Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Current opinion in organ transplantation [journal]
- Editorial introductions. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):v-vi.
- Hand transplants and the mandate for tolerance. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):545-51.
The field of vascularized composite allograft (VCA) to achieve its full potential will require induction of tolerance. This review will introduce a new method of potential inducing tolerance in hand transplantation.Hand transplantation is never a life-extending transplant. This fact resulted in considerable debate both for and against the use of immunosuppression for nonlife-extending transplants. There is considerable debate about the ethics of hand transplantation. There is now consensus that nonlife-extending transplants are acceptable in properly selected patients. However, ideally, hand transplants should not receive life-long immunosuppression. Therefore, attempts to achieve drug-free tolerance through nonlife-endangering therapies are warranted. To this end, we propose implementation of tolerizing therapy long after periinflammation has subsided and drug minimization has proven successful. Evidence that short-term treatment with low doses of IL-2 or a long-lived IL-2 immunoglobulin (Ig) can tilt the balance of immunity from tissue destructive to tolerance come from preclinical demonstrations in mouse and nonhuman primate models of autoimmunity and/or transplantation and even more recent clinical trials.We believe that with the proper use of low-dose IL-2 given at an opportune time in the inflammatory process of transplant that reduce immunosuppression and even tolerance can be induced in hand transplantation. We propose that tolerance can be inducted after a long period of conventional treatment to avoid 'tolerance-hindering' adverse inflammation that occurs in the posttransplant period. With abatement of posttransplant inflammation and with time, we will institute low-dose IL-2-based therapy to support the proliferation, viability and functional phenotype of regulatory T cells.
- Belatacept in kidney transplantation. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):573-7.
Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a selective costimulation blockade agent, is the first biological agent approved for maintenance immunosuppression in renal transplantation.Studies have shown better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared with CNIs. More recent studies have shown that belatacept can be an effective first-line immunosuppressive agent with complete avoidance of CNIs and corticosteroids.Newer biological agents like belatacept may replace CNIs/corticosteroids in renal transplant recipients, with a benefit of better short-term and long-term renal function, better compliance, and ultimately a possible improvement in long-term renal allograft survival.
- Progress toward establishing embryonic stem or induced pluripotent stem cell-based clinical translation. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):598-602.
Embryonic stem cells and induced pluripotent stem cells are pluripotent and therefore capable of differentiating into different cell types and tissues. However, their clinical potential, so far, has not been sufficiently probed. The major obstacle is the lack of protocols that allow efficient derivation of clinical grade cells or tissues. This review will address these questions and discuss the current state of the field.I will address some of the ongoing clinical trials using stem cell-derived retinal pigment epithelial cells, cardiomyocytes, neurons and attempts to establish insulin-producing cells for the treatment of type 1 diabetes.Are we there yet? The answer is clearly no. Progress in the different organs and tissues that are being generated is quite variable. Clearly, there has been more success in the derivation of retinal pigment epithelial cells, neuronal cells and cardiomyocytes than in any other tissues or organs. The derivation of insulin-producing cells and that of definitive hematopoietic progenitor cells in humans remains a challenge. Having said that the progress already made with other tissues is an encouraging sign that we may eventually see progress across the board.
- Acute rejection in vascularized composite allotransplantation. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):531-44.
Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of-the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes.Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation.Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life-changing restorative surgery.
- The unique immunobiology of the skin: implications for tolerance of vascularized composite allografts. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):566-72.
Vascularized composite allograft (VCA) transplantation restores function and form following major soft tissue and musculoskeletal injury. Lifelong immunosuppression is necessary for graft function and survival but acute skin-targeted rejection episodes remain common. We review recent advances in skin immunobiology, emphasizing findings in clinical and experimental VCAs. We also highlight advances in immunotherapy and tolerance protocols with implications for the prevention of VCA rejection, and ultimately, induction of clinically applicable strategies for VCA tolerance.There is now an increasing appreciation for the role of skin-specific mechanisms, including lymphoid neogenesis, in VCA rejection. In contrast, expression of the regulatory master-switch FOXP3 was demonstrated to be significantly upregulated in the skin of tolerant VCAs in large animal models compared with normal skin and rejecting controls.Most VCA transplant centers continue to utilize antibody-mediated induction therapy and triple agent maintenance immunosuppression. Skin remains the primary target of rejection in VCAs, and current multicenter studies hope to elucidate the mechanisms involved. Proposed standardized procedures for skin biopsies, and diligent reporting of clinical data to the international registry, will be important to maximize the strength of these studies.
- The potential role for regulatory T-cell therapy in vascularized composite allograft transplantation. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):558-65.
Vascularized composite allograft (VCA) transplantation restores defects to a degree not possible by conventional techniques. However, it is limited by the need for long-term immunosuppression and high rates of acute rejection directed against skin. There is therefore a need for a therapy that may shift the risk-benefit ratio in favour of VCA transplantation. Regulatory T cells (Tregs) are a subset of T cells with potent immunoregulatory properties and the potential to promote immunosuppression-free allograft survival. In this review, we consider the evidence for Treg therapy in VCA transplantation.CD4 Tregs are the best-studied immunoregulatory cell type, and a large amount of experimental and clinical data is emerging to endorse their use in VCA transplantation. Data from animal and humanized models are particularly encouraging and demonstrate the potent efficacy of Treg at preventing skin allograft rejection. Moreover, central tolerance induction techniques in VCA transplantation models are demonstrating a dependence on Tregs for graft survival.An improvement in outcomes after VCA transplantation has the potential to revolutionize the field. Several effective therapeutic strategies have demonstrated great promise experimentally, and there is now a need to assess their safety and efficacy in a clinical setting.
- Novel immunosuppressive strategies for composite tissue allografts. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):552-7.
Vascularized composite tissue allografts (CTAs) provide excellent restorative options for patients with limb loss and other deformities. Acute rejection remains common with CTA and immunosuppression is used in an attempt to prevent rejection. This has created ethical debates regarding the use of intensive immunosuppression for a nonlife-saving procedure. This highlights the need for newer immunosuppressive strategies for CTA, which are described in this review.Recent studies have looked into immunomodulation and tolerance to decrease toxicity of immunosuppression. Both strategies have had some success but have their own limitations. Although immunomodulation and decrease in immunosuppression decreases toxicity, it has been associated with higher rates of rejection. Induction of tolerance has achieved some initial success, but the initial conditioning regimens are associated with significant morbidity.Although recent advancements have been made in the immunosuppressive strategies in CTA, the ideal immunosuppression strategy with low toxicity and infection risk but with the ability to prevent acute and chronic rejection is yet to be discovered.
- Interpretation of transplant biopsies and immune responses following Treg cell therapy. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):616-20.
Regulatory T cells (Treg) are now well established as vital participants in maintaining self-tolerance and preventing autoimmunity. Tregs have already been shown to be effective in preventing graft-versus-host disease in clinical bone marrow transplantation, and numerous animal studies have suggested a therapeutic role for Treg in solid organ transplantation. Recent advances in Treg isolation and expansion have the field poised to perform trials of therapeutic Treg infusion in solid organ transplantation worldwide. An important component of these trials will be the detection of infused cells and the assessment of Treg activity after infusion.Several animal studies have demonstrated that infused Treg migrate to transplanted tissue in the early period after transplantation. This finding has important implications for the interpretation of biopsy results in human trials. Recent refinements in Treg identification, quantification, and functional assays will be discussed in the context of immune monitoring.Understanding the migration/localization and persistence of infused Treg into transplanted tissues as well as how they impact the peripheral immune response will be critical to the interpretation of early Treg trials.
- Donor-specific antibodies in allograft recipients: etiology, impact and therapeutic approaches. [Journal Article]
- Curr Opin Organ Transplant 2014 Dec; 19(6):591-7.
Kidney transplantation remains the treatment of choice for patients with end-stage renal failure. However, despite significant advancements in detection of donor-specific human leukocyte antigen antibodies, improved immunosuppression and patient management, the durability of this life-saving therapy has not improved. This results in increased morbidity and mortality as well as increased cost to the healthcare system.The identification of immune-pathogenic pathways responsible for allograft failure coupled with targeted interventions will represent one of the most important future objectives of transplant immunologist and physicians. The development of sensitive donor-specific antibody (DSA) detection techniques and advancements in renal allograft pathology assessments have revealed the importance of humoral immunity in mediating allograft failure. This is especially true for complement activating DSAs (C1q+).Our current understanding suggests that reduction of immunosuppressive medications or medication nonadherence is now the major causes of DSA development and attendant pathology. Other important factors in initiation of de-novo DSA production include viral infections, human leukocyte antigen-DR/DQ mismatches and autoimmune diseases. Therapies aimed at antibody reduction, B-cell depletion and modification of the complement system will likely usher in new therapeutic approaches for prevention and treatment of DSA-mediated allograft dysfunction.