主讲人：刘孝明 组 员：杨永波、张东燕、王文兴、王振宇、黄文思、张冲
In the recent few years ,transplantation is the most effective way to cure the founctional failure of organs .Except the rejection ,the lack of donor is also very important. What can we do? Use the organs of animals
Xenotransplantation 狼 心 狗 肺
Concept A tissue transplant from one species to another, e.g. from pig to human. Because of the greater differences between species, these transplants have the least chance of working. The immune system, which is responsible for tissue rejection, will easily recognize the tissue as foreign and will reject it vigorously.
Stage II Stage III Stage I History Blindness Indifference Developing With Technology Xenotransplantation is nothing new. As early as the 17th century， doctors had already had sporadic this attempt. The development of enotransplantation experienced from Prosperity to Indifference, and then to Prosperity again.
Three stages The first stage: 1905. French doctors Princeteau put rabbit thinly sliced kidney into one cases of acute renal failure in patients with kidney, Patients with significantly increased urine output, but 16 days later died of pulmonary edema. 1909 ,German doctor tried to transplant monkey kidney to patients with renal failure in the thigh, 32 hours after the transplant ,renal vein thrombosis was defeated.
In 1964, Reemtsma transplant gorilla‘s renal into patients with renal failure, and gave immunosuppressive therapy at the same time.Only one patients’ renal remained normal for nine months. This shows that xenotransplantation for the long-term functional survival is possible. This is the longest Xenotransplantation Survival record so far .
The second stage： Transplant experts recognize the important role of pre-formed antibodies in xenograft rejection reaction, but they failed to find a relatively effective confrontation. Therefore,In the 15 years since the process of xeno-transplantation of clinical and basic research into a low ebb.
The third stage： Clinical xenotransplantation began to rise again in 1984, Its hallmark is Bailey as Baby Fae premature baby baboons for the implementation of a heart 1993 inaugurated the corresponding magazine Xenotransplantation.
May ensure that there are enough sources of organs Be a planned, full Preoper-ative Prepar-ation To expand the range of treatment Reduce or avoid rejection Advantages 2 3 4 1
1,hyperacute xenograft rejection,HXR 2,delayed xenograft rejection,DXR 3,acute cellular xenograft rejection,ACXR 4,late xenograft rejection,LXR Transplantation rejection
1,hyperacute xenograft rejection,HXR Next HXR is the combine between the natural antibodies and the vascular endothelial cells in xenografts ，which leading to widespread graft thrombosis . within a few minutes to a few hours .
2,delayed xenograft rejection,DXR Next Immune response with the functions of antibodies, complement, coagulation factor, interleukin and others. Pathological phenomenon ：activation of endothelial cells,formation of diffuse thrombosis、 thrombocytopenia, expendable clotting disease, vascular inflammation, Micro disease and so on.
3,acute cellular xenograft rejection,ACXR Next Associated with T cells, macrophages and NK cells. Within a few days to several months。
4,late xenograft rejection,LXR Next After a few months to several years, Similar to the same kinds of chronic transplant rejection, but faster and stronger. The pathogenesis can be devided into immune function and non - immune function.
Mechanism of HXR when the vascular endothelial is activated, it will lose the role of barriers and stimulates the formation of thrombin, and promote lossing blood clotting component. could synthesis platelet-activating factor, activating platelet adhesion and aggregation.
Natural antibodies Complement Activation and functions of Vascular endothelial cell The factors causing HXR HXR
Natural antibody From receptor HXR occurs within a few minutes to a few hours after Xenografts meet the receptor’s blood ， which suggest HXR is induced by “natural” immune-mediated mechanism 。 Tissue injury. Surface antigen from Xenograft donor organs
Functions of complement Normally, the alternative pathway is inhibited by plasma proteins.Because of species-specificity of inhibitors , it results in weakening of inhibition on the surface of graft. So even in the absence of antibodies, the binding of the spontaneous C3b and B factor activates alternative pathway to injury.
Functions of complement The complement activation effect in Xenotransplantation may not be appropriately enlarged .Surface-associated membrane protein regulation complement, including : DAF.HRF and others. Their role in the same species is stronger than dissimilar, resulting in activation of complement but lack of the negative feedback to form injury.
Activation and functions of Vascular endothelial cell Vascular endothelial cell is not only subject and main target of natural antibodies but also the important causes and mediater . In HXR the changes of vascular endothelial cell includes: 1. Structure changes, Integrity of vascular damages, gap forms between endothelial cells ,and endothelial matrix exposes .
Coagulation chain reaction (凝血连锁反应) Tissue Factor Coagulation FactorⅦ Activity Ⅶa 2. Anticoagulant reduced ability to promote and enhance the capacity of coagulation Antithrombin（抗凝血酶） Heparan sulfate Natural antibodies & C5a Coagulation opsonin(凝血调理素) Anticoagulant role
3. Activated endothelial cells secret a series of elements, such as IL-1, IL-6, IL-8, PAF (血小板活化因子), etc.
The strategy of Overcome immune rejection 1,targeted at recepter(such as antibodies or complement consumption or inhibition, tolerance induction, etc.) ， 2,targeted at donor, Transgenic expression of modified human complement regulatory proteins (CRPs人类补体调节蛋白) and the removal or replacement of gala-gal antigen on animals.
Unimmune Difficulties virus Unimmune difficulties Social Ethics Functional differences Integrity for human
In 1992 Dr. Thomas stadhur transferred a kidney of baboons to one patient by the examination of the patient‘s blood and tissue samples files . It is known that he infected Bibi cytomegalovirus virus(细胞巨化病毒)。 In 1997. Professor Robin Weiss found ， the PERV(猪内生反转录病毒) Hidden in pig cells would Practices the human cells in Medium 。
Now we have known that we may be infected by more than 150 objects from the animal. Donororgan is one of the sources . Looking back the recent outbreaks of the disease ，It is not difficult to imagine how Fearful the disaster is.
Prospect Xenotransplantation will Open up a new treatment strategy, including the direction of the future development of medical application of a variety of gene transfer strategy modification of donor organs, immune tolerance invented new methods such as immunosuppressants. Xenotransplantation would clinical approached, to benefit the mankind.