Biomedical subjects

Elaine F Reed

Publications and source records attributed to Elaine F Reed.

At least 19 recordsLinked to original sources

PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗

PubMed2006

CD20+ lymphocytes in renal allografts are associated with poor graft survival in pediatric patients.

BACKGROUND: The presence of CD20+ lymphocyte renal allograft infiltrates has been associated with steroid-resistant rejection and poor graft survival. We quantified the number of CD20+ lymphocytes in renal allograft biopsies and correlated the results with graft survival. We also determined the relationships between CD20+ lymphocytes and acute cellular rejection versus antibody-mediated rejection. METHODS: We examined 45 biopsy samples from 31 pediatric patients biopsied for suspicion of rejection from November 2001 to November 2004. Immunohistochemical staining for CD20 and C4d was performed on all biopsies; CD20+ cell density per high-power field (hpf) was determined for each core. Patient graft status was followed postbiopsy and documented for graft survival or failure using the cutoff date of December 31, 2005. RESULTS: Patients with 2-10 and 11-100 CD20+ cells/hpf had worse graft survival in Kaplan-Meier analysis with a hazard ratio 4.56 (CI 1.07-19.35) two years postbiopsy compared to those with 0-1 cells/hpf (P = 0.02). The presence of CD20+ lymphocytes was significantly associated with acute cellular rejection (P = 0.0001) and not associated with antibody-mediated rejection (P = 0.16). Receiver-operating curve analysis confirmed > or =3 cells/hpf correlating with acute cellular rejection, yielding sensitivity 90% and specificity 76%. CONCLUSIONS: This study shows a significant 4.5-fold risk of graft failure at two years postbiopsy with presence of > or =2 CD20+ cells/hpf. Moreover, > or =3 CD20+ lymphocytes were highly associated with acute cellular rejection. They may be functioning as professional antigen-presenting cells in the graft. In steroid-refractory cellular rejections, therapies that target B cells may prolong graft survival.

Adolescent↗

PubMed2006

Receptor-ligand analyses define minimal killer cell Ig-like receptor (KIR) in humans.

Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and human leukocyte antigen (HLA) class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR receptors and HLA class I ligands and their independent segregation results in a variable number and type of iKIR + HLA pairs inherited in individuals. The diversity in the co-inheritance of iKIR + HLA pairs and activating KIR (aKIR) genes in 759 unrelated individuals from four ethnic populations was analyzed. Every individual studied inherited a minimum of one iKIR + HLA pair; suggesting that major histocompatibility complex class I-dependent inhibitory KIR signaling is essential for human NK cell function. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR + HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3 + HLA-C1 as an iKIR + HLA pair lacked aKIR genes. These data suggest that a single iKIR can constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR + HLA pairs and aKIR genes represented 20% of the study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR + HLA > aKIR) or a dominant activating KIR genotype (iKIR + HLA < aKIR). Genotypes encoding these imbalanced inhibitory and activating interactions may contribute to susceptibility or resistance to human diseases.

Epitope Mapping↗

PubMed2006

Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay.

BACKGROUND: Long-term use of immunosuppressants is associated with significant morbidity and mortality in transplant recipients. A simple whole blood assay that has U.S. Food and Drug Administration clearance directly assesses the net state of immune function of allograft recipients for better individualization of therapy. A meta-analysis of 504 solid organ transplant recipients (heart, kidney, kidney-pancreas, liver and small bowel) from 10 U.S. centers was performed using the Cylex ImmuKnow assay. METHODS: Blood samples were taken from recipients at various times posttransplant and compared with clinical course (stable, rejection, infection). In this analysis, 39 biopsy-proven cellular rejections and 66 diagnosed infections occurred. Odds ratios of infection or rejection were calculated based on measured immune response values. RESULTS: A recipient with an immune response value of 25 ng/ml adenosine triphosphate (ATP) was 12 times (95% confidence of 4 to 36) more likely to develop an infection than a recipient with a stronger immune response. Similarly, a recipient with an immune response of 700 ng/ml ATP was 30 times (95% confidence of 8 to 112) more likely to develop a cellular rejection than a recipient with a lower immune response value. Of note is the intersection of odds ratio curves for infection and rejection in the moderate immune response zone (280 ng/ml ATP). This intersection of risk curves provides an immunological target of immune function for solid organ recipients. CONCLUSION: These data show that the Cylex ImmuKnow assay has a high negative predictive value and provides a target immunological response zone for minimizing risk and managing patients to stability.

Graft Rejection↗

PubMed2006

HLA-B maternal-fetal genotype matching increases risk of schizophrenia.

Schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia.

Female↗

PubMed2006

Noninvasive diagnosis of cellular and antibody-mediated rejection by perforin and granzyme B in renal allografts.

A major milestone in transplantation would be the use of biomarkers to monitor rejection. We examined the association between perforin and granzyme-B gene expression detected in the peripheral blood of renal allograft recipients with cellular and antibody-mediated rejection. Furthermore, we judged the appropriateness of assigning negative rejection statuses to persons without a biopsy whose grafts were functioning well clinically. Of the 46 patients who completed the study, recipients with cellular rejection had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.006). Interestingly, recipients with antibody-mediated rejection also had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.04). Patients with high levels of granzyme B had a probability of rejecting that was 26.7 times greater than those patients with low levels of granzyme B. Perforin and granzyme B had sensitivities of 50% and specificities of 95% in predicting rejection (cutoff value = 140). Assigning negative rejection statuses to recipients without a biopsy whose grafts were functioning well did not have a major effect on the direction or significance of covariate values. This study suggests that perforin and granzyme-B gene expressions in peripheral blood are accurate in detecting both cellular and antibody-mediated rejection.

Adult↗

PubMed2006

Anti-HLA antibodies can induce endothelial cell survival or proliferation depending on their concentration.

Patients exhibiting a humoral immune response to the transplanted organ are at increased risk of antibody-mediated rejection and development of transplant vasculopathy. Historically, antibodies were thought to elicit transplant rejection through complement mediated damage of the endothelium of the graft. More recently, studies from our laboratory and others have shown that antibody ligation of class I molecules on the surface of endothelial cells transduces signals resulting in functional changes including expression of cell survival proteins and cell proliferation. The intracellular events initiated by antibody ligation are dependent upon the degree of molecular aggregation and influenced by the concentration of the antibody and level of human leukocyte antigen (HLA) expression. Herein we describe our recent findings on the effect of molecular aggregation on the class I signaling pathway in human endothelial cells.

Antibodies, Monoclonal↗

PubMed2006

A novel flow assay for the detection of cytokine secreting alloreactive T cells: application to immune monitoring.

The direct and indirect allorecognition pathways play an important role in graft rejection. We hypothesized that the presence of alloreactive memory T cells in the recipient's circulation increases the risk of rejection after transplantation. The objective of this study was to develop a noninvasive, immune monitoring tool that simultaneously measures donor-specific responses via both the direct and indirect recognition pathways. Our laboratory developed a whole blood flow cytometric cytokine secretion assay to identify interferon (IFN)-gamma secreting memory T cells in whole blood of renal transplant patients. The assay readily detected IFN-gamma producing CD3+ T cells in response to recall antigens tetanus toxoid, purified protein derivative, and alloantigens in whole blood from healthy controls. Analysis of sequential posttransplant blood samples from 19 renal allograft recipients showed that alloimmune responses were higher in transplant recipients who had undergone acute rejection than in those without acute rejection episodes. In addition, patients showing increased creatinine levels 3 months after transplantation were more likely to exhibit alloimmune responses than recipients with stable graft function. The flow cytokine secretion assay provides a reliable and simple method for identification of patients at risk of acute rejection and early graft dysfunction.

Adult↗

PubMed2006

Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort.

OBJECTIVE: To determine whether the tumor necrosis factor alpha (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA). METHODS: The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >or=2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score. RESULTS: Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n=49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n=140). Presence of the SE (n=137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n=52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequilibrium between DRB1*0301 and TNFA polymorphism (D'=0.84, r2=0.45, P<0.001). CONCLUSION: This study showed an association between the TNFA -308 polymorphism and progression of radiographic damage in patients with early seropositive RA. This association appeared to be independent of the SE, but might be dependent on other genetic variants in linkage disequilibrium with the -308 TNFA A allele and DRB1*0301. Further studies should be conducted to validate these results in both longitudinal observational cohorts and randomized clinical trials.

Arthritis, Rheumatoid↗

PubMed2006

Acute antibody-mediated rejection of cardiac transplants.

Under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the cardiac biopsy grading system was undertaken in 2004, with task forces examining the areas of histopathology of rejection, clinical issues, and research. An important new area addressed by the Immunopathology Task Force sub-committee was the clinical and diagnostic criteria for antibody-mediated rejection. This article is a companion paper to the revised working formulation for the standardization of nomenclature in the diagnosis of heart rejection and reviews the published literature documenting the serologic and morphologic evidence that antibody-mediated rejection is clinically significant and associated with graft loss, accelerated transplant-associated coronary artery disease, and death. This article also provides a more in-depth analysis of antibody-mediated rejection developed by the Immunopathology Task Force for revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

Antibodies↗

PubMed2006

Array-based methods for diagnosis and prevention of transplant rejection.

DNA microarray is a microhybridization-based assay that is used to simultaneously study the expression of thousands of genes, thus providing a global view of gene expression in a tissue sample. This powerful technique has been adopted by many biomedical disciplines and will likely have a profound impact on the diagnosis, treatment and prognosis of human diseases. This review article presents an overview of the application of microarray technology to the field of solid-organ transplantation.

Chemokines↗

PubMed2005

Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R--no rejection (no change from 1990); Grade 1 R--mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R--moderate rejection (1990 Grade 3A); and Grade 3 R--severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the "A" and "B" designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.

Biopsy↗

PubMed2005

Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction.

BACKGROUND: The goal of this study was to determine whether the production of posttransplant antibodies directed against donor HLA mismatches (donor specific antibody; DSA) is associated with renal allograft rejection and early graft dysfunction. METHODS: Forty-nine adult renal allograft recipients with increased risk of rejection were enrolled during the period of October 2001 through May 2003 and were prospectively monitored for the development of anti-HLA antibodies. RESULTS: Of 49 patients, eight (16.3 %) patients were diagnosed with acute humoral rejection (AHR) and 11/49 (22.4%) patients were diagnosed with acute cellular rejection (ACR). A strong association between pretransplant HLA sensitization and AHR was found (P=0.005). Of the eight patients diagnosed with AHR, the majority developed DSA before or concomitant with episodes of rejection (P<0.001). Only 3 of 41 patients (7.3%) without AHR developed DSA. The pathogenic role of alloantibodies was further substantiated by analyzing their association with graft function as measured by serum creatinine levels. The average serum creatinine after the third month posttransplantation in DSA producers was 2.24+/-1.01 mg/dL, while in non-DSA patients the average serum creatinine was 1.41+/-0.37 mg/dL (P<0.01). CONCLUSION: This study reveals a strong association between the production of DSA, AHR, and early graft dysfunction. Our findings indicate that prospective monitoring for anti-HLA antibodies following transplantation is a useful test for the diagnosis and classification of AHR for identifying patients at risk of early graft dysfunction.

Acute Disease↗

PubMed2005

Anti-HLA class I antibodies activate endothelial cells and promote chronic rejection.

Transplant recipients exhibiting a humoral immune response to the allograft demonstrate lower graft survival and increased risk for the development of chronic rejection and transplant arteriosclerosis. Our studies suggest that anti-HLA class I antibodies (Ab) play an important role in controlling endothelial cell (EC) function by binding to class I molecules on the surface of the EC and transducing intracellular signals. Anti-HLA Ab exhibit two primary effector functions: stimulation of cell proliferation and up-regulation of cell survival genes. Importantly, the intracellular events initiated by class I ligation appear to be influenced by the concentration of the Ab. High-titered anti-HLA Ab stimulate cell proliferation whereas low-titered Ab activate the PI3K/Akt pathway and promote expression of cell survival proteins including Bcl-2 and Bcl-xL. Anti-HLA class I Ab may contribute to the process of chronic allograft rejection by promoting EC survival and proliferation.

Animals↗

PubMed2005

C4d staining of pulmonary allograft biopsies: an immunoperoxidase study.

BACKGROUND: The role of antibody-mediated/humoral rejection in lung allografts is not fully elucidated. In other organ systems, deposition of a specific complement product, C4d, is a sensitive and specific marker for humoral rejection. C4d can be evaluated in tissue biopsies by immunofluorescence or light microscopic immunohistochemical staining techniques. Using immunohistochemical staining techniques we sought to determine whether there was any specific staining pattern for C4d in lung allograft biopsies with or without the diagnosis of acute or chronic cellular or humoral rejection. METHODS: A total of 68 lung transplant biopsies, performed at UCLA Medical Center from January 2002 to August 2004, were collected and the paraffin blocks were re-cut and stained for C4d by an immunoperoxidase technique. The cases were separated by the presence or absence of features of acute and/or chronic rejection based on the International Society for Heart and Lung Transplantation working formulation for the classification of pulmonary allograft rejection, revised 1995. The pattern of staining for C4d was then systematically examined. RESULTS: Positive staining in a variable, focal non-specific pattern was observed. There was no consistent staining pattern within the different diagnostic groups. CONCLUSIONS: C4d staining of paraffin-embedded lung allograft biopsies, using currently available techniques, does not identify acute or chronic cellular or humoral rejection in lung allograft tissue.

Acute Disease↗

PubMed2005

Preformed cytotoxic antibodies in potential allograft recipients: recent data.

Presensitization to donor human leukocyte antigen (HLA) remains a major barrier to cell and organ transplantation, thereby contributing to patient mortality. The risks associated with transplantation in the presence of preformed antidonor HLA antibodies range from hyperacute rejection and increased frequency and severity of rejection to no appreciable effect on transplant outcome. Recent evidence has emphasized the importance of immunologic history, anti-HLA antibody class and titer, and differential organ susceptibility to antibody-mediated damage to explain differences in risk for antibody-mediated rejection. Furthermore, in studies of endothelial cells, ligation of class I molecules by subsaturating concentrations of antibodies stimulated expression of cell survival proteins, raising the possibility that, under certain conditions, antibodies promote graft accommodation providing a mechanism for the endothelium to resist immune and inflammatory damage. The discovery of capillary-bound C4d as a robust diagnostic marker for antibody-mediated rejection, coupled with the development of solid-phase assays for the identification of HLA-specific antibodies, has enhanced our ability to detect antibody-mediated rejection and interpret cross-match results. With new diagnostic tools and immunosuppression regimens such as plasmapheresis and intravenous immunoglobulin therapy targeting the humoral immune response, it is time for a concerted effort to reassess the role of alloantibodies in acute and chronic rejection.

HLA Antigens↗

PubMed2004

HLA class I signal transduction is dependent on Rho GTPase and ROK.

Chronic rejection is the major limitation to long-term allograft survival. HLA class I signaling pathways have been implicated in this process because ligation of class I molecules by anti-HLA antibodies (Ab) initiates intracellular signals in smooth muscle cells (SMC) and endothelial cells (EC) that synergize with growth factor receptors to elicit cell survival and proliferation. Anti-HLA Ab mediate cell proliferation and survival through a focal adhesion kinase dependent pathway that requires the integrity of the actin cytoskeleton. In this study, we investigated the role of Rho and Rho-kinase (ROK) in class I signal transduction. We show that class I ligation results in activation of Rho and increased stress fiber formation. In addition, inhibitors of Rho GTPase and ROK block HLA class I-mediated tyrosyl phosphorylation of paxillin and FAK, central elements of the focal adhesion signaling complex. These results suggest that HLA class I-induced signaling in EC is dependent on Rho GTPase and ROK.

Actins↗

PubMed2004

Polymorphism of transporter associated with antigen presentation 1 as a potential determinant for severity of disease in recurrent respiratory papillomatosis caused by human papillomavirus types 6 and 11.

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomaviruses (HPVs). It is characterized by multiple recurrences of benign neoplasms and has a variable clinical course, ranging from infrequent recurrence to acute airway obstruction. One way in which HPV subverts the immune system in RRP is by interfering with TAP1 (transporter associated with antigen presentation 1). We examined whether a known TAP1 polymorphism in the ATPase domain altered the severity of disease in patients with RRP. The presence of this polymorphism was significantly correlated with severity of disease (P=.015). Because of the proximity of the TAP1 gene to human leukocyte antigen (HLA) class II genes on chromosome 6, we postulated that a linkage disequilibrium may exist. Of the patients with polymorphic TAP1, 36% were positive for HLA-DRB1*0102 (P=.021; P=.147 with Bonferroni's correction). However, this association appeared to mitigate the severity of disease (P=.04). Therefore, severity of disease in a patient with RRP might be determined by sequencing TAP1, in conjunction with HLA class II genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗