scholarly journals Dipeptidyl Peptidase‐4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

Author(s):  
Enbo Zhu ◽  
Lina Hu ◽  
Hongxian Wu ◽  
Limei Piao ◽  
Guangxian Zhao ◽  
...  
Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xian Wu Cheng ◽  
Enbo Zhu ◽  
Lina Hu ◽  
Yanna Lei ◽  
Limei Piao ◽  
...  

Background: Dipeptidyl peptidase-4 (DPP4) inhibition exhibits multiple pleotrophic effects. Hematopoietic stem cell (HSC) activation has been implicated in the pathogenesis of stress-related metabolic disorder and cardiovascular disease. Given that interaction between β3-adrenergic receptor (Adrβ3) signaling and the immune system may link stress and the initiation and progression of disorders, we investigated whether DPP4 regulates immune over-reactions in a chronic stress mouse model, focusing on HSC activation. Methods and Results: Male 8-week-old mice fed a normal diet underwent chronic stress were randomly assigned to one of three groups and administered vehicle or a low or high dose of the DPP4 inhibitor anagliptin. Control mice were left undisturbed. The stress increased the blood and brain DPP4 activity, the levels of plasma adrenaline and noradrenaline, and the bone marrow (BM) niche cell adrenergic receptor (Adrβ3) expression, and it decreased the levels of plasma glucagon-like peptide (GLP-1) as well as brain GLP-1 receptor (GLP-1R) and BM Cxcl12 expressions. These changes were reversed by DPP4 inhibition. The stress activated the BM sca-1 high c-Kit high CD48 low CD150 high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. These DPP4 inhibition-related benefits were mimicked by DPP4 depletion and by GLP-1R activation. Adrβ3 inhibition mitigated BM Cxcl12 expressions and HSC activation. Conclusions: DPP4 activity appears to regulate chronic stress-induced BM HSC activation and inflammatory cell production via an Adrβ3-CXCLl12-dependent mechanism that is mediated by the GLP-1-GLP-1R axis, suggesting that the inhibition of DPP4 or the stimulation of GLP-1R may have applications in the treatment of inflammatory diseases.


Cell Reports ◽  
2020 ◽  
Vol 33 (12) ◽  
pp. 108530
Author(s):  
Marcus A. Florez ◽  
Katie A. Matatall ◽  
Youngjae Jeong ◽  
Laura Ortinau ◽  
Paul W. Shafer ◽  
...  

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5415-5415
Author(s):  
Anna Kopinska ◽  
Malgorzata Krawczyk-Kulis ◽  
Joanna Dziaczkowska-Suszek ◽  
Katarzyna Bieszczad ◽  
Krystyna Jagoda ◽  
...  

Abstract Introduction Autologous hematopoietic stem cell transplantation (AHSCT) remains the treatment of choice in multiple myeloma (MM) patients (pts). In earlier research it has been suggested that the expression of dipeptidyl peptidase-4 (DPP4, CD26) influences both the homing and lymphocyte reconstitution after AHSCT in pts with lymphoproliferative neoplasms. The aim of the study is to investigate the effect of transplanted CD26 positive cells of the hematopoietic recovery and lymphocyte reconstitution in MM pts after AHSCT. Patients and methods Forty eight pts with MM with median age 56 (range 21-76) were undergoing AHSCT in our center in years 2011-2013. Conditioning regimen was Melphalan 200. Number of all CD26+ cells, CD26+ lymphocytes, CD26+ monocytes and CD26+ and CD34+ cells were measured in harvested material. Number of lymphocyte's subpopulations (all lymphocytes CD3+, helpers CD3+CD4+, suppressors CD3+CD8+, natural killer (NK) CD3-CD16+CD56+, cytotoxic NK CD3+CD16+CD56+, lymphocytes B CD3-CD19+) were measured in peripheral blood during regeneration period after AHSCT. In both flow cytometry was used. The hematopoietic regeneration was measured as following: the day of white blood cells' regeneration when WBC count reached >1,0x109/L, the day of granulocytes' regeneration when ANC >0,5x109/L and the day of platelets' regeneration when PLT >20x109/L. Results All pts successfully engrafted. The results of AHSCT are shown in table nr 1. Table 1. The number of transplanted cells and regeneration during the procedure AHSCT in pts with MM. Parameter Median Range Mean Standard deviation Number of transplanted WBCx108/kg b.w. 4,26 0,73-18,8 5,43 4,36 Number of transplanted CD34+cells x106/kg b.w. 3,36 2,2-8,2 3,52 1,28 Number of transplanted CD26+ lymphocytes [109/L] 46,5 9-148 53,6 30,8 Number of transplanted CD26+ monocytes [109/L] 3,65 0-82 8,03 13,05 Number of all transplanted CD26+ cells [109/L] 50,42 9,6-213 62,5 23,2 Regeneration WBC >1x109/L (day) 13 10-20 13 2,64 ANC >0.5x109/L (day) 13 9-20 13,3 2,16 PLT >20x109/L (day) 14 11-20 14,1 2,18 As regards regeneration of hematopoietic cells after AHSCT it was shown that a higher number of transplanted CD26+ monocytes improves the reconstitution of suppressor (p=0,019) and NK lymphocytes (p=0,0237). A higher number of all transplanted CD26+ lymphocytes has a positive impact of the reconstitution of suppressor lymphocytes (p=0,0054), whereas a higher number of all transplanted the CD26+ cells improves the regeneration of cytotoxic NK (p=0,0126) and helper lymphocytes (p=0,0261). There were no confirmed adverse effects of the number of CD26+ cells on the hematopoietic regeneration0 and lymphocytes B reconstitution after AHSCT. Discussion Our research shows that the number of transplanted CD26-positive cells may improve immune reconstitution after AHSCT in patients with multiple myeloma, which was not clearly demonstrated before. As is well known faster lymphocyte reconstitution after AHSCT is associated with improved patient survival. Therefore, the greater the number of transplanted autologous CD26-positive cells may be associated with improved survival, which, however, needs further investigation. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2010-2010
Author(s):  
Irena Frydecka ◽  
Lidia Karabon ◽  
Edyta Pawlak-Adamska ◽  
Anna Tomkiewicz ◽  
Tomasz Wrobel ◽  
...  

Abstract Abstract 2010 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely carried out as a therapy for several hematological malignances and non malignant disorders. Graft–versus -host disease is one of the major complications after allo-HSCT with main cause of morbidity and mortality. Donor T lymphocytes play the crucial role in alloimmune recognition and their ability to detect non –self antigens can lead to aGvHD. The effective recognition and activation of naïve T-cells requires two independent signals. The first, an antigen-specific signal, is sent via the T-cell receptor (TCR) on T-cells. The second signal, termed co-stimulation, is critical for allowing full activation, sustaining cell proliferation, preventing anergy and/or apoptosis, inducing differentiation to effector cells. CD28 is the primary T-cell co-stimulatory molecule. Cytotoxic T-cell antigen (CTLA-4) is a homologous molecule of CD28 which plays an inhibitory role in the early and late stages of T-cell activation. CTLA-4 ligation provides a negative signal for regulation of the cell cycle and inhibits the activity of the transcriptional factors: nuclear factor-kB (NF-kB), nuclear factor of activated T-cells (NF-AT), and activator protein 1 (AP-1). Moreover, CTLA-4 binds to CD28 ligands (CD80 and CD86) with higher affinity and avidity and in that way also inhibits T-cell activation. Since co-stimulatory and down regulatory molecules synthesis depend on the rate of gene transcription and/or translation, polymorphisms in the corresponding genes might result in abnormal expression, function as well as dysregulated trafficking of these molecules within cellular compartments. The human CTLA-4 gene is located on 2q33 which is susceptibility region for autoimmune diseases. The aim of this study is to investigate the associations between polymorphisms in CTLA-4 gene: CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g6230G>A (CT60, rs3087243), CTLA-4g.10223G>T (Jo31, rs11571302) in donors of HSTC and occurrence of aGvH disease in recipients after allogeneic hematopoietic stem cell transplantation. Altogether 136 donors of HSCT (58- related donors, 88 haploidentical unrelated donors) were genotyped for all polymorphisms using allelic discrimination methods with the TaqManÒ SNP Genotyping Assay. In patients without aGvHD and in patients with aGvHD grade I-IV the similar distribution of alleles and genotypes for all investigated polymorphisms in donors was observed. However, we have noticed trend toward increased frequency of CT60 [G] donor allele among recipients with aGvHD I-IV (0.48 vs. 0.39, p=0.1, OR 1.49, 95% CI: 0.90–2.49) compared to recipients without aGvHD in whole group of patients. In patients transplanted from related donor also increased risk of aGvHD grade I-IV was observed for CT60 [G] donor allele (0.75 vs. 0.55, p=0.09, OR 2.11, 95%CI: 0.88–5.26). In contrary the frequencies of CT60 [G] donor allele in patients transplanted from unrelated donors are similar in recipients with and without aGvH symptoms. Haplotype estimation analysis indicated that donor haplotype CTLA-4c.49A>G[A], CTLA-4g.319C>T[C], CT60 [A], Jo31 [T] tended to be protective against aGvHD grade I-IV in whole studied group of patients (0.28 vs. 0.40, p=0.06, OR 0.60, 95% CI: 0.36–1.02) This association reach statistical significance in recipients of related transplantation (0.18 vs. 0.43, p=0.01, OR 0.29, 95% CI: 0.14–0.97) Our study indicated that donor CT60 polymorphism might be associated with occurrence of aGvHD, especially in recipients transplanted from HLA-identical sibling donors. Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 26 (5) ◽  
pp. 722-738.e7 ◽  
Author(s):  
Pia Sommerkamp ◽  
Sandro Altamura ◽  
Simon Renders ◽  
Andreas Narr ◽  
Luisa Ladel ◽  
...  

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