Hematopoetik Kök Hücre Nakli Yapılmış Hastalarda Anjiyogenik Faktör Düzeylerinin Agvhh ile İlişkisi

Abstract

ABSTRACT Şatırer Ö, The relationship between aGvHH and angiogenetic factor levels in hematopoietic stem cell transport. Child Health and Diseases Thesis, Ankara, 2019. Allogeneic hematopoietic stem cell transplantation (HSCT) is a very important treatment for disease eradication, especially in hematological cancers. However, when the effect of graft versus leukemia spreading out of the hematopoietic system, an acute alloreactive immunological reaction, causes acute graft versus host disease (GvHD) which is one of the most important transplant complications. The ongoing laboratory and clinical studies have begun to better understand the etiopathogenesis of aGvHH. However, the efficacy / safety of none of the different biomarker panels (systemic inflammation, immune activation, associated with endothelial injury / activation) to provide early detection of aGvHH development or steroid treatment response could not be established. Recent scientific data have shown that vascular endothelial cell damage, dysfunction and / or activation are as critical as immune activation in the development of aGvHH. Intensive preparation regimens including chemotherapy and radiotherapy given before transplantation, prophylactic immunosuppressive therapies, growth factors used to support engraftment and developing infections may cause endothelial damage. Endothelial damage leads to endothelial cell activation and stimulation of angiogenesis. Although the role of angiogenesis in aGvHH development has been demonstrated by different research results, the role of the relationship between angiogenesis and inflammation in the pathogenesis of aGvHH is still being investigated. In our study, 37 patients with allogeneic HSCT between June 2008 and October 2018 were included in the study of the Bone Marrow Transplantation Unit, Department of Pediatrics, Hacettepe University, Faculty of Medicine. The patient group consisted of all patients who underwent HSCT for malignant or non-malignant reasons [18 girls, 19 men; Mean age: 8.5 (1-22)]. In addition, 10 healthy stem cell donors were included in the study as a control group. The control group consisted of 7 women and 3 men with a mean age of 22.4 (2-39). Before the preparation regimen of the patients (day -9) and immediately after completion of the preparation regimen, plasma samples collected before transplantation (day 0) from endothelial cell-derived angiogenic factors (Epidermal Growth Factor (EGF), Angiopoietin-2 (Ang2), Endoglin, Follistatin (FS), Heparin-binding epidermal growth factor (HB-EGF), Placental growth factor (PLGF) and Vascular endothelial growth factor A (VEGF-A) levels were studied by multiplex immunoassay method VEGF-A, the trophic factors associated with tissue regeneration. The aim of this study is to obtain an angiogenic profile which can be used to determine the risk of aGvHH development by looking at the levels of HBV-EGF, EGF and inflammation / tissue damage in terms of Ang2, Folistatin and Endoglin levels. pre-regime (-9th day) and later (on day 0) were recorded twice. In all patients included in the study, Ang2, Endoglin, EGF, HB-EGF, VEGF-A plasma levels were examined when the pre-treatment regimen (-9th day) values after the regime (day 0) showed a significant decrease but only Ang2 and Endoglin It was determined that this change was statistically significant when compared with the control group (p <0.05). There was no significant difference between these angiogenic factor levels and the control group (p> 0.05). Plasma Folistatin levels are examined; It was observed that the plasma values were significantly higher when compared with the control group both before the regimen (-9th day) and after the regime (day 0). At the same time, uric acid, albumin, abscess lymphocyte and absolute monocyte values, which are the markers of systemic inflammation, were compared before and after the preparation period. The change in abscess lymphocyte and monocyte values on day minus ninth day and zero day were found to be both statistically significant and statistically significant. In other parameters, although there is a difference in terms of numerical difference, no statistically significant difference was found. The groups that did not develop with aGvHH group were evaluated before and after the administration of the groups. There was no difference between them. Afterwards, it was thought that pre-transplant angiogenic profile could be more meaningful and the index values were calculated with the ratio of the values before and after the regime and whether there was any difference between the patients with and without aGvHD. The mean value of Ang2 index was 3.59 ± 2.98 in the developing group. In the group who did not develop GvHH, this value was 1.99 ± 1.11 (p = 0.043). In the index values of Endoglin, VEGF-A, Folistatin, HB-EGF, uric acid, albumin, lymphocyte and monocyte parameters; There was no statistically significant difference between the two groups. Although the mean survival time of the patients with and without acute GvHH was compared with the patients who did not develop aGvHH compared to the patients who developed it, this difference was not found statistically significant (p> 0.05). According to the results of logistic regression analysis, primary disease classification (malignant vs. nonmalign), Ang2 and albumin index variables were found to be significant in the analyzes made for the risk of developing aGVHD (p <0.05). The risk of acute GvHH is 9.72 times higher than the patients who underwent transplantation because of malignant diseases. It was found that a unit increase in Ang2 index increased the risk of aGvHH disease by 2.24 times and a decrease in albumin value after treatment, ie a one-unit increase in the index value increased the risk of aGvHH by 62 (1 / 0.016). In conclusion, endothelium-related angiogenic factor levels before transplantation in patients undergoing allogeneic HSCT were statistically different from Ang2 index, which was associated with vascular endothelial injury and inflammation. Ang2 value is high and it is determined that patients with high Ang2 index are at risk of developing aGvHH after the preparation regimen. Therefore, there was no relationship between the other angioyogenic factors and aGvHH development. This may be due to the limited number of patients in our study. However, the similar patterns of change in patients with and without aGvHH have been shown to be different from the endothelial cell activation / damage mechanisms seen in the onset of inflammation at the beginning of inflammation in the early period when aGvHH has not been developed. Therefore, in order to determine the risk of aGVHH before transplantation, these mechanisms should be illuminated and these results should be verified with a wider clinical research. The Ang2 and Albumin indices obtained at the end of this study and which are significant in terms of the risk of developing aGvHH also indicate the necessity to investigate this relationship between the onset of angiogenic factors in the immune regulated roles and the onset of inflammation.

Keywords: Hematopoietic Stem Cell Transplantation, Graft versus Host Disease, Angiogenetic Factors