小鼠移植物抗宿主病的治疗及初步机理探讨
摘要
急/慢性移植排斥反应是影响移植物长期存活的最主要障碍。寻找更加良好和特异的方法防止和(或)阻断移植物抗宿主病(graft-versus-host disease,GVHD)的发生与发展,将是器官移植领域面临的重要课题。本研究发现：小鼠急性GVHD (acute GVHD, aGVHD)的发生伴随有补体系统的过度活化,抗体中和小鼠体内过量的补体活化产物C5a能减少炎性细胞的浸润,降低体内炎性细胞因子的分泌表达,从而一定程度地延长aGVHD小鼠的存活时间。另一方面,对慢性移植排斥反应诱导的小鼠肾炎模型的研究证实,效应T细胞(Teff)↑/调节性T细胞(Treg)↓免疫失衡是诱导小鼠疾病发生的关键,靶向T细胞的传统免疫抑制剂抗抗CD3单克隆抗体免疫治疗能够通过上调Treg,从而抑制移植效应T细胞(Thl, Th2及Thl7)的活化,减轻慢性GVHD (chronic GVHD, cGVHD)对小鼠的肾脏损伤。总之,我们的研究工作为发现治疗GVHD的新靶点,阐明GVHD治疗机理以及临床上GVHD的辅助治疗提供了一定的理论基础。
Graft-versus-host-disease (GVHD),a major barrier to successful allogeneic hematopoietic cell transplantation (allo-HCT) is a main cause of morbidity and mortality of survivors of allo-HCT and presumably mediated by donor T lymphocytes reactive against the allogeneic antigen of the recipient. Based on different clinical manifestations and histopathology, it can be divided into acute GVHD(aGVHD) and chronic GVHD(cGVHD). Clinically relevant aGVHD develops in 35-50% of patients given HLA-identical hematopoietic cells within the 100 days following transplantation. It primarily affects the skin, liver and the gastrointestinal tract with T cell infiltration, about one half of the patients with moderately severe or severe disease die, because of associated infections. Prophylaxis of acute GVHD by placing the patient in protective isolation,immunosuppressive therapeutics after grafting, or removal of donor lymphocytes from the transplant has not been uniformly successful. Therapy of established GVHD involves the use of immunosuppressants such as glucocorticosteroids, antithymocytc globulin, cyclosporinc, and monoclonal antibodies.cGVHD usually appears 100-500 days after transplantation and affects about 50% of all long-term survivors and can be lethal in approximately 20% to 40% of affected patients in spite of intensive and aggressive drug combination treatments.cGVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to scleroderma and systemic lupus erythematosus(SLE).In addition to the same target organs as aGHVD, cGVHD involves a wider range of organs inclue lacrimal and salivary glands and mucous membranes.Older recipient age and a history of aGVHD are the greatest risk factors for cGVHD. Treatment of cGVHD involves immunosuppressive and cytotoxic drugs which lead to highly susceptible to bacterial and fungal infections that are lethal in a small proportion of patients.
The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. (1) activation of the APCs; (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction.During the whole process of aGVHD,the natural killer (NK) cells,, dendritic cells, macrophages and granulocytes constitute the cellular elements of the innate immune system play a crucial role in inflammatory response and tissue damage. The complement system comprises a strong defense against various pathogens is a major component of the innate immune system.Recently more research demonstrate activation of the complement system can contribute to inflammation and tissue injury and it is described to accelerate the pathogenesis of many diseases. In our study we oberve that the aGVHD mice given allogeneic cell had much higher level of complement-activated product C3a,C5a in liver compared with the mice given syngeneic cell transplantation,an increased hepatic mRNA expression levels of C3a,C5a and their receptors were also detected in aGVHD mice.These findings suggested that activation of the complement system is associated with aGVHD. C5a is one of the most potent inflammatory peptides, with a broad spectrum of functions,displays powerful biological activities that lead to inflammatory disorder.After blocking C5a with C5a polyclonal antibody in aGVHD mice, we observed the level of C5a,C3a in liver was decreased compared with the IgG control, in addition hepatic mRNA abundance for C5a,C3a and their receptors was redued after C5aAb treatment. Interestingly,the inflammatory cell infiltration in liver and the hepatic mRNA expression levels for TNF-a,IFN-y,IL-1β,IL-2 and IL-6 were decresed by C5a Ab.In splenocyt we also found the mRNA expression of TNF-a,IFN-y,IL-6 and IL-10 were down-regulation. These results indicate that C5a Ab may suppresses the biological activities of C5a,such as increased vascular permeability, chemotaxis of inflammatory cells, cytokine and chemokine release and phagocytosis,then reduced tissual lesion, ameliorated the severity of the aGVHD in mice.
Because of the lack of highly satisfactory animal models and basic studies in patients,the pathophysiology of cGVHD remains poorly understood. cGVHD is a pleiotropic disease with clinical and pathological signs and symptoms similar to various autoimmune diseases. Based on the study up on animal models, T cells was the central role in initiating GVHD, numerous research evaluating T cell depletion and inhibitoion as prophylaxis for GVHD. In this paper, we first used 145-2C11 Ab(anti CD3 mAb) to treat lupus nephritis induced by cGVHD in mice.The results showed that short-term low-dose anti-CD3 antibody treatment induced a significant remission of established proteinuria, production of autoantibodies, immune complex deposition and renal parenchyma lesions in cGVHD mice. Of note, we found a robust up-regulation of Foxp3 mRNA expression in the target tissue:kidney from mice with anti-CD3 antibody treatment compared to those with control IgG treatment. Likewise, an increased renal mRNA abundance for IL-10 was also observed in anti-CD3 antibody treated mice. In contrast, genes associated with inflammation and fibrosis as well as cytokines related to effector T cell responses were down-regulated by anti-CD3 mAb treatment. These findings suggested that short-term low-dose anti-CD3 antibody treatment might induced an IL-10-secreting Foxp3+ regulatory T cells in this cGVHD target tissue: kidney, that suppressed the activation of effector T cells (Th1,Th2 and Th17), thus ameliorating the severity of the lupus nephritis in mice.
In conclusion,our studies suggested that undesired complement activation accompany with aGVHD in mice may exert its harmful roles through the generation of complement protein split products, C5a. Administration of C5a antibody blocking C5a reduces aGVHD-induced liver and intestine damage as well as down-regulation of inflammatory cytokine in target organ. We also demonstrated short-term low-dose anti-CD3 antibody treatment ameliorated the severity of the cGVHD-induced lupus nephritis in mice at least in part through the up-regulation of Foxp3+regulatory T cells in the target organ:kidney, suppressed the activation of effector T cells. Based on the results of our research,we can presume that interventions aimed at blocking C5a may represent promising targets for adjuvant therapy in aGVHD,and therapeutics useing anti-T cell antibody for cGVHD will be extensively tested in the future studies.
Graft-versus-host-disease (GVHD),a major barrier to successful allogeneic hematopoietic cell transplantation (allo-HCT) is a main cause of morbidity and mortality of survivors of allo-HCT and presumably mediated by donor T lymphocytes reactive against the allogeneic antigen of the recipient. Based on different clinical manifestations and histopathology, it can be divided into acute GVHD(aGVHD) and chronic GVHD(cGVHD). Clinically relevant aGVHD develops in 35-50% of patients given HLA-identical hematopoietic cells within the 100 days following transplantation. It primarily affects the skin, liver and the gastrointestinal tract with T cell infiltration, about one half of the patients with moderately severe or severe disease die, because of associated infections. Prophylaxis of acute GVHD by placing the patient in protective isolation,immunosuppressive therapeutics after grafting, or removal of donor lymphocytes from the transplant has not been uniformly successful. Therapy of established GVHD involves the use of immunosuppressants such as glucocorticosteroids, antithymocytc globulin, cyclosporinc, and monoclonal antibodies.cGVHD usually appears 100-500 days after transplantation and affects about 50% of all long-term survivors and can be lethal in approximately 20% to 40% of affected patients in spite of intensive and aggressive drug combination treatments.cGVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to scleroderma and systemic lupus erythematosus(SLE).In addition to the same target organs as aGHVD, cGVHD involves a wider range of organs inclue lacrimal and salivary glands and mucous membranes.Older recipient age and a history of aGVHD are the greatest risk factors for cGVHD. Treatment of cGVHD involves immunosuppressive and cytotoxic drugs which lead to highly susceptible to bacterial and fungal infections that are lethal in a small proportion of patients.
The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. (1) activation of the APCs; (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction.During the whole process of aGVHD,the natural killer (NK) cells,, dendritic cells, macrophages and granulocytes constitute the cellular elements of the innate immune system play a crucial role in inflammatory response and tissue damage. The complement system comprises a strong defense against various pathogens is a major component of the innate immune system.Recently more research demonstrate activation of the complement system can contribute to inflammation and tissue injury and it is described to accelerate the pathogenesis of many diseases. In our study we oberve that the aGVHD mice given allogeneic cell had much higher level of complement-activated product C3a,C5a in liver compared with the mice given syngeneic cell transplantation,an increased hepatic mRNA expression levels of C3a,C5a and their receptors were also detected in aGVHD mice.These findings suggested that activation of the complement system is associated with aGVHD. C5a is one of the most potent inflammatory peptides, with a broad spectrum of functions,displays powerful biological activities that lead to inflammatory disorder.After blocking C5a with C5a polyclonal antibody in aGVHD mice, we observed the level of C5a,C3a in liver was decreased compared with the IgG control, in addition hepatic mRNA abundance for C5a,C3a and their receptors was redued after C5aAb treatment. Interestingly,the inflammatory cell infiltration in liver and the hepatic mRNA expression levels for TNF-a,IFN-y,IL-1β,IL-2 and IL-6 were decresed by C5a Ab.In splenocyt we also found the mRNA expression of TNF-a,IFN-y,IL-6 and IL-10 were down-regulation. These results indicate that C5a Ab may suppresses the biological activities of C5a,such as increased vascular permeability, chemotaxis of inflammatory cells, cytokine and chemokine release and phagocytosis,then reduced tissual lesion, ameliorated the severity of the aGVHD in mice.
Because of the lack of highly satisfactory animal models and basic studies in patients,the pathophysiology of cGVHD remains poorly understood. cGVHD is a pleiotropic disease with clinical and pathological signs and symptoms similar to various autoimmune diseases. Based on the study up on animal models, T cells was the central role in initiating GVHD, numerous research evaluating T cell depletion and inhibitoion as prophylaxis for GVHD. In this paper, we first used 145-2C11 Ab(anti CD3 mAb) to treat lupus nephritis induced by cGVHD in mice.The results showed that short-term low-dose anti-CD3 antibody treatment induced a significant remission of established proteinuria, production of autoantibodies, immune complex deposition and renal parenchyma lesions in cGVHD mice. Of note, we found a robust up-regulation of Foxp3 mRNA expression in the target tissue:kidney from mice with anti-CD3 antibody treatment compared to those with control IgG treatment. Likewise, an increased renal mRNA abundance for IL-10 was also observed in anti-CD3 antibody treated mice. In contrast, genes associated with inflammation and fibrosis as well as cytokines related to effector T cell responses were down-regulated by anti-CD3 mAb treatment. These findings suggested that short-term low-dose anti-CD3 antibody treatment might induced an IL-10-secreting Foxp3+ regulatory T cells in this cGVHD target tissue: kidney, that suppressed the activation of effector T cells (Th1,Th2 and Th17), thus ameliorating the severity of the lupus nephritis in mice.
In conclusion,our studies suggested that undesired complement activation accompany with aGVHD in mice may exert its harmful roles through the generation of complement protein split products, C5a. Administration of C5a antibody blocking C5a reduces aGVHD-induced liver and intestine damage as well as down-regulation of inflammatory cytokine in target organ. We also demonstrated short-term low-dose anti-CD3 antibody treatment ameliorated the severity of the cGVHD-induced lupus nephritis in mice at least in part through the up-regulation of Foxp3+regulatory T cells in the target organ:kidney, suppressed the activation of effector T cells. Based on the results of our research,we can presume that interventions aimed at blocking C5a may represent promising targets for adjuvant therapy in aGVHD,and therapeutics useing anti-T cell antibody for cGVHD will be extensively tested in the future studies.
引文
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