摘要:

Apoptosis is crucial for normal lymphocyte homeostasis and for the maintenance of self-tolerance. However, the role of apoptosis in the induction of transplantation tolerance has been unclear. Recent data now strongly suggest that the apoptotic deletion of T cells is an absolute requirement for the induction of peripheral tolerance to major histocompatibility complex–mismatched organ transplants. The authors propose that apoptosis may control acute graft rejection by reducing the size of the allodestructive T-cell pool, whereas the anti-inflammatory effects of apoptotic cell debris may facilitate the maintenance of tolerance by favoring the development of an active immunoregulatory state.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The induction of tolerance in an adult immune system, although possible in animal models, remains an elusive goal in clinical medicine. The study of cytokine expression may help to define the requirements for reliably directing the immune system toward tolerance against either self antigens in autoimmune disease or foreign antigens in transplantation. Recent studies indicate a clear role for various cytokines in this increasingly complex process.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

There is little literature on clinical transplant patients who have stopped receiving immunosuppression. This review summarizes the recent literature, including studies of the mechanism of allograft acceptance in kidney and liver transplant patients who removed themselves from immunosuppression. A model of peripheral tolerance that involves immunoregulation and microchimerism is favored to account for these rare instances of successful noncompliance. In contrast, clonal deletion may be the principal mechanism of tolerance in the setting of kidney transplantation after successful donor bone marrow transplantation.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Developments in methods of immunomodulation of nonhuman primates undergoing pig organ transplantation during the past 12 to 18 months are reviewed in the light of previous studies. Depletion of xenoreactive (anti-Gal) antibodies can be achieved successfully by several techniques, thereby preventing hyperacute rejection; however, continuing production of antibody remains a problem. The pharmacologic agents currently available have proved inadequate in preventing the eventual development of acute vascular or delayed xenograft rejection. However, good function of one orthotopically-transplanted pig heart in a baboon for 39 days suggests that pig hearts will be able to support life in primates for long periods if the immune barriers can be overcome. The ability of therapy with an anti-CD154 monoclonal antibody to completely prevent the induced antibody response to transplanted pig cells and organs is an encouraging step forward. An anti–B-cell monoclonal antibody that depleted all B cells failed to prevent continuing antibody production, indicating that plasma cells, rather than B cells, are probably the major source of these antibodies. Some progress has been made; however, in the absence of a genetically modified pig that does not express Gal epitope, it may be necessary to direct attention toward suppression of plasma cell function.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Advances are being made with the genetic engineering of pigs to make their organs adaptable for transplantation to humans. Hyperacute rejection mediated by anti–Gal&agr;(1,3)Gal antibodies can be avoided using transgenic pigs expressing a complement regulator. Most of this usually has been done with decay accelerating factor, but other regulators are under study. A major problem is vascular thrombosis, which occurs in 7 to 30 days in transgenic organs transplanted to primates. Work is proceeding to either produce a Gal knockout pig or remove Gal&agr;(1,3)Gal by other means. It is clear that pig organs can survive in primates for as long as 60 days, and at this time, there appear to be no hidden molecular incompatibilities.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Antibodies against pig antigens mediate much of the pig xenograft rejection process in humans and in evolutionarily related primates. The main, and possibly the only, natural antibody that induces rejection of pig xenografts is anti-Gal, which interacts with &agr;-gal epitopes (Gal&agr;1-3Galβ1-4GlcNAc-R) on pig cells. However, in xenograft recipients there are two types of elicited (ie, induced) anti-pig antibodies that are detrimental to the xenograft: 1) elicited anti-Gal IgG, which displays approximately 100-fold increase in activity in comparison with the natural anti-Gal, and 2) anti–non-gal antibodies against a large number of immunogenic pig proteins. If complement activation is prevented, these antibodies destroy xenograft cells, primarily via the antibody-dependent cell-mediated cytotoxicity mechanism. Progress in xenotransplantation requires the development of novel methods for preventing the production of these natural and elicited antibodies.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Therapeutic strategies to prevent intravascular thrombosis and platelet activation after xenotransplantation have received increasing attention during the past few years for several reasons. First, there are reasons to believe that targeting xenoreactive natural antibody binding and complement may not prevent some forms of vascular rejection. Second, porcine xenografts may have unusual prothrombogenic properties in primates, leading to systemic hematologic disturbances. Third, evidence suggests that inhibiting thrombosis and platelet activation are effective for preventing the hyperacute rejection of vascularized organs. This review focuses on these areas, placing emphasis on recent developments.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The development of effective strategies to prevent the rejection of xenografts will require new approaches to preventing host humoral responses to the grafts. The evidence accumulated to date suggests that host antibody responses to xenografts are more difficult to control than the rejection reactions mounted against comparable allografts. Current methods of immunosuppression that might be used to prevent the cellular and humoral responses to xenograft produce serious side effects in experimental animals, indicating that the margin of safety for their use as a routine therapy in patients may be very narrow. Accordingly, understanding the precise mechanisms by which the host mounts a rejection reaction to the graft may provide new directions for the development of more effective and safer therapies to prolong graft survival. Examination of the structural and functional characteristics of the immunoglobulin genes used to encode xenoantibody activity has demonstrated that many characteristics of this component of the host response to xenografts are unique. The number of immunoglobulin genes used to encode antibodies directed against the grafts is relatively small. In the early stages of the response, they are expressed in their original germline configuration, and, as the response matures evidence for the use of both germline and antigen-driven Ig gene expression begins to appear. The response is encoded by variable region genes that display significant similarities in the amino acid residues found in specific sites within antibody combining sites, suggesting the evolutionary conservation of the Ig genes that control the xenoantibody response.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

One of the early characteristics of hyperacute rejection of a vascularized xenograft is the disturbance and breakdown of the microcirculation of the organ. For xenotransplantation, virtually noin vivoinformation exists about this damage. Intravital microscopy for the first time permits the differentiation between perfused and unperfused arterioles, capillaries, and postcapillary venules of a xenograft. Intravital microscopy permits visualization of the capillary network and allows the quantification of transient and permanent adhesion of leukocytes and platelets. Intravital microscopy allows the analysis of the dynamics of microvascular perfusion, the calculation of the perfusion ratio of the selected tissue, and thus the definition of the changes of perfusion in the early phase of disturbance by either ischemia/reperfusion injury or hyperacute xenogeneic rejection. The authors are in the process of modifying this method for application in the pig-to-human xenogeneic system.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Recent studies of the expression and tropism of pig endogenous retroviruses for many types of cells have provided new insights into the risk for cross-species transmission of infection in xenotransplantation. All pigs contain several copies of porcine endogenous retrovirus (PERV), and at least three variants of PERV can infect human cell lines in culture. A number of retroviruses that are in the same family as PERV produce leukemia and lymphoma in their natural hosts. Certainly the ongoing tragedy of the AIDS pandemic is an example of cross-species infection. There has been an ongoing public debate on the safety of xenotransplantation that considers both the risk to individual patients and the risk to the general public. In this review the authors discuss evidence of PERV release and infection of different primary cells in culture as well as current animal and clinical studies of PERV infection risks in transplantation.

ISSN:1087-2418    

出版商:OVID    

年代:2001

数据来源: OVID