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Current opinion in organ transplantation [journal]
- Interpretation of transplant biopsies and immune responses following Treg cell therapy. [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Oct 13.
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 Oct 8.
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.
- Recellularization of organs: what is the future for solid organ transplantation? [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Oct 8.
Allogeneic organ transplantation is burdened by donor shortage, graft rejection and adverse effects of lifelong immune suppression. Engineering bioartificial organs from acellular organ scaffolds and patient-derived cells are a new approach to potentially overcome these limitations.Decellularized organs yield a scaffold of extracellular matrix on which cells can adhere, integrate and ultimately form functional tissue. Various cell sources are currently used to repopulate acellular scaffolds, however, all have limitations. Patient-derived pluripotent stem cells hold great promise for tissue and organ engineering, when robust and mature cells can be directed in a reliable and safe manner. Finally, to produce mature organotypic tissue from a nonfunctional seeded scaffold, cellular scaffolds are cultured under biomimetic conditions in vitro. Alternatively, organs may be implanted at an immature stage to harness the recipient's body's regenerative capacity. In proof of principle experiments to date, bioengineered small animal organs have shown rudimentary function and maintained patency for limited time when transplanted in vivo.Recent advances in bioengineering organs raise the hope that we can overcome organ donor shortage and eliminate the need for livelong immunosuppression. However, significant challenges remain in generating mature large-scale donor-like bioartificial organs.
- Islet cell transplant and the incorporation of Tregs. [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Oct 8.
T regulatory cells (Tregs) play a central role in maintaining immune homeostasis and peripheral tolerance to foreign antigens in humans. The immune response to alloantigens and recurrence of autoimmunity contribute to pancreatic islet transplant dysfunction, hence the adoptive transfer of Tregs has the potential to significantly improve islet graft survival. In this review, we provide an in-depth analysis of challenges associated with the application of ex-vivo expanded Tregs therapy in pancreatic islet transplant.Tregs administered systemically may poorly migrate to the site of transplantation, which is critical for tolerance induction and graft protection. Intraportal administration of pancreatic tissue exerts some limitations on the ability to cotransplant Tregs at the same site of islet transplantation. In order to maximize therapeutic potential of Tregs, islet transplantation protocols may need additional refinement. Further to this, the Tregs may require cryopreservation in order to make them readily available at the same time as islet transplant.On the basis of current experience and technology, the combination of islet and Treg cotransplantation is feasible and has great potential to improve islet graft survival. The possibility to wean off, or withdraw, traditional immunosuppressive agents and improve patient quality of life makes it an interesting avenue to be pursued.
- How can the latest technologies advance cell therapy manufacturing? [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Sep 25.
Cellular therapies show early proof of safety and efficacy in a, so far, limited number of clinical trials. Technical and regulatory difficulties in translating innovative preclinical cell therapy approaches into clinical protocols have been and still are a major roadblock for a more rapid progress. This is particularly true for broad clinical applications of cellular therapies outside specialized clinical centers and for the initiation of multicenter clinical trials. The increased awareness of such deficits in availability of cGMP-compliant technologies and integration of multistep procedures into one clinical manufacturing process has initiated efforts from both basic researchers and biotech companies to overcome these problems. These developments will be exemplified with a focus on T-cell therapies and, in particular, the use of regulatory T cells for bone marrow and organ transplantation or autoimmunity.Recent developments in the field of clinical cell sorting, identification of therapeutically relevant T-cell subsets, in-vitro cell culture technologies and automation have the potential to provide solutions for long-standing problems in the field of clinical cell processing.Recent technological developments and further attempts aiming at simplification, integration of multistep procedures and automation of clinical cell processing are key for the development of successful cellular therapies and their broad implementation in the clinics.
- Future direction of immunosuppression in lung transplantation. [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Sep 25.
Immunosuppression regimens have helped improve rejection episodes following lung transplantation, but long-term outcomes are still not comparable with cardiac, hepatic, or renal transplantation. This review summarizes the immunobiology that contributes to rejection events and future opportunities in outcomes on the basis of providing optimized delivery of the immunosuppression based on immune-monitoring techniques, taking into account individual patient pharmacokinetics and phenotypic variance.Drug toxicities, narrow therapeutic drug monitoring windows, and current immunoassays currently do not assist in detecting the global degree of immunosuppression. The currently available randomized control trials for induction therapy or maintenance therapies do not provide additional benefits compared with previously reported retrospective trials. To push beyond the current barriers, transplant teams are focusing on the role of pharmacokinetics, assessing phenotypic variable to potentially modify to quadruple therapy and using extracorporeal photopheresis.Conventional practice for the choices of immunosuppression is being evaluated on the basis of randomized control trials as opposed to retrospective studies or single-center trials. The future direction of immunosuppression will be continued by dynamic processes taking into consideration measures to improve tolerance, reducing treatment burden, and providing the best level of evidence while accounting for rejection, infections, renal function, and other comorbidities.
- Everolimus in liver transplantation. [JOURNAL ARTICLE]
- Curr Opin Organ Transplant 2014 Sep 24.
In this review, we discuss the mechanism of action, side-effects, and role of everolimus (EVR) in liver transplant, specifically the most recent de-novo (within 1 month of transplant) and conversion (months to years after transplant) trials in the literature.Everolimus was recently approved by the Food and Drug Administration for use in liver transplantation. Its primary benefit over other immunosuppressive agents is the absence of renal toxicity. De-novo liver recipients receiving EVR with reduced-dose tacrolimus had similar rates of death, graft loss, and rejection compared with tacrolimus monotherapy, but significantly better renal function. The most common side effects are manageable and include stomatitis, hyperlipidemia, and cytopenias. Compared with the other mammalian target of rapamycin inhibitor, sirolimus, EVR is not associated with impaired wound healing or hepatic artery thrombosis. In addition, EVR may provide some benefit as an antineoplastic agent that may be particularly applicable to liver recipients with hepatocellular carcinoma.Everolimus is the only Food and Drug Administration-approved mammalian target of rapamycin inhibitor for liver transplantation. It offers noninferior immunosuppression (compared with standard therapy) with the absence of renal toxicity. Its use will likely increase over time as clinicians become more familiar with this drug.
- Terminal heart failure: who should be transplanted and who should have mechanical circulatory support? [Journal Article]
- Curr Opin Organ Transplant 2014 Oct; 19(5):486-93.
Permanent long-term mechanical circulatory support (MCS) is currently reserved for patients who are transplant ineligible. In light of improved outcomes with current continuous flow devices, increased interest has focused on the potential extension of MCS therapy to ambulatory advanced heart failure patients and as an alternative to cardiac transplantation.Average 1-year and 2-year survival with heart transplantation is about 85 and 80%, and with MCS therapy, it is 85 and 70% (with censoring at transplant). Specific subsets of destination therapy patients enjoy survival out to 2 years, which is comparable with transplant survival. Risk factor analyses identify similar risk profiles for each therapy. Life satisfaction after each is highly dependent on the frequency and severity of adverse events, which are quite different for these interventions. Patients with long expected waiting times will likely be the initial group for triage off the transplant wait list to MCS therapy.MCS has progressively improved and may become a reasonable alternative to transplantation for highly selected patients with long expected waiting time. More routine extension of MCS therapy to the transplant population awaits further reduction of major adverse events, miniaturized devices, and less invasive implant techniques.
- Current techniques for pediatric liver transplantation. [Journal Article]
- Curr Opin Organ Transplant 2014 Oct; 19(5):468-73.
Orthotopic liver transplantation in the pediatric population is a technically challenging undertaking, requiring highly specialized surgical techniques unique to this group. This review describes the most current method of transplantation for these patients.Pediatric liver transplantation employs multiple modifications of standard transplant technique, including alternative methods of vascular and biliary anastomoses as well as technical variant grafts. We herein describe how these methods are employed in procurement, back-table preparation, hepatectomy, and allograft implantation.This review provides concise direction of surgical technique for pediatric liver transplant recipients.
- Donation after cardiac death for lung transplantation: a review of current clinical practice. [Journal Article]
- Curr Opin Organ Transplant 2014 Oct; 19(5):455-9.
This review presents a concise update on clinical donation after cardiac death (DCD or DDCD) lung transplantation. Lung allografts have predominantly been procured from donors after determination of neurologic death but will not meet the existing demand. A steadily increasing need for lungs is evident worldwide, especially in an era of improved outcomes for recipients. Other solid organ utilization from donors after determination of cardiac death has markedly increased internationally, but the utilization rate of lungs from such donors is still considerably less. The multifaceted reasons for this discrepancy are considered, and the recent evidence available supporting DCD for lung transplantation in clinical practice is presented in context. The recent experimental research studies are not within the remit of this appraisal.The more recent and markedly increased lung recipient cohorts showed very satisfactory survival outcomes for DCD transplantation in several programs. The overall utilization rate, however, remains low. The background and the rationale of lung donor allograft expansion to proactively include DCD allografts from controlled (Maastricht category III donors) is re-emphasized in this review. The feasibility of other DCD categories for lung transplantation is considered. This is particularly prudent with the advent of the ex-vivo lung perfusion modality in pulmonary procurement.Despite evidence for adequate survival outcomes and reported favorable primary graft dysfunction rates, DCD lung transplantation remains underutilized in most countries. Waiting times could be notably reduced and mortality of lung candidates arguably decreased by a more decided and appropriate implementation of proven DCD lung transplant strategies.