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Mo1737 Granulo-Monocytes Apheresis Induce TGFβ1 Modulation in Neutrophils of Patients Suffering From Ulcerative Colitis: A Possible Role of Soluble HLA-I Molecules

Massimo Ghio, Giorgia Bodini, Paola Contini, Vincenzo Savarino, Edoardo Savarino Gastroenterology, 2015 148(4), S-698–. doi:10.1016/S0016-5085(15)32367-2 

Background Plasmapheresis is used in immune-mediate disease in order to remove humoral factors and, in addition, to modulate cellular immunity. It has been shown that during aphaeretic centrifugation , whole and/or re-folded soluble HLA class I molecules (sHLAI) bind to the circuit surfaces. Similarly, neutrophils can bind sHLA-I molecules with immunoglobulin-like transcript (ILT) membrane receptors, becoming hereafter sensitive to
the immunomodulation of sHLA-I such as transcriptional and post-transcriptional transforming growth factor (TGF)-β1 modulation. On the other hand, TGFβ signaling plays a major role in the pathogenesis of inflammatory bowel diseases and it is known to directly induce Foxp3 expression. Besides, Foxp3 expression has been reported increased in patients who responded to granulocytes apheresis with remission of clinical symptoms. Aim The aim of this prospective study was to evaluate a possible sHLA-I mediated immunomodulation in granulocytes and monocytes apheresis in ulcerative colitis patients who responded to therapy. Methods We prospectively enrolled a total of 10 patients (4M/6F; mean age 49, range 27-73) who achieved clinical remission with GMA. The GMA sessions (5 cycle/session) were performed using Adacolumn device. Instantly before each single apheresis and immediately after each procedure, neutrophils were analyzed for a possible in vivo aftermath of sHLA-I binding with corresponding ligands Ig-like-transcripts. The concentrations of sFasL molecules were determined by double-determinant immunoassay (DDIA) and the concentrations of TGFb1 were determined by double-determinant immunoassays utilizing a commercially available kits. Results Between every GMA cycle a significant upregulation of intracytoplasmic TGFβ1 molecule or TGFβ1-mRNA was observed in neutrophils and CD8+ T lymphocytes drawn along the apheretic therapeutic treatments. In particular, the greatest mean increase was found after the first and the forth GMA cycles (from +1% to +30%). A significant up-regulation of sFasL and TGFβ1 concentrations in plasma was observed along the procedures. Similarly, the mean difference increases in comparison with previous samples were constantly found raising during scheduled blood sampling for both molecules. In CD4+ T lymphocytes, unable to bind sHLA-I, the aphaeretic procedures never induced TGFβ1 modulation Conclusion: Our findings suggest that the immunosuppressive effects following therapeutic apheresis might at least in part depend on activated leukocyte sensitivity to sHLA-I molecule bioactivity.

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HLA-DR(hi) and CCR9 Define a Pro-Inflammatory Monocyte Subset in IBD.

Ludvig Linton 1Mats KarlssonJeanette GrundströmEric HjalmarssonAnnelie LindbergEmma LindhHans GliseRagnar BefritsIzabella JanczewskaPer KarlénOla WinqvistMichael Eberhardson, Clin Transl Gastroenterol. 2012 Dec 20;3(12):e29.

CD14(+)HLA-DR(hi) blood monocytes were increased in patients with active IBD. These monocytes exhibit a pro-inflammatory, gut-homing phenotype with regard to their TNF-α production and expression of CCR9. Our results suggest that these monocytes are important in mediating intestinal inflammation, and provide potential therapeutic targets in IBD.

Scientific corner

Granulocyte and Monocyte Adsorption Apheresis Therapy Modulates Monocyte-Derived Dendritic Cell Function in Patients With Ulcerative Colitis

Yuko Iwakami,Atsushi Sakuraba,Toshiro Sato,Yasuhiro Takada,Motoko Izumiya,Hitoshi Ichikawa,Toshifumi Hibi Ther Apher Dial 13, 2 (2009); 138-146

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-γ (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16+ monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocytcde antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-γ and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.

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