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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 3  |  Page : 521-525
The Interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation


1 Organ Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Web Publication7-May-2012
 

   Abstract 

We studied the correlation between changes in the serum levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) with complications such as acute graft versus host disease (aGVHD), veno-occlusive disease (VOD) or occurrence of infection after hematopoietic stem cell transplantation (HSCT). Serum VEGF and IL-6 levels were sequentially measured by enzyme-linked immunosorbant assay (ELISA) in 35 patients who had undergone HSCT. Serum levels of IL-6 in patients with aGVHD were increased in comparison with patients without aGVHD, but the difference was not statistically significant. Serum levels of VEGF were only increased in patients with aGVHD during the early days after transplantation. No signi­ficantly altered levels of IL-6 and VEGF were observed in patients with VOD or sepsis. These results demonstrate that rising levels of VEGF and IL-6 may be good and specific biomarkers for transplant aGVHD.

How to cite this article:
Azarpira N, Dehghani M, Darai M. The Interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation. Saudi J Kidney Dis Transpl 2012;23:521-5

How to cite this URL:
Azarpira N, Dehghani M, Darai M. The Interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Aug 25];23:521-5. Available from: http://www.sjkdt.org/text.asp?2012/23/3/521/95787

   Introduction Top


Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several ma­lignant and non-malignant disorders. Transplant-related complications (TRC) such as graft-versus-host disease (GVHD), infections or veno-occlusive disease (VOD) following HSCT may present with similar symptoms. Therefore, detection of these complications is essential for early appropriate intervention. Monitoring serum levels of cytokines before and after transplantation may be predictive of the occur­rence of these complications. [1]

Interleukin-6 (IL-6) acts as a pro-inflamma­tory and anti-inflammatory cytokine. Its role as an anti-inflammatory cytokine is mediated through its inhibitory effects on tumor necrosis factor-alfa and IL-1, and activation of IL-10. [2] There is an association between elevated IL-6 serum level with TRC in HSCT, [3] and other organ recipients. [4]

Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis. It also acts as a potent chemo-attractive cytokine for leukocytes. It might be one of the regulatory factors in immune reactions. [5]

VEGF has been observed in human renal and cardiac allografts, and its expression is asso­ciated with acute and chronic rejection. [6],[7],[8],[9]

High VEGF serum levels were reported in HSCT recipients with GVHD. [10] However, low circulating levels of VEGF were reported in patients with severe GVHD. [11]

We aimed from our study to evaluate the serum levels of the VEGF and IL-6 and asso­ciation of these markers with aGVHD, VOD or infection occurrence.


   Materials and Methods Top


We studied prospectively 35 HSCT patients followed-up at the Bone Marrow Transplan­tation Center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran (11 females and 24 males with an age range from 3 to 48 years). There were 16 cases of acute and chro­nic leukemia, 12 cases of thalassemia and seven cases of metastatic bone marrow lesions [Table 1]. Written informed consent was obtained from all patients allowing analyses of the clinical data and testing mentioned in this article. The ethics committee of Shiraz University of Me­dical Sciences approved the study.
Table 1: Transplant characteristic of the studied patients.

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Engraftment was confirmed by peripheral blood counts (myeloid: peripheral absolute neutrophil count of more than 0.5 × 10 9 /L, megakaryocyte: peripheral platelet count of more than 20 × 10 9 /L for at least three consecutive days without requiring transfusion).

Uncomplicated HSCT was defined as absence of any organ dysfunction. Acute and chronic GVHD were diagnosed and graded using esta­blished criteria. [12] Hepatic VOD was diagnosed and classified by the clinical syndrome of hepatomegaly and pain, fluid retention and weight gain, with serum bilirubin concentra­tion >2 mg/dL. [13] Sampling was done on days 0 (before transplantation) and one and three weeks after transplantation.

The clinical status of the patients (e.g., com­plications) was reported on the same day of blood sampling.

The commonly used conditioning regimen consisted of busulfan, cyclophosphamide and antithymocyte globulin. Conditioning regimens for thalasemic patients were composed of cyclophosphamide and busulfan. GVHD prophy­laxis included cyclosporine A (CSA)/methotrexate (MTX, 6-10 mg/m 2 only on days 1, 3 and 6 after transplantation).

IL-6 was measured with a commercially available enzyme-linked immunosorbant assay (ELISA) kit (Biosource Europe, Fleurus, Bel­gium). VEGF was also measured with the ELISA kit (VEGF Immunoassay; R and D Systems, Minneapolis, MN, USA).


   Statistical Analysis Top


The Mann-Whitney U-test, Pearson Chi-Square and Fisher's exact tests were used for the different statistical analyses. P-values <0.05 were considered significant. Analyses were performed with the SPSS software (Statistical Package for the Social Sciences, version 15, SSPS Inc, Chicago, IL, USA).


   Results Top


Nineteen (54.3%) patients received autolo-gous HSCT and 16 (45.7%) received allogeneic HSCT. Eleven patients (34.37%) developed aGVHD (Grade I-III, mean of 17 days). Engraftment succeeded earlier in patients without aGVHD (Day 10) than in those with aGVHD (Day 13). We did not find a significant corre­lation between donor age, underlying disease and sex with the aGVHD (P >0.05). Serum le­vels of IL-6 in patients with aGVHD+ were increased in comparison with patients who were aGVHD-, but the difference was not statistically significant (P >0.05). There were no significant differences in the patients with different grades of aGVHD.

Serum levels of VEGF, in aGVHD+ patients, were increased after transplantation apart from aGVHD- patients who did not show any dif­ferences after transplantation (P >0.05). There were also no significant differences in patients with different grades of GVHD (P >0.05). As aGVHD improved, the IL-6 levels decreased, but there was no relationship between VEGF levels and aGVHD status after treatment.

VOD developed in one patient and sepsis was detected in two others. No altered levels of IL-6 and VEGF were observed in the patient with VOD, but increased levels of IL-6 was obser­ved in patients with sepsis. Finally, there was no significant correlation between the under­lying diseases, the age of the patient, the day of engraftment, donor age and sex with the severity of aGVHD (P >0.05).


   Discussion Top


The underlying pathophysiology of TRC is unclear [14] ; however, the identification of a new biomarker that can be used to predict these complications is of interest.

IL-6 is a pleiotropic cytokine with multiple endocrine, paracrine and possibly autocrine activities in various tissues.

Various cells, including T- and B-cells, monocytes, endothelial cells, bone marrow stroma cells and several tumor cells produce it. It regulates the growth and differentiation of various cell types with major activities on the immune system, hematopoiesis and inflam­mation. It seems to play a role in the pathophysiology of aG-VHD. [2] Pihusch et al found an association of elevated IL-6 serum levels with TRC, especially GVHD, VOD and infection. [3] In our study, the IL-6 serum levels in­creased in aGVHD and infection similar to a previous study. [11] The association between IL-6 -174 GG genotype and increased risk of aGVHD was found in a recent study. [15]

IL-6 also has anti-inflammatory properties; therefore, an opposite function is anticipated from this cytokine. Perez-Villa et al [16] and Tomura et al [17] suggested that IL-6 down-regulates the immune response by inhibiting interferon-gamma production. Accordingly, a protective role for IL-6 that might result in prolongation of graft survival was suggested. Deng et al. found higher levels of IL-6 after heart transplantation associated with lower biopsy scores. [4]

VEGF is a potent angiogenesis factor that has important roles in both normal physiological as well as pathological angiogenesis. [3] It is pro­duced by endothelial cells, macrophages and activated T cells, [4],[5] and acts as a pro-inflam­matory cytokine, which can induce the expres­sion of endothelial cell adhesion molecules, and also acts as a monocyte chemoattractant. [18] Lunn et al. found that serum VEGF levels were significantly higher in the HSCT reci­pients with aGVHD. [10] According to Min et al, low circulating levels of VEGF after transplantation were associated with an incidence of severe aGV-HD. [11] Kim et al. found that pat­ients with low VEGF production (i.e., +936CT genotype and two copies of the ACG haplotype) had a higher incidence of aGVHD, and suggested that VE-GF might have a protective role in the pathogenesis of aGVHD. [19] As men­tioned earlier, VEGF has been observed in human renal and cardiac allografts, and its expression is associated with acute and chro­nic rejection. [6],[7],[8],[9],[20] In our study, the VEGF se­rum levels increased in recipients suffering from aGVHD, and this finding is similar to a previous study. [10]

In this study, although the IL-6 and VEGF serum levels increased in aGVHD, the rela­tionship was not significant. No significant correlation was found between the underlying disease, age of the patient and the levels of these markers. One of the limitations of our study was the sample size. Therefore, we reco­mmend a large prospective trial in allogeneic stem cell recipients with longer follow-up to validate the clinical significance of IL-6 and VEGF serum levels for discrimination bet­ween the different TRC following HSCT.

 
   References Top

1.Lunn RA, Sumar N, Bansal AS, Treleaven J. Cytokine profiles in stem cell transplantation: possible use as a predictor of graft-versus-host disease. Hematology 2005;10:107-14.  Back to cited text no. 1
    
2.Symington FW, Symington BE, Liu PY, Viguet H, Santhanam U, Sehgal PB. The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation. Transplantation 1992;54:457-62.  Back to cited text no. 2
    
3.Pihusch M, Pihusch R, Fraunberger P, et al. Evaluation of C-reactive protein, interleukin-6, and procalcitonin levels in allogeneic hematopoietic stem cell recipients. Eur J Haematol 2006;76:93-101.  Back to cited text no. 3
    
4.Deng MC, Erren M, Kammerling L, et al. The relation of interleukin-6, tumor necrosis factor-alpha, IL-2, and IL-2 receptor levels to cellular rejection, allograft dysfunction, and clinical events early after cardiac transplantation. Transplantation 1995;60:1118-24.  Back to cited text no. 4
    
5.Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000;55:15-35.  Back to cited text no. 5
    
6.Reinders ME, Fang JC, Wong W, Ganz P, Briscoe DM. Expression patterns of vascular endothelial growth factor in human cardiac allografts: Association with rejection. Transplantation 2003;76:224-30.  Back to cited text no. 6
    
7.Shahbazi M, Fryer AA, Pravica V, et al. Vas­cular endothelial growth factor gene poly­morphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 2002;13: 260-4.  Back to cited text no. 7
    
8.Pilmore HL, Eris JM, Painter DM, Bishop GA, McCaughan GW. Vascular endothelial growth factor expression in human chronic renal allograft rejection. Transplantation 1999;67:929-33.  Back to cited text no. 8
    
9.Torry RJ, Labarrere CA, Torry DS, Holt VJ, Faulk WP. Vascular endothelial growth factor expression in transplanted human hearts. Transplantation 1995;60:1451-7.  Back to cited text no. 9
    
10.Lunn RA, Sumar N, Bansal AS, Treleaven J. Cytokine profiles in stem cell transplantation: possible use as a predictor of graft-versus-host disease. Hematology 2005;10:107-14.  Back to cited text no. 10
    
11.Min CK, Kim SY, Lee MJ, et al. Vascular endothelial growth factor (VEGF) is associated with reduced severity of acute graft-versus-host disease and nonrelapse mortality after allogeneic stem cell transplantation. Bone Marrow Transplant 2006;38:149-56.  Back to cited text no. 11
    
12.Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995;15: 825-8.  Back to cited text no. 12
    
13.Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987;44:778-83.  Back to cited text no. 13
    
14.Visentainer JE, Lieber SR, Persoli LB, et al. Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol 2003; 31:1044-50.  Back to cited text no. 14
    
15.Ambruzova Z, Mrazek F, Raida L, et al. Asso­ciation of IL6 and CCL2 gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. Bone Marrow Trans­plant 2009;44:227-35.  Back to cited text no. 15
    
16.Perez-Villa F, Benito B, Llancaqueo M, Cuppoletti A, Roig E. Elevated levels of serum interleukin-6 are associated with low grade cellular rejection in patients with heart trans­plantation. Heart Failure and Heart Transplantation Program, Hospital Clinic, IDIBAPS, Barcelona, Spain. Transplant Proc 2006;38: 3012-5.  Back to cited text no. 16
    
17.Tomura M, Nakatani I, Murachi M, Tai XG, To-yo-oka K, Fujiwara H. Suppression of allograft responses induced by interleukin-6, which selectively modulates interferon-gamma but not interleukin-2 production. Transplantation 1997;64:757-63.  Back to cited text no. 17
    
18.Melter M, Reinders ME, Sho M, et al. Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo. Blood 2000;96:3801-8.  Back to cited text no. 18
    
19.Kim DH, Lee NY, Lee MH, Sohn SK. Vas­cular endothelial growth factor gene poly­morphisms may predict the risk of acute graft versus-host disease following allogeneic transplantation: preventive effect of vascular endothelial growth factor gene on acute graft-versus-host disease. Biol Blood Marrow Transplant 2008;14:1408-16.  Back to cited text no. 19
    
20.Malmström NK, Kallio EA, Rintala JM, et al. Vascular endothelial growth factor in chronic rat allograft nephropathy. Transpl Immunol 2008;19:136-44.  Back to cited text no. 20
    

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Correspondence Address:
Negar Azarpira
Organ Transplant Research Center, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz
Iran
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