ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Considering the role of alloreactive donor lymphocytes in mediating graft-versus-leukemia and graft-versus-tumor effects, including in patients who are resistant to conventional anticancer modalities, we have introduced the concept of using the bone marrow transplantation procedure as a platform for induction of host-versus-graft transplantation tolerance rather than as a means of eradicating all tumor cells. Safe and stable transplantation tolerance can best be accomplished by induction of mixed chimerism, which can be achieved using nonmyeloablative conditioning. Once host-versus-graft tolerance allows consistent and durable engraftment of donor immunohematopoietic cells, donor lymphocytes can be added if needed for induction of graft-versus-leukemia and graft-versus-tumor effects to displace residual malignant or genetically abnormal host cells. In principle, a similar approach can be used for induction of transplantation tolerance to all donor tissues and perfused organ allografts. Our preliminary data in nearly 100 patients are reviewed here. The conclusion of our working hypothesis, supported by many studies in animal models and a growing clinical experience, suggests that well-tolerated, safer nonmyeloablative stem cell transplantation may replace the use of myeloablative chemoradiotherapy for most patients in need of allogeneic bone marrow transplantation, toward a general goal of replacing aggressive and ineffective anticancer modalities with improved immunotherapy that is to become more selective and less hazardous as the experience accumulates.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The transplantation of solid organs and cellular grafts has become a clinical standard for patients with end-organ failure. However, the effort to fully implement organ transplantation as conventional therapy has been hindered by the toxicities associated with immunosuppression, which is the mainstay to graft survival. Despite use of these agents, chronic rejection remains the primary cause of late graft loss. The induction of tolerance to donor organs or cells is one way of limiting the requirement for immunosuppression and avoiding the progression to chronic rejection. Allogeneic hematopoietic stem cell chimerism via bone marrow transplantation has classically been the most effective means to establish donor-specific tolerance. This review focuses on the progress that has been made toward the successful use of bone marrow transplantation for the induction of tolerance to solid organ and cellular grafts.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The diverse manifestations and variable response to immune suppression of autoimmune disorders have made them one of the most challenging areas of medicine. The ability of hematopoietic stem cell transplantation to alter the immune system is currently being tested both experimentally and clinically as a strategy to treat autoimmune diseases. The major limitation of transplantation is toxicity and less toxic regimens are being developed. Minimal conditioning regimens such as low-dose irradiation and transplantation of high numbers of stem cells have formed the basis for promising strategies for clinical stem cell transplantation. Newer strategies to manipulate the immune system have been developed as well including T-cell depletion, antigen-presenting cell:T-cell costimulator blockade, and novel pharmacologic agents such as mycophenolate mofetil. These approaches offer the hope for reinduction of self-tolerance and open new horizons for the potential cure of autoimmune diseases.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

There is a severe shortage of organs for transplantation that many conclude will never be solved by increasing organ donation. Xenotransplantation may offer a permanent solution to the donor organ shortage. The vigorous nature of immune responses to xenografts and our inability to control these responses using conventional immunosuppressive regimens limit the application of xenotransplantation to the clinic. Natural antibody-mediated hyperacute and cell-mediated delayed rejection constitute two forms of xenograft rejection reactions that have been the subject of intensive studies. Although these studies resulted in the design of molecular approaches, including phenotypic manipulation of the host and genetic modification of the donor, that have been effective in preventing hyperacute rejection in the preclinical pig-to-primate model, graft rejection remains a major limitation. The induction of donor-specific tolerance to xenografts remains a far-reaching goal of clinical transplantation and will probably be one key component in enabling xenotransplantation to become a clinical reality. The use of bone marrow transplantation to induce durable hematopoietic stem cell xenogeneic chimerism, however, holds great promise for achieving such a goal.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Our understanding of the mechanisms involved in the immune system’s response to antigen has increased our awareness of many potential sites that may serve as targets for future immunosuppressant strategies. The determination of the crystalline structure of both the major histocompatibility complex molecule and the T-cell receptor has highlighted the integral role of the major histocompatibility complex–bound peptide in the interaction between the antigen-presenting cell and the T cell. There is now increasing experimental evidence that peptides offer an effective means of altering or inhibiting the immune response. Despite this initial concept that peptides would interfere with antigen recognition through binding to the major histocompatibility complex molecule, it now appears that they may exert their effects at many diverse sites, including prevention of signal transduction, cell cycle progression, and the induction of apoptosis. Peptides, therefore, offer the potential for development of an exciting new class of immunosuppressants.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The induction of donor-specific tolerance remains an important objective in transplantation to obviate the need for immunosuppression and prevent chronic rejection. Operational tolerance to cardiac allografts can certainly be induced in small animal models. Recent interest has focused on refining the tolerance induction regimens to minimize toxicity and on examining the mechanisms responsible for donor-specific unresponsiveness in these experimental systems. Particular progress has been made on strategies to block T-cell costimulation and on delivery of alloantigens via donor-specific transfusion or bone marrow infusion. Interactions between various forms of immunotherapy and conventional immunosuppression are being studied and there is early evidence of synergy, as well as data suggesting inhibition of tolerance induction by calcineurin inhibitors.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Recent evidence suggests that antibody plays a role in the pathogenesis of both acute rejection and accelerated coronary artery disease following human cardiac transplantation. There is strong evidence that posttransplant monitoring identifies patients at risk of developing transplant-associated coronary artery disease. That antibody is either essential for or influences the nature of the vascular lesion is supported by experimental models of cardiac graft vasculopathy. One of the major concerns in this area is that the specificities of antibodies (formed in patients) remain poorly defined. Major histocompatibility and non–major histocompatibility target antigens have been described. Traditionally, cytotoxic antibodies have been detected, but newer methods of detecting noncytotoxic antibodies and use of endothelial cells as targets should expand and clarify the range of antibodies being produced. The mechanism whereby antibody causes vascular lesions is not understood but almost certainly involves activation of donor endothelial cells. Indirect presentation of graft antigens (including non-HLA or minor antigens) and epitope spreading drive chronic rejection; such an expansion of the immune response probably includes antibody production against many different HLA and non-HLA antigens.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Despite major recent improvements in medical management, the mortality rate in heart failure remains higher than for many cancers. Cardiac transplantation is now a well-established treatment for end-stage cardiac failure, with more than 40,000 patients undergoing transplant up to 1998. With improvements in perioperative management, better immunosuppression, and improved management of opportunistic infections, 10-year survival after cardiac transplantation is now about 40%. Longer recipient survival and greater experience in larger transplant centers have led to the recognition that a number a important new medical problems may develop in these patients including a high prevalence of de novo hypertension. Hypertension in the donor and poorly controlled blood pressure after transplantation are risk factors for cardiovascular complications in heart transplant recipients. Endothelin activation and reduced bioactivity of nitric oxide provide two important therapeutic targets for reducing the severity of hypertension and its complications after heart transplantation.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The significance of two important hormones not usually associated with transplantation has been examined for their role in organ allograft rejection. We conclude that estradiol-17β and somatostatin octapeptide subtypes may have significant beneficial immunomodulatory effects regulating cytokines, growth factors, adhesion molecules, and major histocompatibility complex class II expressions in T lymphocytes, antigen-presenting cells, and vascular tissues.

ISSN:1087-2418    

出版商:OVID    

年代:1999

数据来源: OVID