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The Journal of Clinical Investigation Jul 2023Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context...
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.
Topics: Kidney Transplantation; Transcriptome; Receptors, Antigen, T-Cell, alpha-beta; RNA; Allografts; Graft Rejection
PubMed: 37227784
DOI: 10.1172/JCI170191 -
Transplant International : Official... 2023Organ preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for... (Review)
Review
Organ preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for transplantation. Nevertheless, the discard of organs considered too damaged still sustains the imbalance between donor organs supply and demands. Therefore, there is the pressing clinical need for strategies to repair and/or regenerate organs before transplantation, and MP is uniquely positioned to satisfy this need. The systemic administration of mesenchymal stromal cells (MSC) was shown to reduce ischemia-reperfusion injury in pre-clinical organ transplant models but could not be reproduced in clinical transplantation, largely because of inefficient cell delivery. The administration of MSC during MP is one strategy that recently gained much attention as an alternative delivery method to target MSC directly to the donor organ. However, careful reinterpretation of preliminary results reveals that this approach is equally limited by a suboptimal delivery of short-lived MSC to the target organ. In contrast, the use of MSC secretome and/or extracellular vesicles therapy during MP seems to be more efficient in harnessing MSC properties during MP. In this mini review we speculate on the future of the novel niche of organ repair and regeneration before transplantation.
Topics: Humans; Organ Preservation; Organ Transplantation; Regeneration; Perfusion; Mesenchymal Stem Cell Transplantation
PubMed: 38020754
DOI: 10.3389/ti.2023.11947 -
Advanced Science (Weinheim,... Dec 2023Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach for dysbiosis-related diseases. However, the clinical practice of crude fecal... (Review)
Review
Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach for dysbiosis-related diseases. However, the clinical practice of crude fecal transplants presents limitations in terms of acceptability and reproductivity. Consequently, two alternative solutions to FMT are developed: transplanting bacteria communities or virome. Advanced methods for transplanting bacteria mainly include washed microbiota transplantation and bacteria spores treatment. Transplanting the virome is also explored, with the development of fecal virome transplantation, which involves filtering the virome from feces. These approaches provide more palatable options for patients and healthcare providers while minimizing research heterogeneity. In general, the evolution of the next generation of FMT in global trends is fecal microbiota components transplantation which mainly focuses on transplanting bacteria or virome.
Topics: Humans; Fecal Microbiota Transplantation; Virome; Feces; Bacteria
PubMed: 37914662
DOI: 10.1002/advs.202301097 -
Progress in building clinically relevant patient-derived tumor xenograft models for cancer research.Animal Models and Experimental Medicine Oct 2023Patient-derived tumor xenograft (PDX) models, a method involving the surgical extraction of tumor tissues from cancer patients and subsequent transplantation into... (Review)
Review
Patient-derived tumor xenograft (PDX) models, a method involving the surgical extraction of tumor tissues from cancer patients and subsequent transplantation into immunodeficient mice, have emerged as a pivotal approach in translational research, particularly in advancing precision medicine. As the first stage of PDX development, the patient-derived orthotopic xenograft (PDOX) models implant tumor tissue in mice in the corresponding anatomical locations of the patient. The PDOX models have several advantages, including high fidelity to the original tumor, heightened drug sensitivity, and an elevated rate of successful transplantation. However, the PDOX models present significant challenges, requiring advanced surgical techniques and resource-intensive imaging technologies, which limit its application. And then, the humanized mouse models, as well as the zebrafish models, were developed. Humanized mouse models contain a human immune environment resembling the tumor and immune system interplay. The humanized mouse models are a hot topic in PDX model research. Regarding zebrafish patient-derived tumor xenografts (zPDX) and patient-derived organoids (PDO) as promising models for studying cancer and drug discovery, zPDX models are used to transplant tumors into zebrafish as novel personalized medical animal models with the advantage of reducing patient waiting time. PDO models provide a cost-effective approach for drug testing that replicates the in vivo environment and preserves important tumor-related information for patients. The present review highlights the functional characteristics of each new phase of PDX and provides insights into the challenges and prospective developments in this rapidly evolving field.
Topics: Humans; Animals; Mice; Heterografts; Zebrafish; Xenograft Model Antitumor Assays; Prospective Studies; Neoplasms; Disease Models, Animal
PubMed: 37679891
DOI: 10.1002/ame2.12349 -
Facial Plastic Surgery : FPS Dec 2023A wide variety of grafting materials and techniques can be used to create functional and aesthetic changes in rhinoplasty. Choosing the optimal grafting approach is... (Review)
Review
A wide variety of grafting materials and techniques can be used to create functional and aesthetic changes in rhinoplasty. Choosing the optimal grafting approach is critical to achieving an optimal patient outcome. We present a review of autografts, allografts, and alloplasts used in primary and revision rhinoplasty and discuss factors that impact graft choice. Autologous grafts serve as the pillar for grafting material in rhinoplasty given their reliable long-term outcomes, low rates of infection, resorption, and extrusion, and ability to provide structural scaffolding as well as contour. Cadaveric allografts can be utilized as a source of grafting material in certain clinical scenarios including revision rhinoplasty and have been shown to be equally safe and effective as autologous grafts while avoiding donor-site morbidity. Alloplasts can prove useful in rhinoplasty in cases of iatrogenic nasal deformities or revision cases. Careful consideration of clinical scenario, patient factors, and outcome goals is necessary to choose the appropriate grafting approach to address functional and cosmetic outcomes.
Topics: Humans; Rhinoplasty; Esthetics, Dental; Transplantation, Autologous; Autografts; Reoperation; Retrospective Studies
PubMed: 37348541
DOI: 10.1055/a-2116-4566 -
Experimental and Clinical... Apr 2024The first living donor kidney transplant in Syria was performed 44 years ago; by the end of 2022, 6265 renal transplants had been performed in Syria. Kidney, bone... (Review)
Review
The first living donor kidney transplant in Syria was performed 44 years ago; by the end of 2022, 6265 renal transplants had been performed in Syria. Kidney, bone marrow, cornea, and stem cells are the only organs or tissues that can be transplanted in Syria. Although 3 heart transplants from deceased donors were performed in the late 1980s, cardiac transplant activities have since discontinued. In 2003, national Syrian legislation was enacted authorizing the use of organs from living unrelated and deceased donors. This important law was preceded by another big stride: the acceptance by the higher Islamic religious authorities in Syria in 2001 of the principle of procurement of organs from deceased donors, provided that consent is given by a first- or second-degree relative. After the law was enacted, kidney transplant rates increased from 7 per million population in 2002 to 17 per million population in 2007. Kidney transplants performed abroad for Syrian patients declined from 25% in 2002 to <2% in 2007. Rates plateaued through 2010, before the political crisis started in 2011. Forty-four years after the first successful kidney transplant in Syria, patients needing an organ transplant rely on living donors only. Moreover, 20 years after the law authorizing use of organs from deceased donors, a program is still not in place in Syria. The war, limited resources, and lack of public awareness about the importance of organ donation and transplant appear to be factors inhibiting initiation of a deceased donor program in Syria. A concerted and ongoing education campaign is needed to increase awareness of organ donation, change negative public attitudes, and gain societal acceptance. Every effort must be made to initiate a deceased donor program to lessen the burden on living donors and to enable national self-sufficiency in organs for transplant.
Topics: Humans; Syria; Tissue and Organ Procurement; Organ Transplantation; Living Donors; Tissue Donors; Religion and Medicine; Kidney Transplantation; Islam; Time Factors; Health Policy; Government Regulation
PubMed: 38775694
DOI: 10.6002/ect.BDCDSymp.L10 -
Clinical and Experimental Immunology Jul 2023Innate lymphoid cells (ILCs) are a family of lymphocytes with essential roles in tissue homeostasis and immunity. Along with other tissue-resident immune populations,... (Review)
Review
Innate lymphoid cells (ILCs) are a family of lymphocytes with essential roles in tissue homeostasis and immunity. Along with other tissue-resident immune populations, distinct subsets of ILCs have important roles in either promoting or inhibiting immune tolerance in a variety of contexts, including cancer and autoimmunity. In solid organ and hematopoietic stem cell transplantation, both donor and recipient-derived ILCs could contribute to immune tolerance or rejection, yet understanding of protective or pathogenic functions are only beginning to emerge. In addition to roles in directing or regulating immune responses, ILCs interface with parenchymal cells to support tissue homeostasis and even regeneration. Whether specific ILCs are tissue-protective or enhance ischemia reperfusion injury or fibrosis is of particular interest to the field of transplantation, beyond any roles in limiting or promoting allograft rejection or graft-versus host disease. Within this review, we discuss the current understanding of ILCs functions in promoting immune tolerance and tissue repair at homeostasis and in the context of transplantation and highlight where targeting or harnessing ILCs could have applications in novel transplant therapies.
Topics: Humans; Lymphocytes; Immunity, Innate; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease
PubMed: 37119279
DOI: 10.1093/cei/uxad050 -
Blood Cancer Journal Aug 2023Allogeneic stem cell transplant (allo SCT) for multiple myeloma (MM) is potentially curative in some, while toxic in many others. We retrospectively analyzed 85 patients...
Allogeneic stem cell transplant (allo SCT) for multiple myeloma (MM) is potentially curative in some, while toxic in many others. We retrospectively analyzed 85 patients diagnosed with MM who underwent allo SCT as frontline or salvage therapy between 2000 and 2022 at Mayo Clinic Rochester and examined patient outcomes and prognostic markers. Overall survival (OS), progression free survival (PFS), treatment related mortality (TRM), and relapse rates (RR) were estimated using the Kaplan Meier method and competing risk models. Median follow-up was 11.5 years. Median OS and PFS were 1.7 and 0.71 years, respectively. Five-year OS and PFS were 22.2% and 15.1%, respectively. One-year TRM was 23.5%. Twelve patients demonstrated durable overall survival, living 10+ years beyond their allo SCT. This subgroup was more likely to have no or one prior auto SCT (p = 0.03) and to have been transplanted between 2000 and 2010 (p = 0.03). Outcomes were poor in this cohort with long follow-up, with few patients surviving 5 years or more, and most relapsing or dying within 2 years. We would expect better outcomes and tolerability with an expanded array of novel therapeutics and would prefer them to allo SCT.
Topics: Humans; Multiple Myeloma; Retrospective Studies; Progression-Free Survival; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation
PubMed: 37591876
DOI: 10.1038/s41408-023-00900-z -
World Journal of Gastroenterology Dec 2023Pancreatic transplantation is considered by the American Diabetes Association and the European Association for the Study of Diabetes an acceptable surgical procedure in... (Review)
Review
Pancreatic transplantation is considered by the American Diabetes Association and the European Association for the Study of Diabetes an acceptable surgical procedure in patients with type 1 diabetes also undergoing kidney transplantation in pre-final or end-stage renal disease if no contraindications are present. Pancreatic transplantation, however, is a complex surgical procedure and may lead to a range of postoperative complications that can significantly impact graft function and patient outcomes. Postoperative computed tomography (CT) is often adopted to evaluate perfusion of the transplanted pancreas, identify complications and as a guide for interventional radiology procedures. CT assessment after pancreatic transplantation should start with the evaluation of the arterial Y-graft, the venous anastomosis and the duodenojejunostomy. With regard to complications, CT allows for the identification of vascular complications, such as thrombosis or stenosis of blood vessels supplying the graft, the detection of pancreatic fluid collections, including pseudocysts, abscesses, or leaks, the assessment of bowel complications (anastomotic leaks, ileus or obstruction), and the identification of bleeding. The aim of this pictorial review is to illustrate CT findings of surgical-related complications after pancreatic transplantation. The knowledge of surgical techniques is of key importance to understand postoperative anatomic changes and imaging evaluation. Therefore, we first provide a short summary of the main techniques of pancreatic transplantation. Then, we provide a practical imaging approach to pancreatic transplantation and its complications providing tips and tricks for the prompt imaging diagnosis on CT.
Topics: Humans; Pancreas Transplantation; Tomography, X-Ray Computed; Diabetes Mellitus, Type 1; Kidney Transplantation; Kidney Failure, Chronic; Postoperative Complications
PubMed: 38130739
DOI: 10.3748/wjg.v29.i46.6049 -
Lipids in Health and Disease Dec 2023Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring...
BACKGROUND
Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear.
METHODS
Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis.
RESULTS
Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation.
CONCLUSIONS
This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.
Topics: Humans; Rats; Animals; Kidney Transplantation; Fenofibrate; Kidney; Fibrosis; Fatty Acids, Omega-3; Allografts; Hyperlipidemias; Cholesterol
PubMed: 38049842
DOI: 10.1186/s12944-023-01978-x