Molecular Targets for Therapy

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

Abstract

The contribution of Th17 cells in acute graft-versus-host disease (aGVHD) has been demonstrated in aGVHD mouse models. However, their contribution in human gastrointestinal aGVHD remains unclear. We evaluated Th17 cells in a cohort of 23 patients at diagnosis of aGVHD. In this study, we have shown that the absolute number of Th17 cells using the CCR6 and CD161 markers were significantly higher in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD. Moreover, in keeping with the increase of CCR6+ and CD161+ T cells, RORγt the key transcription factor that orchestrates the differentiation of Th17 cells, was significantly increased in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD (P=0.01). Since plasmacytoid dendritic cells (PDCs) have been reported to drive the differentiation of the Th17 subset, we quantified PDCs in these patients. PDC CD123+ cells were increased in the intestinal mucosa of patients with aGVHD. Furthermore, the number of CD123+ PDCs paralleled the histological grade of aGVHD, providing evidence for a role of Th17-mediated responses and a potential new pathophysiological link between PDCs and Th17 in human aGVHD.

Introduction

Acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (allo-SCT) is an exaggerated immune response against alloantigens involving dysregulation of inflammatory cytokine cascades. Previous studies established an important role of Th1 cells in aGVHD pathophysiology.1, 2, 3 However, the identification of proinflammatory Th17 cells, which contribute to autoimmune diseases, especially inflammatory bowel disease4 raised the question of the role of Th17 cells in human aGVHD. The contribution of Th17 cells in aGVHD has been explored in GVHD mouse models with conflicting results. Some data suggested that interleukin (IL)-17 is protective,5 while others indicated a pathogenic role.6, 7 Of note, transplantation of Th17 cells caused lethal GVHD hallmarked by extensive tissue damage.8 Finally, blockade of both Th1 and Th17 differentiation is required to prevent GVHD in mice.9 In humans, an increased Th17 population in blood was observed in patients with aGVHD,10 it was also reported that the imbalance between Th17 and regulatory T cells can be correlated with the pathological grade of GVHD.11 In cutaneous GVHD, Broady et al.12 found an expansion of tissue-localized Th1 and not Th17 cells. However, the contribution of Th17 cells to gastrointestinal aGVHD pathogenesis remains unclear. With this background, we investigated the role of Th17 cells in the gastrointestinal biopsies of aGVHD patients.

Patients and methods

Patients and study design

Studies described in this report were undertaken in a cohort of 23 patients who underwent allo-SCT at the University-Hospital of Nantes (Nantes, France) between May 2007 and December 2010. Patients included in this study were diagnosed with gastrointestinal aGVHD by histological examination of biopsies. The non-GVHD controls were asymptomatic allo-SCT patients. All patients were enrolled in clinical research protocols approved by local ethical committees. The control patients were all-SCT patients who volunteered to participate to the study and did not have digestive symptoms. Written informed consent was obtained in accordance with the Declaration of Helsinki. Patients, donors and allo-SCT characteristics of these patients are summarized in Table 1.

Table 1 Patients, disease and transplant characteristics

Morphological and immunohistochemical studies

Intestinal biopsies (n=16 colonic, 4 rectal and 3 duodenal biopsies), obtained by fiber-optic examination for digestive symptoms (vomiting, diarrhea…) or in asymptomatic controls, were performed before any steroid treatment. One biopsy was analyzed for each patient. The median post-transplant time of biopsies was 42 days (range, 14–137): 35 days (range, 27–50) in the control group, 47 days (range, 14–137) in the aGVHD group. GI aGVHD was confirmed on formalin-fixed and paraffin-embedded biopsies and graded on hematoxylin and eosin-stained sections according to the grading system described by Sale et al.13 and Epstein et al.14 grade 1=isolated apoptotic epithelial cells without crypt loss; grade 2=individual crypt loss; grade 3=contiguous area of multiple crypt loss; grade 4=extensive crypt dropout with denudation of epithelium. As controls, colonic and duodenal biopsies from five patients without clinical and pathological GI aGVHD were also examined on hematoxylin and eosin-stained sections. None had evidence of viral infection. Immunohistochemistry was performed on 5 μm formalin-fixed, paraffin-embedded sections using an indirect immunoperoxidase method. Slides were stained with the following primary antibodies: Tbet (clone 4B10; Santa Cruz Biotechnology, Santa Cruz, CA, USA), CD161 (clone B199.2; AbD Serotec, Colmar, France), CCR6 (clone 53103; R&D Systems, Abingdon, UK), RORγt (rabbit polyclonal antibody; Abcam, Paris, France) and CD123 (clone 9F5; BD Biosciences, Franklin Lakes, NJ, USA). The immunological reaction was visualized with the Bond Polymer Refine Detection system (Leica Biosystems, Newcastle upon Tyne, UK) and 3,3-diaminobenzidine tetrahydrochloride as the chromogen. As negative control, omission of primary antibodies was performed. Quantitative evaluation of antigens expression was performed independently by two examiners (CB, FM) by counting the absolute number of positive cells in the whole biopsy at 200 magnifications (mean 10 fields) for each sample.

Statistical analysis

Clinical, morphological information as well as the number of Tbet, CD161, CCR6, RORγt and CD123+ cells were entered in a database. Data were computed using GraphPad Prism 5.0 (GraphPad Software, San Diego, CA, USA). Mann–Whitney non-parametric test and analysis of variance test were used to assess (1) the correlation between the number of Th1, Th17 and CD123+ cells and the presence of aGVHD and (2) the correlation between the number of Th17 cells and CD123+ cells and the histological grade of aGVHD.

Results and discussion

Th17 cells have a major role in the pathogenesis of human inflammatory bowel disease,4 and mouse studies have shown the presence of Th17 cells in the gastrointestinal mucosa of mice with gastrointestinal aGVHD.7 We hypothesized that Th17 cells could preferentially accumulate within the target tissues of aGVHD. Thus, gastrointestinal biopsies obtained from a cohort of 23 allo-SCT patients (n=5 without and 18 with histologically proven GI aGVHD taken before starting corticosteroids) were analyzed for Th17 cell infiltration. Th17 cells have been found to express the mucosal chemokine receptor CCR6 but not CCR10.15, 16 Also, the C-type lectin-like receptor CD161 is another well-established marker of human Th17 cells.17

In this study, we have shown that the absolute number of CD161+cells was significantly higher in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD (P=0.0045). The absolute number of CCR6+cells was also higher in intestinal mucosa of patients with aGVHD, but the difference was not statistically significant. These CD161 and CCR6 + cells were mainly found in the lamina propria but also in the epithelium of altered glands (Figures 1a–d). To confirm the Th17 cells infiltration, we assessed the expression of RORγt, the key transcription factor that orchestrates the differentiation of Th17 cells.18 In keeping with the increase of CCR6+ and CD161+ T cells, RORγt+ cells with a nuclear staining were significantly increased in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD (P=0.01) (Figures 1e and f), further supporting a role for Th17 cells in gastrointestinal aGVHD pathophysiology. As reported elsewhere, we also found an increased number of the cells expressing Tbet, the transcription factor characterizing the Th1 cells, in the intestinal mucosa of patients with aGVHD compared with patients without aGVHD (P=0.02, data not shown).

Figure 1
figure1

Th17 cells and PDCs infiltrate the intestinal mucosa of GI aGVHD patients. Formalin-fixed and paraffin-embedded tissue samples of colonic and/or duodenal biopsies. Biopsies from 23 patients including patients with histologically confirmed GI aGVHD (N=18) or no aGVHD (N=5) were collected and analyzed morphologically and by immunohistochemistry. For the quantitative evaluation, the mean number of positive cells for each marker, obtained from each patient, was retained for the statistical analysis. Examples of CCR6+ (a), CD161+ (c), RORγT+ (e) or CD123+ (g) mononuclear cells around altered mucosal glands with numerous apoptotic epithelial cells (arrows) are shown (original magnification × 400). The quantitative evaluation of CCR6+ (b), CD161+ (d), RORγT+ (f) or CD123+ (h) cells in intestinal mucosa is represented. The quantitative evaluation of CD123 (h) cells is represented according to the histological grade (grade 0 aGVHD, N=5; grades 1–2 aGVHD, N=7; grades 3–4 aGVHD, N=11). The mean value and s.e.m. for each group is represented.

Since plasmacytoid dendritic cells (PDCs), the professional type I interferon (IFN)-secreting cells, were shown to have a major role in different autoimmune diseases19, 20 and in triggering Th17-related cytokines,21, 22, 23, 24 we sought next to determine the density of PDCs in intestinal biopsies from patients with and without aGVHD. We observed a significant increase of CD123+ PDCs in the intestinal mucosa of patients with aGVHD compared with mucosa of patients without aGVHD (P=0.01, data not shown), these positive cells being around altered glands. Furthermore, the number of CD123+ cells paralleled the histological grade of aGVHD: the higher the grade, the higher the number of PDC (P=0.01) (Figures 1g and h). There was also a tendency to an increased number of CD161+ cells and RORγt+ cells in histological grades 3–4 aGVHD compared with grades 1–2 aGVHD, but this difference was not statistically significant.

The current study shed some light on the role of Th17 cells in the context of GI aGVHD. Using well-established specific markers, we have shown that Th17 cells infiltrate intestinal mucosa from patients with aGVHD. In addition, Th17 cells infiltration paralleled the infiltration of CD123+ PDCs, suggesting a potential new pathophysiological link between PDCs and Th17 response in the context of gastrointestinal aGVHD. Unfortunately, the relatively limited number of patients analyzed as part of this study, did not allow establishing statistically significant correlations between immunosuppression levels or types (e.g., use of mycophenolate mofetil or not) and PDCs and Th17 infiltration. Also, there was no statistically significant correlation between the Th17 cells and GVHD histology grade, endoscopic GVHD grading or response to steroids.

Controversies exist regarding the role of Th17 cells in the pathogenesis of human aGVHD. Broady et al.12 did not find an association between Th17 cells and the onset of human aGVHD. But this study focused only on skin pathology, and it remains possible that T-cell differentiation differs depending on the environment and was not the same in skin aGVHD and gastrointestinal aGVHD. Also, conditioning and immunosuppressive regimens, stem cell source, disease features and different experimental conditions such as in vitro culture might all have impacted the cytokine profile of pathogenic cells described by Broady et al.12 Ratajczak et al.11 did not find a significant infiltration of CD4+ IL-17+ T cells in the intestinal mucosa of patients with aGVHD. This study was based on the in situ detection of IL-17 by CD4+cells. However, recent in vivo studies in mice have shown that Th17 cells can acquire the capacity to completely shut off IL-17 production in the course of inflammatory immune responses.25 Similarly, conditioning and immunosuppressive regimens are very different in the study by Ratajczak et al.,11 with a majority of myeloablative conditioning regimens, compared with our study. The latter might explain the observed differences between both studies. Furthermore, some studies, especially in autoimmune diseases, proposed that the Th17 phenotype is unstable and that Th17 cells may convert to Th1 cells.26 We can suggest that in a context of gastrointestinal aGVHD, some Th17 cells infiltrate early the intestinal mucosa and then can differentiate into Th1 cells making their detection more difficult if intestinal biopsies are performed too late after the onset of aGVHD. Recently, Esplugues et al.27 proposed a general mechanism for controlling immunopathogenic Th17 response by acquisition of an immune-suppressive phenotype or elimination into the intestinal lumen. We can speculate that Th17 recruited in the intestine of patients after allo-SCT are retained in the inflamed tissues and either conserve their pathologic properties or convert into a Th1 phenotype rather than a regulatory phenotype.

From the pathophysiological standpoint, our findings support a gut aGVHD induction model that can mimic data from other autoimmune diseases,20, 21, 28, 29 where recruited PDCs in GVHD target tissues following local damage (e.g., conditioning regimen), can promote the production of Th17 cytokines, as the induction of Th17-related cytokines is abrogated in PDC-depleted mice.21 This is consistent with studies showing that PDCs can drive the differentiation of Th17 cells.22, 23, 24 Moreover, type I IFN produced by PDCs after stimulation with a TLR7 agonist could drive Th17 responses in vivo.30 Although the exact mechanism that links type I IFN production to PDC-mediated Th17 response is still unclear in aGVHD, data described in this paper does not contradict the established role of Th1 cells in aGVHD pathophysiology.31 In fact, human Th17 cells may exhibit a close developmental relationship with Th1 cells.26 A likely scenario is a synchronized or reciprocal interplay between Th1 and Th17 as reported in autoimmune arthritis.26

In summary, our study provides a framework for a role of PDCs and Th17-mediated responses in human aGVHD. As a matter of fact, the current study does not provide a specific cause-effect link between Th17 cells and GI aGVHD, as multiple other pathways could be triggered by PDCs and type I IFNs. However, these data raise the prospect of future innovative approaches to optimize immunosuppression regimens for the treatment or prophylaxis of aGVHD by targeting PDCs and the Th17 response. There are already clinical trials aiming to block the Th17 response using anti-IL-17 monoclonal antibodies for autoimmune diseases.32

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Acknowledgements

We acknowledge the technical and logistical support of V Dehame, S Leclercq, S Blandin, C Deleine and E Drouet. We also thank the nursing staff for providing excellent care for our patients, and the following physicians: N Blin, E Brissot, X Cahu, V Dubruille, T Gastinne, JL Harousseau, S Le Gouill, B Mahe, F Mechinaud, P Moreau and F Rialland for their dedicated patient care. We also thank the ‘Région Pays de Loire,’ the ‘Association pour la Recherchesur le Cancer (ARC; Grant #3175 to MM and BG),’ the ‘Fondation de France,’ the ‘Fondation contre la Leucémie,’ the ‘Agence de Biomédecine,’ the ‘Association Cent pour Sang la Vie,’ the ‘Association Laurette Fuguain’ and the IRGHET for their generous and continuous support for our clinical and basic research work. Our transplant program was supported by several grants from the French national cancer institute (PHRC INCa to MM). We acknowledge the continuous support of the cell banking facility (‘tumorotheque’) of the CHU de Nantes.

Author contributions

All authors listed in the manuscript have contributed substantially to this work: conception and design: Mohamad Mohty, Béatrice Gaugler, Céline Bossard and Jean-François Mosnier; financial support: Mohamad Mohty, Béatrice Gaugler, Pierre Tiberghien and Philippe Saas; administrative and logistical support: Mohamad Mohty, Béatrice Gaugler, Pierre Tiberghien and Philippe Saas; provision of study materials and patients care: Patrice Chevallier, Thierry Guillaume, Jacques Delaunay and Mohamad Mohty; experimental work: Céline Bossard, Florent Malard, Jessy Arbez and Béatrice Gaugler; collection and assembly of clinical data: Florent Malard and Mohamad Mohty; data analysis and interpretation: Céline Bossard, Florent Malard, Jessy Arbez, Mohamad Mohty, Béatrice Gaugler, Philippe Saas and Pierre Tiberghien; manuscript writing and revision: Mohamad Mohty, Céline Bossard, Florent Malard and Béatrice Gaugler; final approval of manuscript: all co-authors.

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Bossard, C., Malard, F., Arbez, J. et al. Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease. Leukemia 26, 1471–1474 (2012). https://doi.org/10.1038/leu.2012.41

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Keywords

  • acute GVHD
  • Th17 cells
  • plasmacytoid dendritic cells

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