Effect of perioperative autologous versus allogeneic blood transfusion on the immune system in gastric cancer patients

Effect of perioperative autologous versus allogeneic blood transfusion on the immune system in gastric cancer patients first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:yanminnina@hotmail.com †E-mail:yanminnina@hotmail.com yanminnina@hotmail.com Department of Anesthesiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Anesthesiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Background: 2 Allogeneic blood transfusion-induced immunomodulation (TRIM) and its adverse effect on the prognosis of patients treated surgically for cancer remain complex and controversial. However, the potential risk associated with allogeneic blood transfusion has heightened interest in the use of autologous blood transfusion. In the present study, the serum concentrations of neopterin, interferon-gamma (IFN-γ), T lymphocyte subsets (CD3 + , CD4 + , CD8 + , CD4 + /CD8 + ) and a possible association between these variables were investigated. The purpose was to further evaluate the effect of autologous versus allogeneic blood transfusion on immunological status in patients undergoing surgery for gastric cancer. Methods: 2 Sixty ASA I~II (American Society of Anesthesiologists) patients undergoing elective radical resection for stomach cancer were randomly allocated to receive either allogeneic blood transfusion ( n =30) or autologous blood transfusion ( n =30). Serum concentrations of the neopterin, IFN-γ and T lymphocyte subsets in the recipients were measured before induction of anesthesia, after operation, and on the 5th postoperative day. Results: 2 Both two groups, serum neopterin, IFN-γ, percentages of T-cell subsets (CD3 + , CD4 + ), and CD4 + /CD8 + ratio had significantly decreased after operation, but decreased more significantly in group H (receiving allogeneic blood transfusion) than those in group A (receiving autologous whole blood transfusion) ( P < 0.05). On the 5th postoperative day, serum neopterin, IFN-γ, CD3 + , CD4 + T-cells, and CD4 + /CD8 + ratio returned to the baseline values in group A. In contrast, the above remain decreasing in group H, where there were no significant relations between serum neopterin and IFN-γ. Conclusion: 2 Perioperative surgical trauma and stress have an immunosuppressive impact on gastric cancer patients. Allogeneic blood transfusion exacerbates the impaired immune response. Autologous blood transfusion might be significantly beneficial for immune-compromised patients in the perioperative period, clearly showing its superiority over allogeneic blood transfusion. Transfusion-induced immunomodulation (TRIM) Autologous blood transfusion Allogeneic blood transfusion Neopterin Interferon-gamma (IFN-γ) CD3 + CD4 + CD4 + /CD8 + ratio INTRODUCTION 1 Cancer radical resection is often associated with greater surgical trauma and longer operative time, as well as more blood loss. It is not surprising that patients demand blood transfusion support to save life during the perioperative period. Unfortunately, an untoward effect of blood transfusion is immunosuppression, which has been postulated to result in promoting tumor recurrence and metastasis, etc. Several studies indicated that immunosuppressive effect is mediated by the leukocytes presence in allogeneic blood (Kirkley, 1999 1999 ; Chu, 1999 1999 ). The infusion of incompatible major histocompatibility complex antigens between donor and recipient may be responsible for this deleterious effect (Lin et al., 2002 2002 ). Perioperative decrease in the interleukin-2 (IL-2) and natural killer (NK) cells activity suggested that allogeneic blood transfusion compromises the immune response (Bar-Yosef et al., 2001 2001 ; Yan et al., 2005 2005 ). In summary, there are many transfusion-induced immunomodulatory complications, whose exact mechanism has not been fully elucidated. Nevertheless, these above-mentioned potential risks have heightened interest in the use of autologous blood transfusion. Many researches showed that autologous blood transfusion was a cost-effective alternative to reduce allogeneic blood consumption in perioperative period (Carless et al., 2004 2004 ; Vanderlinde et al., 2002 2002 ; Lewis et al., 2005 2005 ). But up to now, there are few data available on the effects of autologous blood transfusion on immune function. Recently, it has become clear that an effective immune response is largely dependent on the activation of T lymphocytes. The various cytokines secreted by activated T lymphocytes are involved in immune regulation. Hereinto, interferon-gamma (IFN-γ) is one of cytokines produced by T lymphocytes of the CD8 + cytotoxic/suppressor cells and CD4 + helper cells, which plays an important role in innate and adaptive immunity. IFN-γ may upregulate the expression of major histocompatibility complex (MHC) to contribute to the immunological responses (Nagao et al., 2000 2000 ). It also activates macrophages to kill tumor cells by releasing reactive oxygen intermediates and TNF-α (tumor necrosis factor-α) (Ray and Kirschner, 2006 2006 ). Additionally, neopterin is mainly synthesized by activated monocytes/macrophages in response to induction by IFN-γ. Measurement of neopterin concentrations in body fluids like serum, cerebrospinal fluid or urine provides information about T helper cell 1-derived cellular immune activation (Murr et al., 2002 2002 ). Due to its early and highly change to various pathological situations, neopterin in human body fluids is considered a reliable marker as monitoring processes, development and prognosis of many diseases including immune disorders, inflammations, and coronary artery diseases (Murr et al., 2002 2002 ; Melichar et al., 2006 2006 ). Taken together, these findings indicate that cell-mediated immune response is highly related to the activity of IFN-γ and neopterin. Therefore, in the present study, we hypothesize that the levels of IFN-γ and neopterin may reliably and sensitively reflect autologous or allogeneic blood transfusion-associated immunomodulation. We measured the serum concentrations of neopterin, IFN-γ, T lymphocyte subsets (CD3 + , CD4 + , CD8 + , CD4 + /CD8 + ) in the perioperative period and investigated a possible association between neopterin and IFN-γ. The aim was to further evaluate the effect of autologous versus allogeneic blood transfusion on immunological status in patients with gastric carcinoma. MATERIALS AND METHODS 1 Patients 2 After the protocol for the present study was approved by the Ethics Committee of Zhejiang University (Hangzhou, China), sixty ASA I~II (American Society of Anesthesiologists) patients, aged 40~65 years (33 male, 27 female), undergoing elective radical resection for stomach cancer were studied. All the patients’ preoperative hemoglobin (Hb) was >110 g/L, and hematocrit (Hct) >33%. The patients with cardiovascular, respiratory, hepatic, renal diseases, endocrinopathy and immune disease were excluded. Patients with a history of blood transfusion were excluded from this study to avoid the effects of previous transfusion. The patients undergoing radiotherapy, chemotherapy and hormone therapy were not included. They were divided randomly into two groups: group A and group H. Group A received autologous whole blood transfusion, whereas group H received allogeneic blood transfusion. Anesthesia 2 Patients were premedicated with intramuscular injection of diazepam (10 mg) and atropine (0.5 mg). Anesthesia was induced with intravenous midazolam (0.1 mg/kg), fentanyl (5 μg/kg), propofol (1 mg/kg) and vecuronium (0.12 mg/kg), and was maintained with isoflurane inhalation (1%~2%) and intermittent boluses of fentanyl and vecuronium. The patients were ventilated mechanically. Monitoring consisted of electrocardiogram, heart rate, respiratory rate, invasive arterial pressure (systolic, diastolic, and mean), and peripheral arterial oxygen saturation by pulse oximetry (SpO 2 ), end-tidal CO 2 (EtCO 2 ). The patients were subjected to radical gastrectomy (for cancer) and gastroenterostomy. When operation was over, all patients recovered in the PACU (post anesthesia care unit). Methods 2 Group H received 400 ml of allogeneic blood during the period of gastroenterostomy only if the loss of blood exceeded 500 ml and Hb was below 100 g/L. In group A, 400 ml of autologous blood was removed from radical artery before surgery and 500 ml of plasma substitute was given via internal jugular vein at the same time. Mean arterial pressure was maintained at 70~90 mmHg on average all along. Group A also received autologous blood at the time of gastroenterostomy. Sample collections 2 Blood samples (5 ml venous blood) were taken from internal jugular vein before induction of anesthesia (baseline), after operation (day 0), and on the 5th postoperative day (day 5) into Vacutainer tubes containing or not ethylenediaminetetraacetic acid (EDTA), respectively. Determination of serum neopterin, plasma IFN-γ 2 All blood samples without EDTA were centrifuged immediately and supernatants were stored at −70 °C till assay. The concentrations of serum neopterin and IFN-γ were determined by enzyme-linked immunosorbent assay (ELISA). The kits of neopterin were provided by the tumor graduate school of the Second Affiliated Hospital of Zhejiang University. The kits of IFN-γ were produced by Genzyme Company in Cambridge, MA, USA. Determination of T lymphocyte subsets 2 T lymphocyte subsets were determined using whole-blood flow cytometry. A hundred microlitres anticoagulated blood samples with EDTA were incubated with 20 μl of relevant monoclonal antibody reagent containing CD3-peridnin-chlorophyll protein (PerCP), CD4-fluorescein isothiocyanate (FITC), and CD8-phycoerythrin (PE) at room temperature for 45 min, followed by adding 2 ml erythrocytes lysis solution and incubation at room temperature for 10 min. The mixture was centrifuged at 4 °C for 12 000 r/min×5 min and the supernatant was removed. The cell pellets were washed with 1×PBS (phosphate-buffered saline) solution, collected by centrifugation, resuspended in 1 ml 1% paraformaldehyde (pH 7.3) immediately, then measured with a FACSCalibur™ flow cytometer and analyzed with CellQuest 3.1™ software (Becton Dickinson Immunocytometry Systems) that counts 10 000 cells. Statistics 2 The patients’ data were recorded and calculated with SPSS 11.0. t -test was used to compare the character of patients between different groups. After test of homogeneity (all P > 0.05), one-way analysis of variance (ANOVA) was used to compare the difference of time within A or H group; LSD (least significant difference) was used to test the difference for day 0 and day 5 compared with baseline. When compare the difference between A and H groups, two-way ANOVA was used. Linear correlation analysis between neopterin and IFN-γ was also conducted. P < 0.05 was considered statistically significant. RESULTS 1 Patient characteristics 2 There were no significant differences between the two groups in age, weight, sex, time length of surgery and amount of blood loss (Table 1 1 ). Values are expressed as mean± SD . No significant changes between the groups. Group H received allogeneic blood transfusion; Group A received autologous whole blood transfusion Sex (male/female) Age (year) Weight (kg) Operation time (h) Total blood loss (ml) Group H ( n =30) 17/13 51.3±6.5 61.0±3.1 3.3±0.4 604.2±178.2 Group A ( n =30) 16/14 49.3±6.5 64.2±5.9 3.1±0.5 583.3±182.5 Serum neopterin and IFN-γ analysis 2 In the group H, serum neopterin and IFN-γ decreased significantly after operation and on the 5th postoperative day as compared with the baseline (before induction of anesthesia) values ( P < 0.05 or P < 0.01). In the group A, serum neopterin and IFN-γ also decreased significantly after operation as compared with the baseline values ( P < 0.05). However, on the 5th postoperative day, they returned to the baseline values. Between the two groups there were no differences in serum neopterin and IFN-γ before induction of anesthesia ( P > 0.05). Serum neopterin in the group H decreased significantly compared with that in group A ( P < 0.05) after operation. On the 5th postoperative day, in the group H, serum neopterin and IFN-γ decreased significantly compared with those in the group A ( P < 0.05 or P < 0.01) (Fig. 1 1 ). Group H received allogeneic blood transfusion; Group A received autologous whole blood transfusion. * P < 0.05, ** P < 0.01, compared with before operation; # P < 0.05, ## P < 0.01, compared with group H Correlation analysis: In the group H, the correlation coefficients of serum neopterin and IFN-γ before operation, after operation, and on the 5th postoperative day were: r =0.082, P > 0.05; r =0.089, P > 0.05; r =0.092, P > 0.05. There were no significant differences. T lymphocyte subsets analysis 2 Before induction of anesthesia, no significant differences were observed in the percentages of T-cell subsets (CD3 + , CD4 + , CD8 + ) and CD4 + /CD8 + ratio between the two groups. After operation (day 0), CD3 + , CD4 + T-cells and CD4 + /CD8 + ratio decreased significantly relative to baseline (before induction of anesthesia) values in both groups ( P < 0.05 or P < 0.01), but decreased more significantly in group H than in group A ( P < 0.05). On the 5th postoperative day (day 5), CD3 + , CD4 + T-cells and CD4 + /CD8 + ratio were basically close to the baseline values in group A ( P > 0.05) but remained low in group H. CD8 + T-cells had no significant changes in both groups during the perioperative period (Table 2 2 ). Values are expressed as mean± SD . Expression of CD3 + , CD4 + , and CD8 + before induction of anesthesia (baseline), after operation (day 0) and on the 5th postoperative day (day 5) in the two groups. Group H received allogeneic blood transfusion; Group A received autologous whole blood transfusion. P < 0.05, compared with before operation P < 0.01, compared with before operation P < 0.05, compared with group H P < 0.01, compared with group H Group ( n =30) CD3 + (%) CD4 + (%) CD8 + (%) CD4 + /CD8 + Baseline H 65.0±4.1 38.2±5.1 28.6±4.9 1.36±0.31 A 67.2±5.1 39.9±4.9 27.3±4.1 1.44±0.23 Day 0 H 53.7±4.5 * * 27.0±5.2 ** ** 26.4±4.2 1.02±0.33 * * A 59.7±5.3 * * # # 31.7±5.0 * * # # 27.1±3.9 1.15±0.29 * * Day 5 H 52.1±5.4 ** ** 26.5±3.9 ** ** 26.7±4.3 0.99±0.21 ** ** A 63.1±4.7 ## ## 37.4±4.9 ## ## 26.9±4.6 1.32±0.26 ## ## DISCUSSION 1 Recently, multiple proposed pathologic mechanisms that account for the allogeneic blood transfusion-induced immunomodulation (TRIM) were complex and surrounded by controversy in the perioperative period. In this study, we showed that in gastric cancer patients undergoing allogeneic blood transfusion concentrations of serum neopterin significantly reduced after surgery (day 0) and remained in decreasing trend on the 5th postoperative day (day 5). Such a reduction has been paralleled to the drop of IFN-γ cytokine, CD3 + , CD4 + T lymphocyte cells and the CD4 + /CD8 + ratio. As compared with autologous blood transfusion, these results demonstrate that allogeneic blood transfusion causes long-term cell-mediated immunosuppression and suggest that various immune cells and cytokines are involved in TRIM complications. Several investigations have indicated that an observed reduction of CD3 + , CD4 + T lymphocyte subsets after allogeneic blood transfusion is likely to be mediated by leukocyte alloantigens and plasma components (Claas et al., 2001 2001 ; Biedler et al., 2002 2002 ). Patients with documented recurrence and metastasis of cancer at the time of blood drawing had the lower T cell counts of many of those studied (Kuss et al., 2004 2004 ). Accordingly, we consider the possibility that the decrease in CD3 + , CD4 + T cells, as well as CD4 + /CD8 + ratio, might adversely influence antitumor response. Furthermore, not CD8 + T cells, but reduction of CD4 + T cells showed imbalance in lymphocyte differentiation and proliferation. This disturbed lymphocyte homeostasis might be especially detrimental in malignant patients with poor prognosis (Kuss et al., 2004 2004 ). The depressed secretion of IFN-γ cytokine in the postoperative period accorded with the findings of other investigators. We have demonstrated a decrease in IL-2 production in stimulated lymphocytes after allogeneic blood transfusion (Yan et al., 2005 2005 ). Such a decrease could be simply related to the impaired CD4 + Th1 (T help) of which IFN-γ and IL-2 are products. In contrast, a preponderance of CD4 + Th2 cytokines (IL-4, IL-5, IL-10) over CD4 + Th1 cytokines (IFN-γ, IL-2) in posttransfusion stimulated lymphocytes was found in both mice and humans (Potter et al., 2003 2003 ; Kirkley et al., 1995 1995 ; Babcock and Alexander, 1996 1996 ). The Th2 cytokine pattern is associated with decreased cytotoxic cell functions and inhibition of macrophage activation (Potter et al., 2003 2003 ; Kirkley et al., 1998 1998 ). These studies also seem to show a hypothetical mechanism of TRIM that Th2 cells can produce immunosuppression in transfusion recipients by down-regulating the activity of Th1 cells. Increasing amounts of neopterin synthesis in body fluids are associated with activated cell-mediated immunity. Jin et al.( 2005 2005 ) and Altindağ et al.( 1998 1998 ) showed that increased productions of neopterin are proportional to the progression of autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus (SLE). In other words, the results of the present study indicate that down-modulation of serum neopterin sensitively reflects immunosuppressive situation. Additionally, Wirleitner et al.( 2002 2002 ) suggested that monocytes/macrophages were thought to be the unique source of neopterin biosynthesis. In vitro IFN-γ is usually a potent inducer (Murr et al., 2002 2002 ). Interestingly, in this study despite a significant decrease in serum neopterin and IFN-γ cytokine in patients undergoing allogeneic blood transfusion, no correlation was observed between the two phenomena. This investigation was supported by Sghiri et al. ( 2005 2005 ), who demonstrated that IFN-γ is not the only stimulus in vivo needed for the synthesis of neopterin in patients with impairment of the IFN-γ pathway. Therefore, rather than the depressed secretion of IFN-γ cytokine, we speculate that allogeneic blood transfusion directly and/or by other cytokines down-regulates monocytes/macrophage function to exert their inhibitory and regulatory properties on neopterin production. Certainly, further studies need to be done to substantiate this. In the autologous blood group, the decrease in serum neopterin, IFN-γ cytokine and T lymphocyte subsets shows immune suppression after surgery (day 0). However, its inhibitory effect significantly dropped as compared with allogeneic blood transfusion. This observed decreased immune response is mainly attributed to surgical trauma in the autologous blood group (Schneemilch et al., 2005 2005 ). Moreover, anesthetic agents, blood loss and psychological stress may contribute to perioperative immunosuppression (Andersen et al., 1998 1998 ; Bar-Yosef et al., 2001 2001 ). The above-mentioned assumptions were also confirmed by the present findings. On the 5th postoperative day, once trauma and stress reactions weakened, cell-mediated immune response basically got its breath again. Thus, evidence from the present study suggests that autologous blood transfusion had no significant immune suppression effects. Whereas, Heiss et al.( 1997 1997 ) reported that autologous blood transfusions probably stimulated a Th1 pattern with decreased IL-10 and increased IL-2 plasma levels to up-regulate cell-mediated immune function. Several evidences exist that in patients with malignant tumor, anti-tumor cellular responses are suppressed (Yan et al., 2005 2005 ; Ordemann et al., 2002 2002 ). Immunosuppression further increases undergoing surgical procedures. Significant immunosuppression was suggested to contribute to cancer recurrence and metastasis, which brings high morbidity and mortality (Kuss et al., 2004 2004 ; Angele and Faist, 2002 2002 ; Biedler et al., 2002 2002 ). 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Immunologic changes to autologous transfusion after operational trauma in malignant tumor patients: neopterin and interleukin-2 10.1631/jzus.2007.B0560 Project supported by the Health Department of Zhejiang Province (No. 2004A040) and the Education Department of Zhejiang Province (No. G20030486), China 2007-04-25 2007-06-28 2022-01-05 Copyright © 2007, Journal of Zhejiang University Science 2007 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 08 08