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Journal of Personalized Medicine Dec 2023Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With... (Review)
Review
Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor-recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. : Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.
PubMed: 38138933
DOI: 10.3390/jpm13121706 -
Biomedicines Jul 2023Infectious agents can pose a significant challenge in kidney transplantation, as they have the potential to cause direct infections in the transplanted kidney. These... (Review)
Review
Infectious agents can pose a significant challenge in kidney transplantation, as they have the potential to cause direct infections in the transplanted kidney. These infections can lead to a decline in kidney function and reduce the longevity of the transplanted kidney. Common post-transplant allograft infections include bacterial pyelonephritis and the BK virus infection, while adenovirus, JC virus, and cytomegalovirus are less frequent but can also lead to significant allograft dysfunctions. The histopathological features of these infections are characterized by the infiltration of inflammatory cells in the kidney interstitial area and the presence of viral nuclear inclusions or cytopathic changes in the renal tubular epithelial cells. The confirmation of causative organisms can be achieved by immunohistochemical staining or the visualization of viral particles using electron microscopic examination. However, these methods typically require a longer turnaround time and are not readily available in developing countries, unlike standard hematoxylin-eosin staining. Notably, the differential diagnosis of interstitial inflammation in kidney allografts almost always includes T cell-mediated rejection, which has a different treatment approach than allograft infections. The aim of this review was to prompt clinicians to identify diverse pathological alterations as observed in kidney allograft biopsies, thereby facilitating further investigations and the management of suspected kidney allograft infections.
PubMed: 37509541
DOI: 10.3390/biomedicines11071902 -
ELife Dec 2023Nucleotide and force-dependent mechanisms control how the viral genome of lambda bacteriophage is inserted into capsids.
Nucleotide and force-dependent mechanisms control how the viral genome of lambda bacteriophage is inserted into capsids.
Topics: DNA, Viral; Bacteriophage lambda; Capsid; Genome, Viral; Nucleotides; Virus Assembly
PubMed: 38095555
DOI: 10.7554/eLife.94128 -
Gastroenterology Oct 2023Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide...
BACKGROUND & AIMS
Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.
METHODS
HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.
RESULTS
These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401 individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 IECs. HLA-DP401 IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44 NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301 organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.
CONCLUSIONS
We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44 NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44 NK cell-mediated destruction of the intestinal epithelium in UC.
Topics: Humans; HLA-DP Antigens; Colitis, Ulcerative; Killer Cells, Natural; Haplotypes; Epithelial Cells
PubMed: 37454979
DOI: 10.1053/j.gastro.2023.06.034 -
Molecular Therapy : the Journal of the... Sep 2023The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major...
The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome gene therapy vectors to date. Our team designed a new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression of MECP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months after injection. Additionally, this new vector is highly efficacious at lower doses compared with previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of Mecp2. Overall, data from this multicenter study highlight the efficacy and safety of this gene therapy construct, making it a promising candidate for first-in-human studies to treat Rett syndrome.
Topics: Humans; Mice; Animals; Rett Syndrome; Primates; Genetic Therapy; Mutation
PubMed: 37481701
DOI: 10.1016/j.ymthe.2023.07.013 -
Frontiers in Cellular and Infection... 2023The identification of the first human polyomavirus BK (BKV) has been over half century, The previous epidemiological and phylogenetic studies suggest that BKV prevailed... (Review)
Review
The identification of the first human polyomavirus BK (BKV) has been over half century, The previous epidemiological and phylogenetic studies suggest that BKV prevailed and co-evolved with humans, leading to high seroprevalence all over the world. In general, BKV stays latent and symptomless reactivation in healthy individuals. BKV has been mainly interlinked with BKV-associated nephropathy (BKVAN) in kidney-transplant recipients and hemorrhagic cystitis (HC) in hematopoietic stem cell transplant recipients (HSCTRs). However, the mechanisms underlying BKV latency and reactivation are not fully understood and lack of extensive debate. As Merkel cell polyomavirus (MCV) was identified as a pathogenic agent of malignant cutaneous cancer Merkel cell carcinoma (MCC) since 2008, linking BKV to tumorigenesis of urologic tumors raised concerns in the scientific community. In this review, we mainly focus on advances of mechanisms of BKV latency and reactivation, and BKV-associated diseases or tumorigenesis with systematical review of formerly published papers following the PRISMA guidelines. The potential tumorigenesis of BKV in two major types of cancers, head and neck cancer and urologic cancer, was systematically updated and discussed in depth. Besides, BKV may also play an infectious role contributing to HIV-associated salivary gland disease (HIVSGD) presentation. As more evidence indicates the key role of BKV in potential tumorigenesis, it is important to pay more attention on its etiology and pathogenicity and .
Topics: Humans; BK Virus; Phylogeny; Seroepidemiologic Studies; Polyomavirus Infections; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37771695
DOI: 10.3389/fcimb.2023.1263983 -
International Journal of Nephrology and... 2024Glomeruli can be damaged in several conditions after kidney transplantation, with a potential impact on the graft function and survival. Primary glomerulonephritis, a... (Review)
Review
Glomeruli can be damaged in several conditions after kidney transplantation, with a potential impact on the graft function and survival. Primary glomerulonephritis, a group of glomerular immunological damage that results in variable histological patterns and clinical phenotypes, can occur in kidney transplant recipients as a recurrent or de novo condition. Specific immunologic conditions associated with kidney transplantation, such as acute rejection episodes, can act as an additional trigger after transplantation, impacting the incidence of these glomerulopathies. The post-transplant GN recurrence ranges from 3% to 15%, varying according to the GN subtype and post-transplant time, mainly occurring after 3-5 years of kidney transplantation. Advances in the knowledge of glomerulonephritis pathophysiology have provided new approaches to pre-transplant risk evaluation and post-transplant monitoring. Glomeruli can be affected by several systemic viral infections, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), cytomegalovirus (CMV), and BK virus. The diagnosis of these infections, as well as the identification of possible complications associated with them, are important to minimize the negative impacts of these conditions on kidney transplant recipients' outcomes.
PubMed: 38495741
DOI: 10.2147/IJNRD.S391779 -
JCI Insight Nov 2023Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role...
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.
Topics: Humans; Kidney Transplantation; Immunologic Memory; CD8-Positive T-Lymphocytes; Receptors, Antigen, T-Cell; Viruses
PubMed: 37751288
DOI: 10.1172/jci.insight.172681 -
International Journal of Molecular... Dec 2023Polyomaviruses are widespread, with BK viruses being most common in humans who require immunosuppression due to allotransplantation. Infection with BK polyomavirus (BKV)...
Polyomaviruses are widespread, with BK viruses being most common in humans who require immunosuppression due to allotransplantation. Infection with BK polyomavirus (BKV) may manifest as BK virus-associated nephropathy and hemorrhagic cystitis. Established diagnostic methods include the detection of polyomavirus in urine and blood by PCR and in tissue biopsies via immunohistochemistry. In this study, 79 patients with pathological renal retention parameters and acute kidney injury (AKI) were screened for BK polyomavirus replication by RNA extraction, reverse transcription, and virus-specific qPCR in urine sediment cells. A short fragment of the VP2 coding region was the target of qPCR amplification; patients with (n = 31) and without (n = 48) a history of renal transplantation were included. Urine sediment cell immunofluorescence staining for VP1 BK polyomavirus protein was performed using confocal microscopy. In 22 patients with acute renal injury, urinary sediment cells from 11 participants with kidney transplantation (KTX) and from 11 non-kidney transplanted patients (nonKTX) were positive for BK virus replication. BK virus copies were found more frequently in patients with AKI stage III (n = 14). Higher copy numbers were detected in KTX patients having experienced BK polyoma-nephropathy (BKPyVAN) in the past or diagnosed recently by histology (5.6 × 10-3.1 × 10). One patient developed BK viremia following delayed graft function (DGF) with BK virus-positive urine sediment. In nonKTX patients with BK copies, decoy cells were absent; however, positive staining of cells was found with epithelial morphology. Decoy cells were only found in KTX patients with BKPyVAN. In AKI, damage to the tubular epithelium itself may render the epithelial cells more permissive for polyoma replication. This non-invasive diagnostic approach to assess BK polyomavirus replication in urine sediment cells has the potential to identify KTX patients at risk for viremia and BKPyVAN during AKI. This method might serve as a valuable screening tool for close monitoring and tailored immunosuppression decisions.
Topics: Humans; BK Virus; Viremia; Kidney Transplantation; Kidney; Polyomavirus; Polyomavirus Infections; Acute Kidney Injury
PubMed: 38139342
DOI: 10.3390/ijms242417511