CD45: a niche marker for allotransplantation.
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SUBMITTER: Li Z
PROVIDER: S-EPMC8931515 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
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Project description:Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
| S-EPMC9792517 | biostudies-literature
Project description:Exploration of proteome differences between CD45+ and CD45- cell types in renal cell carcinoma tumors and normal adjacent tissue patient samples.
2020-10-14 | PXD014370 | Pride
Project description:Background: To date, there is no satisfactory treatment for patients with calcium and vitamin D supplementation refractive hypoparathyroidism. Parathyroid allotransplantation by design is a one-time cure through its restoration of the parathyroid function and, therefore, could be the solution. A systematic literature review is conducted in the present paper, with the aim of outlining the possibilities of parathyroid allotransplantation and to calculate its efficacy. Additionally, various transplantation characteristics are linked to success. Methods: This review is carried out according to the PRISMA statement and checklist. Relevant articles were searched for in medical databases with the most recent literature search performed on 9 December 2021. Results: In total, 24 articles involving 22 unique patient cohorts were identified with 203 transplantations performed on 148 patients. Numerous types of (exploratory) interventions were carried out with virtually no protocols that were alike: there was the use of (non-) cryopreserved parathyroid tissue combined with direct transplantation or pretreatment using in vitro techniques, such as culturing cells and macro-/microencapsulation. The variability increased further when considering immunosuppression, graft histology, and donor-recipient compatibility, but this was found to be reported in its entirety by exception. As a result of the large heterogeneity among studies, we constructed our own criterium for transplantation success. With only the studies eligible for our assessment, the pooled success rate for parathyroid allotransplantation emerged to be 46% (13/28 transplantations) with a median follow-up duration of 12 months (Q1-Q3: 8-24 months). Conclusions: Manifold possibilities have been explored around parathyroid allotransplantation but are presented as a double-edged sword due to high clinical diverseness, low expertise in carrying out the procedure, and unsatisfactory study quality. Transplantations carried out with permanent immunosuppression seem to be the most promising, but, in its current state, little could be said about the treatment efficacy with a high quality of evidence. Of foremost importance in pursuing the answer whether parathyroid allotransplantation is a suitable treatment for hypoparathyroidism, a standardized definition of transplantation success must be established with a high-quality trial.
| S-EPMC8953572 | biostudies-literature
Project description:CD45 is a transmembrane protein tyrosine phosphatase, which in mammals plays an important role in T and B cell receptor and cytokine signaling. Recently, a catfish cDNA was shown to contain all characteristic CD45 features: an alternatively spliced amino-terminus, a cysteine-rich region, three fibronectin domains, a transmembrane region, and two phosphotyrosine phosphatase domains. However, analyses of CD45 cDNAs from various catfish lymphoid cell lines demonstrated that catfish CD45 is unique in that it contains a large number of alternatively spliced exons. Sequence analyses of cDNAs derived from the catfish clonal B cell line 3B11 indicated that this cell line expresses up to 13 alternatively spliced exons. Furthermore, sequence similarity among the alternatively spliced exons suggested duplication events. To establish the exact number and organization of alternatively spliced exons, a bacterial artificial chromosome library was screened, and the catfish functional CD45 gene plus six CD45 pseudogenes were sequenced. The catfish functional CD45 gene spans 37 kb and contains 49 exons. In comparison, the human and pufferfish CD45 genes consist of 34 and 30 exons, respectively. This difference in the otherwise structurally conserved catfish gene is due to the presence of 18 alternatively spliced exons that were likely derived through several duplication events. In addition, duplication events were also likely involved in generating the six pseudogenes, truncated at the 3' ends. A similarly 3' truncated CD45 pseudogene is also present in the pufferfish genome, suggesting that this specific CD45 gene duplication occurred before catfish and pufferfish diverged (approximately 400 million years ago).
| S-EPMC1352342 | biostudies-literature
Project description:Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.
| S-EPMC7527523 | biostudies-literature
Project description:BackgroundKidney dysfunction is a major complication after nonrenal solid organ transplants. Transplantation of vascularized composite allografts (VCA) has yielded successful midterm outcomes despite high rates of acute rejection and greater requirements of immunosuppression. Whether this translates in higher risks of kidney complications is unknown.MethodsNinety-nine recipients of facial or extremity transplants from the Brigham and Women's Hospital (BWH) and the International Registry on Hand and Composite Tissue Transplantation (IR) were reviewed. We assessed immunosuppression, markers of renal function over time, as well as pretransplant and posttransplant renal risk factors.ResultsData were obtained from 10 patients from BWH (age at transplant, 42.5 ± 13.8 years) and 89 patients (37.8 ± 11.5 years) from IR. A significant rise in creatinine levels (BWH, P = 0.0195; IR, P < 0.0001) and drop in estimated glomerular filtration rate (GFR) within the first year posttransplant was observed. The BWH and IR patients lost a mean of 22 mL/min GFR and 60 mL/min estimated GFR in the first year, respectively. This decrease occurred mostly in the first 6 months posttransplant (BWH). Pretransplant creatinine levels were not restored in either cohort. A mixed linear model identified multiple variables correlating with renal dysfunction, particularly tacrolimus trough levels.ConclusionsKidney dysfunction represents a major complication posttransplantation in VCA recipients early on. Strategies to mitigate this complication, such as reducing calcineurin inhibitor trough levels or using alternative immunosuppressive agents, may improve long-term patient outcomes. Standardizing laboratory and data collection of kidney parameters and risk factors in VCA patients will be critical for better understanding of this complication.
| S-EPMC6056276 | biostudies-literature
Project description:ObjectiveUpper extremity (UE) transplantation is the most commonly performed composite tissue allotransplantation worldwide. However, there is a lack of imaging standards for pre- and posttransplant evaluation. This study highlights the protocols and findings of UE allotransplantation toward standardization and implementation for clinical trials.MethodsMultimodality imaging protocols for a unilateral hand transplant candidate and a bilateral mid-forearm level UE transplant recipient include radiography, computed tomography (CT), magnetic resonance (MR) imaging, catheter angiography, and vascular ultrasonography. Pre- and posttransplant findings, including dynamic CT and MR performed for assessment of motor activity of transplanted hands, are assessed, and image quality of vessels and bones on CT and MR evaluated.ResultsPreoperative imaging demonstrates extensive skeletal deformity and variation in vascular anatomy and vessel patency. Posttransplant images confirm bony union in anatomical alignment and patency of vascular anastomoses. Mild differences in rate of vascular enhancement and extent of vascular networks are noted between the 2 transplanted limbs. Dynamic CT and MR demonstrate a 15° to 30° range of motion at metacarpophalangeal joints and 90° to 110° at proximal interphalangeal joints of both transplanted hands at 8 months posttransplant. Image quality was slightly better for CT than for MR in the first subject, while MR was slightly better in the second subject.ConclusionAdvanced vascular and musculoskeletal imaging play an important role in surgical planning and can provide novel posttransplantation data to monitor the success of the procedure. Implementation of more standardized protocols should enable a more comprehensive assessment to evaluate the efficacy in clinical trials.
| S-EPMC3716341 | biostudies-literature
Project description: Not available
| S-EPMC11295284 | biostudies-literature
Project description:The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.
| S-EPMC3252956 | biostudies-literature
Project description:CD45, the predominant transmembrane tyrosine phosphatase in leukocytes, is required for the efficient induction of T cell receptor signaling and activation. We recently reported that the CD45-intracellular signals in peripheral blood mononuclear cells (PBMCs) of triple negative breast cancer (TNBC) patients are inhibited. We also reported that C24D, an immune modulating therapeutic peptide, binds to CD45 on immune-suppressed cells and resets the functionality of the immune system via the CD45 signaling pathway. Various studies have demonstrated that also viruses can interfere with the functions of CD45 and that patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are immune-suppressed. Given the similarity between the role of CD45 in viral immune suppression and our findings on TNBC, we hypothesized that the C24D peptide may have a similar "immune-resetting" effect on PBMCs from COVID-19 patients as it did on PBMCs from TNBC patients. We tested this hypothesis by comparing the CD45/TCR intracellular signaling in PBMCs from ten COVID-19 patients vs. PBMCs from ten healthy volunteers. Herein, we report our findings, demonstrating the immune reactivating effect of C24D via the phosphorylation of the tyrosine 505 and 394 in Lck, the tyrosine 493 in ZAP-70 and the tyrosine 172 in VAV-1 proteins in the CD45 signaling pathway. Despite the relatively small number of patients in this report, the results demonstrate that C24D rescued CD45 signaling. Given the central role played by CD45 in the immune system, we suggest CD45 as a potential therapeutic target.
| S-EPMC8369232 | biostudies-literature