Background The role of donor-specific HLA antibodies (DSA) following pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Methods Serum samples were collected at routine clinic visits from fifty pediatric LTx recipients classified into three clinical phenotypes: non-tolerant (n=18) with de-novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n=25) on maintenance tacrolimus; operationally tolerant (n=7). Samples were blinded and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. Results DSA were detected in 54% (n=27) of patients, with the majority directed at HLA class II antigens (41% DR, 53% DQ). Patients with DSA were younger at time of LTx (p=0.016) and time of study (p=0.024). Mean AST, ALT, total bilirubin, and GGT were higher in DSA positive patients, though did not reach statistical significance. Non-tolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (p=0.021). The non-tolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (p=0.015) and 8.6 (p=0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (p=0.004) and 10.8 (p=0.006), respectively. Conclusions Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.
Intracerebral infection of mice with mouse hepatitis virus, a member of the Coronaviridae family, reproducibly results in an acute encephalomyelitis that progresses to a chronic demyelinating disease. The ensuing neuropathology during the chronic stage of disease is primarily immune mediated and similar to that of the human demyelinating disease multiple sclerosis. Secretion of chemokines within the CNS signals the infiltration of leukocytes, which results in destruction of white matter and neurological impairment. The CC chemokine ligand (CCL)5 is localized in white matter tracts undergoing demyelination, suggesting that this chemokine participates in the pathogenesis of disease by attracting inflammatory cells into the CNS. In this study, we administer a mAb directed against CCL5 to mice with established mouse hepatitis virus-induced demyelination and impaired motor skills. Anti-CCL5 treatment decreased T cell accumulation within the CNS based, in part, on viral Ag specificity, indicating the ability to differentially target select populations of T cells. In addition, administration of anti-CCL5 improved neurological function and significantly (p ≤ 0.005) reduced the severity of demyelination and macrophage accumulation within the CNS. These results demonstrate that the severity of CNS disease can be reduced through the use of a neutralizing mAb directed against CCL5 in a viral model of demyelination.
Allorecognition is the activation of the adaptive immune system to foreign human leukocyte antigen (HLA) resulting in the generation of alloantibodies. Due to a high polymorphism, foreign HLA is recognized by the immune system following transplant, transfusion, or pregnancy resulting in the formation of the germinal center and the generation of long-lived alloantibody-producing memory B cells. Alloantibodies recognize antigenic epitopes displayed by the HLA molecule on the transplanted allograft and contribute to graft damage through multiple mechanisms, including (1) activation of the complement cascade resulting in the formation of the MAC complex and inflammatory anaphylatoxins, (2) transduction of intracellular signals leading to cytoskeletal rearrangement, growth, and proliferation of graft vasculature, and (3) immune cell infiltration into the allograft via FcγR interactions with the FC portion of the antibody. This review focuses on the generation of HLA alloantibody, routes of sensitization, alloantibody specificity, and mechanisms of antibody-mediated graft damage.
BackgroundRasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy.MethodsQuantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method.ResultsConsensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-γ, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset.ConclusionsActive disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE.
Inflammation plays a critical role in the secondary degenerative response to spinal cord injury (SCI). The influx of inflammatory cells following SCI is preceded by the expression of specific chemoattractants, including chemokines. The chemokine CXCL10 is a potent T lymphocyte recruiter and has been strongly implicated in the pathology of many CNS disorders. We have previously demonstrated that CXCL10 exacerbates secondary degeneration by blocking the function of CXCL10 prior to SCI. Here we administered neutralizing antibodies against CXCL10 1 h after SCI in order to investigate the efficacy of this therapeutic intervention in abating histologic and functional deficit following acute SCI and further assess the functional role of CXCL10 in secondary degeneration. Neutralization of CXCL10 significantly reduced inflammation, apoptosis, neuronal loss and whole tissue loss. Notably, this therapeutic treatment also promoted revascularization of the injured spinal cord and functional recovery. These data suggest that anti-CXCL10 antibody treatment is a viable therapeutic strategy for acute SCI.
Acute AMR is well reported following ABO-incompatible LTx. However, it remains uncommon in ABO-compatible LTx. It typically presents with graft dysfunction ≤2 weeks post-LTx and is often associated with graft loss. We report the clinical presentation, treatment regimen, and outcome of six pediatric LTx recipients diagnosed with early acute AMR based on (i) clinical signs of graft dysfunction, (ii) histopathology indicative of acute injury ± C4d staining, and (iii) presence of HLA DSA. All patients developed elevated ALT and GGT ≤ 45 days post-LTx. All showed HLA class I (n=4) and/or II (n=6) DSA (peak MFI 6153-11 910). Four had de novo DSA, and two had preformed DSA. Five were initially diagnosed with ACR refractory to steroid therapy. Four exhibited resolution of graft dysfunction with AMR therapy. Two had refractory AMR-one was re-transplanted; the other was treated with eculizumab and showed improvement in graft function but later died due to a tracheostomy complication. Our case series suggests that AMR following ABO-compatible LTx may be under-diagnosed. The presentation can be variable, and treatment should be individualized. Eculizumab may be an option for refractory AMR. Ultimately, future multicenter studies are needed to better define diagnostic criteria, characterize optimal treatment, and assess long-term outcomes following liver AMR.
Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.
This is the accepted version of the paper.This version of the publication may differ from the final published version. In order to further understand the contribution of venous and arterial effects to the photoplethysmographic (PPG) signal, recordings were made from twenty healthy volunteer subjects during an exercise in which the right hand was raised and lowered with reference to heart level. Red (R) and infrared (IR) PPG signals were obtained from the right index finger using a custom-made PPG processing system. Laser Doppler flowmetry (LDF) signals were also recorded from an adjacent fingertip. The signals were compared with simultaneous PPG signals obtained from the left index finger. On lowering the hand to 50 cm below heart level, both ac and dc PPG amplitudes from the finger decreased (e.g. 18.70% and 63.15% decrease in infrared dc and ac signals respectively). The decrease in dc amplitude most likely corresponded to increased venous volume, while the decrease in ac PPG amplitude was due to regulatory adjustments on the arterial side in response to venous distension. Conversely, ac and dc PPG amplitudes increased on raising the arm above heart level. Morphological changes in the ac PPG signal are thought to be due to vascular resistance changes, predominately venous, as the hand position is changed. Permanent repository link
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.