Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation - single centre experience.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients' and donors' age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. PATIENTS AND METHODS: Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1-218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. RESULTS: GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. CONCLUSION: We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.

Soluble HLA-G, its diagnostic and prognostic value and potential target molecule for future therapy in cancer.

Human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule that regulates many immune functions. The physiologic HLA-G expression is restricted to foetal tissues such as: amniotic cells, erythroid precursors, and cytotrophoblasts, and, in adults, to immune-privileged organs. The ectopic expression in tumours could point out to a strategy used by malignant cells to escape the immune surveillance. There are two forms of HLA-G, membrane-bound and soluble. The structure of the soluble and membrane bound isoforms differs at the C-terminus. The extracellular domain and the intracytoplasmic tail are replaced in the secreted isoforms by a short hydrophilic tail. These differences could serve as a marker to distinguish shed or proteolytically cleaved HLA-G isoforms from secreted HLA-G isoforms. HLA-G induces tolerance by inhibiting different cells and this function is mediated by binding of both soluble and membrane-bound HLA-G to the inhibitory receptors. There exists a consistent evidence in literature that HLA-G represents an important factor in determining prognosis in various types of cancer. In this review, we will focus on soluble form of HLA-G (sHLA-G) in cancers and its association with the prognosis of cancer patients, because this immune check-point molecule appears as a promising relevant target for cancer immunotherapy (Fig. 2, Ref. 115). Keywords: cancer, diagnosis, HLA-G, soluble HLA-G, tumour.

Triggering receptor expressed on myeloid cells 1 and 2 in patients with chronic maxillary sinusitis.

PURPOSE: Chronic sinusitis can result from variable types of immune-mediated process, whose pathogenesis is not fully understood. Triggering receptors expressed on myeloid cells 1 and 2 (TREM-1, TREM-2) are involved in myeloid cell activation enabling these cells to fine-tune the inflammatory response, which may have an impact on subsequent adaptive immunity and may be the key factor in pathogenesis. The aim of the study was to analyse soluble TREM-1 and TREM-2 molecules in maxillary sinus lavage fluid and compare the defined subgroups selected from patients with chronic sinusitis with/without nasal polyps and allergy (asthma and allergic rhinitis). METHODS: The levels of soluble TREM-1 and TREM-2 were measured by Elisa test in a cohort of patients with chronic maxillary sinusitis (n=45). We compared subgroups of patients with nasal polyps (n=33) and allergy (n=25: inclusive of asthma (n=11) and allergic rhinitis (n=14)) with the control group of patients without nasal polyps (n=13), and without allergy (n=21). RESULTS: The study did not prove the difference between subgroups with and without nasal polyps. The levels of soluble TREM-1 did not differ significantly between patients with allergy (asthma and allergic rhinitis) and the control group without allergy (p=0.4804). The levels of soluble TREM-2 were significantly higher in patients with allergy (p=0.0028), asthma (p=0.0103) and allergic rhinitis (p=0.0137) as compared with the control group. CONCLUSION: Our results suggest the role of TREM-2­mediated activation of myeloid cells in chronic sinusitis accompanied by allergy, asthma, and allergic rhinitis (Tab. 6, Ref. 25).

Low serum vitamin D levels are associated with a low percentage of TREM-2+ monocytes in low-grade gliomas and poorer overall survival in patients with high-grade gliomas.

INTRODUCTION: Anti-inflammatory effect of vitamin D (VD) could be beneficial in improving the survival of glioma patients. The aim of our study was to analyse the serum levels of vitamin D in glioma patients and to find an association with the prognosis of glioma patients and other investigated parameters. MATERIAL AND METHODS: The study included 63 patients with gliomas. Percentage of CD14+ monocytes, TREM-1+ and TREM-2+ monocytes were determined by flow cytometry, serum levels of 25(OH)D were evaluated by electrochemiluminescent binding test. RESULTS: Six patients out of 63 had normal levels of VD. A significant difference in the overall survival (OS) in the patients with severe VD deficiency, VD deficiency and insufficiency in grade IV was found. In grade II and III, the levels of vitamin D positively correlated with the percentage of TREM-2+ monocytes, and in grade II also a negative correlation of VD with TREM-1/TREM-2 ratio was observed. CONCLUSION: Levels of VD could influence the prognosis of patients with high-grade gliomas. Serum level of 25(OH)D in low-grade gliomas positively correlated with the percentage of anti-inflammatory acting TREM-2+ monocytes and negatively with TREM-1/TREM-2 ratio. This could be protective against the progression to high-grade glioma, because TREM-2 is associated with protective functions such as: tissue repair, control of local inflammation, or phagocytosis (Tab. 4, Fig. 4, Ref. 79).

TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients.

OBJECTIVE: In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. RESULTS: Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. CONCLUSION: We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.

Decreased plasma levels of 25(OH)D in multiple sclerosis patients. Correlation with disease severity expressed by EDSS, MSSS, progression index and Herbert´s scale severity grade.

OBJECTIVES: Multiple sclerosis is a chronic inflammatory and autoimmune demyelinating disease of the brain and spinal cord. Vitamin D has anti-inflammatory and anti-Th1, Th17 activities, activates the function of regulatory T cells, shifts the immune response towards Th2, so it might be favorable for downregulation of the disease pathogenesis, and if inflammation and Th1 and Th17 immunity are hyperactivated. The aim of our study was to highlight the role of vitamin D in multiple sclerosis pathogenesis. METHODS: We investigated 178 patients with multiple sclerosis. Plasma levels of 25(OH)D and HMGB1 were investigated. RESULTS: Despite a regular use of VD by patients, the plasma levels of 25(0H)D were significantly decreased in 57% of them, 14.1% had VD deficiency (level of 25(OH)D < 20 ng/mL) and more than 6 % of patients had VD severe deficiency with the plasma level of 25(OH)D < 12 ng/mL. The level of 25(OH)D negatively correlated with the severity of the disease (EDSS, index of progression, duration of the disease) and negative association was found also with Herbert´s six severity grades. HMGB1 levels were higher in patients (p < 0.0001). CONCLUSION: Our result showed that vitamin D deficiency plays a role in multiple sclerosis pathogenesis. We believe that administration of vitamin D to patients at a sufficient dose providing a physiological level of vitamin D could have a positive effect on the course of the disease. However, regular monitoring of vitamin D levels is required, which should be at least within 30-75 ng/mL, and even more, but below the toxicity limit (Tab. 6, Ref. 66).

Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation.

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qp site by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qp site inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qp site inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qp site unless intracellular succinate is high. In addition, this validates the Qp site of CII as a target for cell death induction with relevance to cancer therapy.