ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Apoptotic cell death contributes to the regulation of immunologic tolerance at a number of levels, beginning with negative and positive selection of T and B cells to establish an appropriately self-tolerant lymphocyte repertoire and extending to inducible immune privilege and peripheral tolerance. Apoptotic cells provide crucial signals for engulfment by professional phagocytes, inducing release of immunoregulatory cytokines, a function that cannot be performed by necrotic cells. Failure to induce apoptosis in immune cells can lead to hyperlymphoproliferation and an inability to moderate the immune response. Significant advances have been made in understanding of intracellular mechanisms of apoptosis and, perhaps more importantly, of the difference in effects of apoptotic cells and necrotic cells in inducing and maintaining immune homeostasis and tolerance.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Transplantation has become a routine therapy for end-stage organ disease. Despite improvements in patient and allograft outcomes, chronic rejection and the complications from lifelong immunosuppressive therapy remain significant problems. The induction of transplantation tolerance, indefinite allograft acceptance independent of chronic immunosuppressive therapy, remains the ultimate ambition in transplantation. Recent advances in immunobiology have described costimulatory pathways that are critical for T-cell function. Numerous tolerance strategies have incorporated agents designed to manipulate these pathways. Although new molecules continue to be described, their use alone has failed to promote lasting tolerance. The use of costimulation blockade in nonmyelosuppressive mixed chimerism strategies has emerged as one of the most promising strategies thus far.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The Th subsets Th1 and Th2 are cells that produce cytokines with differing effector functions. Th1 cells are thought to be more responsible for allograft rejection, whereas Th2 cells may more predominantly affect anergy in transplantation. The cytokines produced by these cells induce Th0 or naive cells to differentiate (polarize) into specific Th types. This review deals with advances in the effect of cytokines, antigen concentration, costimulatory molecules, microenvironment, route of antigen introduction, adhesion molecules, and transcription factors influencing the development of Th subsets. Resolving the chronologic molecular events for the induction of Th type differentiation and the maintenance of these cells will ultimately benefit the understanding of their role in transplantation tolerance.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Recent therapeutic strategies to combat organ allograft rejection have focused on T-cell signaling pathways and the molecules that comprise them. While some pharmaceuticals have shown promise in blocking acute rejection, chronic graft destruction and permanent allograft acceptance in the absence of continuous immune suppression are problematic. Recent data now suggest T-cells hold the key to generation of transplantation tolerance and alleviation of long-term drug intervention. These new targets are spread across the T cell receptor, costimulatory, and T-cell growth factor signaling pathways. Development of mice deficient in T-cell genes and identification of new drug classes has accelerated our understanding of how these effector molecules contribute to T- cell activation, anergy, apoptosis, and survival. These observations have provided valuable insight into reasons for unsuccessful tolerogenic strategies while inspiring the design of new ones. This review is focused on the most recent developments in T-cell signaling cascades and their potential role for the induction of transplantation tolerance.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Allotransplantation is the preferred means of organ replacement; however, application is limited by a severe shortage of human organ donors. Several alternate approaches to treat organ failure are under exploration. These approaches include development of artificial organs, cellular transplants, organogenesis and xenotransplantation. The feasibility of each approach may be limited by physical, biochemical, and immunologic obstacles. Here we consider how each approach, either alone or in conjunction with other approaches, may be used to replace or supplement the function of diseased or injured human organs.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Human donors have not met the growing need for transplantable organs. Purpose-bred pigs may potentially be used as a source of donor organs. However, the immunologic barriers to xenotransplantation are formidable. Considerable progress has been made in overcoming immediate hyperacute rejection. However, delayed xenograft rejection occurs and responds poorly to conventional immunosuppression. Whether this process can be controlled by the use of organs derived from pigs that do not express the xenoantigen Gal &agr;1–3 Gal is not known. Porcine cardiac and renal xenografts can sustain life for several weeks. The long-term efficacy of these grafts will need to be reassessed when delayed xenograft rejection is better controlled. Significantly less is known regarding the ability of liver and lung xenografts to provide life-supporting function. Extracorporeal pig liver perfusion can provide short-term metabolic support for patients with liver failure, and pig hepatocytes appear to correct liver failure in cirrhotic rodents. The risks associated with pig endogenous retroviruses remain unclear.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The widespread use of xenografts in clinical transplantation is limited by immune barriers that prevent the long-term survival of the grafts. The rapid induction of IgM xenoantibodies, the use of a restricted population of Ig genes expressed in germline configuration, and the production of the anti-&agr;gal antibodies by B-1b B cells are consistent with the use of an early and relatively primitive humoral immune response pathway to mediate the rejection of vascularized xenografts, especially during the early phases of the rejection reaction. The current difficulty in preventing the rejection of xenografts associated with the induction of antibody responses after graft placement is a reflection of a lack of effective immunosuppressive strategies to prevent this host response. The demonstration that the host response is encoded by relatively small numbers of Ig genes and that a subset of B cells is important in the xenograft humoral responses may provide important new approaches to preventing graft rejection. There is a significant body of data in rodents to suggest that specific and effective disruption of this response, particularly when combined with modest levels of immunosuppression to prevent subsequent T-cell–driven events, can allow long-term graft survival. These studies suggest that targeting selected B-cell populations responsible for generating xenoantibody responses or the using techniques to induce tolerance to prevent antibody production may prove to be effective strategies to prolong xenograft survival in higher species, including humans.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Potential benefit from the application of xenotransplantation as a remedy for donor shortage is limited by the intense antigenic challenge of the xenograft. Rodent models recently identified potential solutions to this problem, including xenospecific costimulatory blockade and new immunosuppressive therapies. Improved methods of conditioning to achieve mixed hematopoietic chimerism illustrate mechanisms for graft rejection and failure unique to xenotransplantation. New evidence from larger animal experiments illustrates the challenge of translating these lessons to models with clinical application.

ISSN:1087-2418    

出版商:OVID    

年代:2002

数据来源: OVID