating into lymphatic vessels, traveling to secondary or primary lymphoid organs, and inducing alloantigen-responsive T cell apoptosis, clonal deletion or Treg generation, thus exerting an immunosuppressive effect. Therefore, we cannot neglect the potential role of the renal allograft microenvironment in DC_reg development, and we need to prepare DC_reg with high stability and chemotactic performance.

The origin of DC_reg and induction method selection

The team of Professor Li YP at Sichuan University of China conducted a meta-analysis of the effects of adoptively transferred DC_reg on renal allografts according to cell source, infusion route, mechanism and so on. They concluded that DC_reg derived from rat and mouse bone marrow precursor cells could induce immune tolerance in MHC-mismatched renal allografts and extend survival time; the effects of tolerance induction by immature DCs and genetically modified DC_reg were not significant [50]. The consulted references were all reports on rodent KT_x, and the DC_reg were derived from unrelated individuals; thus, the authors did not refer to the origin of the DC_reg. However, the obtained results are of great significance for reference [51]. To enhance the specificity of DC_reg, the study gradually shifted to performing KT_x in larger animals, and bone marrow precursor cells or peripheral blood mononuclear cells were collected from donors or recipients to induce DC_reg.

Professor Thomas AW and his team completed a series of studies. They carried out rhesus monkey KT_x and cell therapy with DC_reg. In their studies, DC_reg were induced from donor peripheral blood mononuclear cells with vitamin D3 and IL-10 in combination with GM-CSF and IL-4. During the course of cell therapy, 8 weeks of CTLA4-Ig administration and 6 months of rapamycin treatment were continued. The results showed that DC_reg significantly prolonged the survival of renal allografts [52]. Further analysis indicated that the function of DC_reg was associated with downregulation of Emos transcript levels and upregulation of CTLA4 expression in donor responsive CD8+ memory T cells [53]. Infusion of DC_reg before transplantation sustained a high frequency of CD4+CTLA4hi T cells after transplantation, even if CD28 costimulatory signaling was blocked [54]. The authors obtained enhanced immunosuppressive effects with combined usage of donor antigen-loaded autologousderived DC_reg and low-dose immunosuppressants [55]. Their research results indicate the great potential of DC_reg application in organ transplantation recipients [56-58]. Now, their team is recruiting volunteers for phase I clinical trials of a DC_reg-based cell therapy, and they plan to apply donor-derived DC_reg induced with vitamin D3 and IL-10. Another team that carried out an in-depth study of DC_reg is Professor Cuturi MC’s team at Nantes University of France [59,60]. In the clinical trial “The One Study”, they adoptively transferred autologous DC_reg pulsed with low-dose GM-CSF to treat living KT_x recipients only once before surgery. Although no report has been published, the authors reported that no signs of rejection were observed after immunosuppressant withdrawal [61]. In these clinical trials, conventional induction methods were applied, and clinical effects remain to be reported. With developments in structural biology, pharmacology, genomics, immunology and other related disciplines, new induction methods are being developed to improve the performance and stability of DC_reg.

It has been accepted that adoptive transfer of DC_reg should have good clinical application prospects given capability of these DCs to protect allografts [62]. We need to establish a treatment plan that can be referred to before clinical usage [63]. For solid organ transplantation, such as KT_x, the characteristics of kidney immunology and immunosuppressive regimens should be considered during the preparation of DC_reg. Furthermore, the development of sensitive, safe and effective immunosurveillance markers is also a priority.

The authors gratefully acknowledge financial support from the 15th batch of the “six talent peaks” project in Jiangsu Province and the Science and Technology Project of the Changzhou Health Committee of Jiangsu Province (ZD201761).

None.

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