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Basic and Clinical Research of the Role of TIM-3in Transplantation Immunity

Author: LuoYu
Tutor: ShiBingYi
School:
Course: Organ transplant
Keywords: TIM-3 renal transplantation immunologic surveillanceGalectin-9 skin transplantation Treg immunological regulation
CLC: R392
Type: PhD thesis
Year: 2011
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Abstract


Subject:TIM-3has been demonstrated expression on primary T effectors cells which played essential roles in acute allograft rejection (AR), including Thl, CTL, and Th17. In this study we monitored sequential changes of TIM-3gene expression in the peripheral blood leukocytes (PBL) from renal transplant recipients to provide a deeper insight of the role of TIM-3in allograft rejection.Methods:The study consisted of AR-group (n=24), NO-AR group (n=20) and Stable-group (n=18). Prospective, serial blood samples were collected in recent recipients post allograft transplantation and during AR episode. The mRNA encoding for TIM-3was quantified using real time RT-PCR. Statistical analyses were performed to investigate the gene transcripts measurements with the clinical events.Results:TIM-3mRNA in PBL was significantly higher expressed in AR-group comparing to NO-AR group and Stable-group (286.72±86.28vs126.10±28.31;286.72±86.28vs96.91±17.88, p=0.00). The ROC (receiver operating characteristic) curve showed a specificity of90.91%and a sensitivity of90.00%for rejection diagnosis utility of TIM-3.Anti-rejection therapy decreased the TIM-3mRNA expression in all patients with AR at initial time. There was a positive correlation between TIM-3mRNA expression level and serum creatinine (r2=0.716,p=0.00).Conclusions:TIM-3mRNA quantification by real time RT-PCR in PBL may be a promising tool for a noninvasive diagnosis of AR. But the utility for predicting the prognosis of AR after anti-rejection was limited due to the great variation of TIM-3mRNA expression during AR episode. Subject:To explore the effect of Galectin-9on the survival of allogeneic skin grafts in mice and to explore the related mechanism for regulating the immune balance.Methods:Construct the allogeneic skin transplantation model between BALB/c and C57BL/6mice. Median survival time of skin grafts in control-group and study-group were observed. The lymphocytes infiltration in skins on7day after transplantation was investigated by hematoxylin-eosin staining. Analyzed the ratio of CD4+TIM-3+T、CD4+TIM-1+、Thl7、CD4+CD25+Foxp3+Treg in T lymphocytes of PBL and spleen lymphocytes on7,14day after skin transplantation by FCM (flow cytometry).Evaluated the cytokine expression of IL-2、IL-4、IL-17and IFN-γ in blood on7day after transplantation.Results:1. Galectin-9could prolong the survival time of allogeneic skin grafts in mice and the MST in control-group and study-group were12.5days and16days separately.2. Galectin-9could alleviate the lymphocytes infiltration in skin grafts on7day post-operation.3. Galectin-9could down-regulate the retio of Teff cells in CD4+T lymphocytes and have no effection on Treg cells. It was as followings:①CD4+TIM-3+T Galectin-9could down-regulate the CD4+TIM-3+T ratio in blood and spleen lymphocytes on7day after transplantation in study-group (spleen4.82±1.01%vs2.84±0.89%, blood7.13±1.82%vs4.94±1.56%, p<0.05); but have no effect on14day after transplantation (spleen3.34±1.10%vs 3.44±0.98%, blood2.79±0.87%vs2.67±0.84%, p>0.05).②Th17Galectin-9could down-regulate the Th17ratio in PBL on7day after transplantation in study-group (12.42±3.67%vs5.79±1.68%, p<0.05) and have no difference in spleen lymphocytes (5.54±1.38%vs5.78±1.64%, p>0.05); on14day after transplantation, there was no significant differences in PBL (5.21±1.96%vs5.91±2.03%, p>0.05) and the Th17ratio was down-regulated in spleen lymphocytes in study-group (4.61±1.78%vs7.91±2.34%, p<0.05).③CD4+TIM-1+T Galectin-9had no effect on CD4+TIM-1+T ratio in spleen lymphocytes on7,14day after transplantation between two groups (7day3.79±1.35%vs4.27±1.52%,14day3.19±1.26%vs3.92±1.34%, p>0.05); no differences in PBL was found (34.74±4.80%vs34.50±5.00%, p>0.05) on7day, but it was up-regulated in study-group on14day after transplantation (52.80±8.79%vs34.86±5.67%, p<0.05).④CD4+CD25+Foxp3+Treg Galectin-9had no effect on CD4+CD25+Foxp3+Treg ratio in PBL and spleen lymphocytes on7,14day after transplantation (spleen7day10.57±2.56%vs10.02±3.04%,14day11.49±2.87%vs12.93±3.12%, p>0.05;blood7day8.00±1.78%vs8.20±2.01%,14day9.76±2.45%vs10.90±2.67%, p>0.05).4. Galectin-9could decreased the expression of IFN-y (51.33±8.16pg/ml vs98.41±15.01pg/ml, p=0.00) and IL-17(48.50±8.48pg/ml vs15.17±5.46pg/ml, p=0.00) in blood on7day after transplantation; but have no effect on expression of IL-2(23.17±4.22pg/ml vs26.50±3.78pg/ml, p=0.180) and IL-4(86.83±13.33pg/ml vs99.67±11.64pg/ml, p=0.107).Conclusions:Galectin-9could prolong the survival time of allogeneic skin grafts in mice. This was related to the down-regulation of CD4+TIM-3+T and Th17in PBL and spleen lymphocytes. Galectin-9had no effect of CD4+CD25+Foxp3Treg in vivo.

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