Xenogeneic organ transplantation

Over the past few years, several major advances have occurred in the understanding of how the humoral and cellular immune system of humans recognizes and destroys transplant cells, tissues and organs derived from animal sources. Consequently, armed with this new knowledge, several laboratories have now developed novel immunoprotective technologies that may allow xenotransplantation to be clinically feasible.     

Monoclonal antibodies in organ transplantation

Monoclonal antibody (mAb) technology has made possible the production of designer proteins, specifically reactive with almost any conceivable biological molecule. Using these reagents, the surface molecules on cells crucial for allograft rejection have been identified and described in detail. These structures can now be selectively targeted by mAb-based therapy in order to prevent rejection. For instance, the CD3 molecule, expressed on all mature T lymphocytes, triggers T cell activation, a key event in rejection. OKT3, an anti-CD3 mAb, disrupts T cell function and is now the agent of choice for the treatment of severe rejection episodes. MAbs targeting other T cell molecules are currently being investigated. Some of the most promising, the anti-CD4, anti-ICAM-1, and anti-interleukin 2 receptor mAbs, have already induced donor-specific tolerance in rodent models. These hosts accept permanently a genetically incompatible graft after only a limited period of mAb therapy. Interestingly, anti-ICAM-1 also diminishes the ischemic injury of preservation. The development of these new molecular agents, effectively directed to specific cellular targets, will likely play an increasingly important role in future clinical protocols, and perhaps finally provide a means to achieve long-term tolerance in human allograft recipients.     

Nonhuman primate infections after organ transplantation

Nonhuman primates, primarily rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), and baboons (Papio spp.), have been used extensively in research models of solid organ transplantation, mainly because the nonhuman primate (NHP) immune system closely resembles that of the human. Nonhuman primates are also frequently the model of choice for preclinical testing of new immunosuppressive strategies. But the management of post-transplant nonhuman primates is complex, because it often involves multiple immunosuppressive agents, many of which are new and have unknown effects. Additionally, the resulting immunosuppression carries a risk of infectious complications, which are challenging to diagnose. Last, because of the natural tendency of animals to hide signs of weakness, infectious complications may not be obvious until the animal becomes severely ill. For these reasons the diagnosis of infectious complications is difficult among post-transplant NHPs. Because most nonhuman primate studies in organ transplantation are quite small, there are only a few published reports concerning infections after transplantation in nonhuman primates. Based on our survey of these reports, the incidence of infection in NHP transplant models is 14%. The majority of reports suggest that many of these infections are due to reactivation of viruses endemic to the primate species, such as cytomegalovirus (CMV), polyomavirus, and Epstein-Barr virus (EBV)-related infections. In this review, we address the epidemiology, pathogenesis, role of prophylaxis, clinical presentation, and treatment of infectious complications after solid organ transplantation in nonhuman primates.     

Mitochondrial dysfunction in liver disease and organ transplantation

The mitochondria play a crucial role in maintaining hepatocyte integrity and functions. Mitochondrial defects are either inherited or acquired. Mitochondria dysfunction occurs when the hepatocyte experience excessive physiologic stress. Its clinical presentation depends on the severity of the stress. It varies from mild abnormalities in liver biochemical tests to manifestations of acute or chronic liver failure. Mitochondria dysfunction is implicated in most liver disease and in early graft dysfunction after liver transplantation. This review will address the role of mitochondria in liver disease.     

Cyclosporin A in cadaveric organ transplantation.

The use of cyclosporin A (CyA) with a protocol designed to avoid the effects of nephrotoxicity resulted in a one-year survival of 86% in recipients of renal allografts from unmatched cadaveric donors. The drug also controlled rejection of liver and pancreatic allografts. It was possible to change patients initially treated with CyA to azathioprine and corticosteroids and vice versa, thus enlarging the potential value of CyA in organ allografting. Of 34 recipients of renal allografts, 29 were currently receiving only CyA as immunosuppressive treatment. Twelve patients never required any adjuvant steroid treatment. These results suggest that CyA is an effective immunosuppressant, and if used with care side effects need not be severe.     

我国器官移植中的伦理困境及解决思路

我国的器官移植近10年来有了发展,无论从技术层面、移植数量和质量、临床管理以及法规建设上都有了长足的进步。然而,由于我们在开展器官移植方面的先天不足,例如从事器官移植的技术队伍主要是来自海外学成归来的专家;技术主要靠引进西方的临床技术,在基础研究和创新方面相对薄弱;在法律和管理制度的建设方面相对滞后,没有建立一个从制度上保证器官移植健康开展的系统,使得在器官供体来源和器官的公正分配上存在许多欠缺。因此有必要对我国的器官移植历史进行回顾和总结,对我国在器官移植中存在的错误观念和伦理困境进行剖析,寻找适合我国开展器官移植的正确途径,促进我国的器官移植事业健康发展。     

Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration

Emerging evidence suggests that bone marrow-derived endothelial, hematopoietic stem and progenitor cells contribute to tissue vascularization during both embryonic and postnatal physiological processes. Recent preclinical and pioneering clinical studies have shown that introduction of bone marrow-derived endothelial and hematopoietic progenitors can restore tissue vascularization after ischemic events in limbs, retina and myocardium. Corecruitment of angiocompetent hematopoietic cells delivering specific angiogenic factors facilitates incorporation of endothelial progenitor cells (EPCs) into newly sprouting blood vessels. Identification of cellular mediators and tissue-specific chemokines, which facilitate selective recruitment of bone marrow-derived stem and progenitor cells to specific organs, will open up new avenues of research to accelerate organ vascularization and regeneration. In addition, identification of factors that promote differentiation of the progenitor cells will permit functional incorporation into neo-vessels of specific tissues while diminishing potential toxicity to other organs. In this review, we discuss the clinical potential of vascular progenitor and stem cells to restore long-lasting organ vascularization and function.     

Protein—drug complexes important for immunoregulation and organ transplantation

Recently, two structures of the Ser/Thr phosphorylase calcineurin in complex with FK506 and its cognate immunophilin, FKBP12, have been reported, both solved by small pharmaceutical companies focused on structure-based drug design. A realization, however, that the toxicities associated with calcineurin-mediated immunosuppressants might be mechanism based has driven the current interest in alternative approaches to autoimmunity prophylaxis and preventing transplant rejection. Regulatory approval in 1995 of the immunosuppressant prodrug mycophenolate mofetil, whose active metabolite, mycophenolic acid, inhibits inosine monophosphate dehydrogenase, has focused attention on the potential significance of the de novo purine-biosynthesis pathway as a target for immunosuppressive drugs, leading ultimately to the solution of enzyme structure as a drug design target. As this and other clinically relevant targets are discovered, elaborated and refined via the activity of their cognate agents (as was the case for the phosphatase calcineurin via the activity of cyclosporin), a critical opportunity should ensue for structural biology to exert a profound effect on the future development of these therapies.