scholarly journals Regulatory T Cell Adoptive Immunotherapy Promotes B Cell Immunity after Haploidentical Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1917-1917
Author(s):  
Sara Piccinelli ◽  
Antonella Mancusi ◽  
Eni Hoxha ◽  
Loredana Ruggeri ◽  
Franca Falzetti ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Adoptive Transfer ◽  
Post Transplant ◽  
Cell Immunity ◽  
Human Hscs ◽  
Cmv Reactivation ◽  
B Cell Immunity

Background: Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Tregs) effectively prevents conventional T cell (Tcons) mediated Graft versus Host Disease (GvHD) while it does not impair graft-versus-leukemia effect in haploidentical hematopoietic cell transplantation (haplo-HCT). Moreover Treg immunotherapy promotes fast donor T cell recovery after transplant. Recent studies showed that mouse bone marrow (BM) Tregs localize in the hematopoietic stem cell (HSC) niche, where they contribute to HSCs maintenance and promote donor engraftment and B cell lymphopoiesis. We are investigating if human Tregs promote B cell reconstitution and immunity in preclinical models and in haplo-HCT patients. Methods: Human sample analysis: B cell reconstitution was analysed monthly by FACS in BM and peripheral blood (PB) samples from 66 patients who underwent either Treg/Tcon haplo-HCT (45 patients), or T-cell depleted haplo-HCT (8 patients) or haplo-HCT with post-transplant cyclophosphamide (PTCy, 13 patients). Diagnosis was acute leukemia in 52 patients, lymphoma in 11 and multiple myeloma in 3. PB total immunoglobulin (Ig), anti-Cytomegalovirus (CMV) IgM and CMV viremia were monitored. Humanized mouse model: donor derived human Tregs and purified CD34+ HSCs were co-infused in sublethally irradiated (2 Gy) immune-deficient NSG mice. Donor engraftment and B cell reconstitution were analysed by FACS and histology. Results: B cell reconstitution was faster after Treg/Tcon haplo-HCT when compared to other haplo-HCT protocols. B cell counts were higher in PB of patients that received Treg/Tcon haplo-HCT (p<.05) and were comparable to those of healthy subjects by 4 months after transplant (117±148 cells/mm, Fig.1A). We could detect early frequencies of CD34+CD38+CD10+CD127+ common lymphoid progenitors, CD45+CD10+CD38+CD19- Pre/Pro-B, CD45+CD10+CD38+CD19+ Pre-B, and Pro-B cells in the BM of these patients, that resulted in an increased production of CD38+CD19+CD5-IgM+ immature B cells, CD38+CD19+CD5+IgM+ transitional B cells and CD19+CD20+ mature B cells. We used a mouse model of xenotransplantation to understand whether donor B cell reconstitution in Treg/Tcon haplo-HCT is boosted by a Treg-mediated effect on donor human HSCs. We found that infusion of human Tregs facilitated donor HSC engraftment. BM and PB human chimerism was increased (p<.05) in mice that received Treg infusion. BM histology revealed the presence of in vivo expanded human CXCR4+ Tregs in the femurs of Treg receiving mice 1 month after transplant. In the same samples we observed a lower number of CD34+ HSCs, suggesting BM Tregs facilitate donor HSC differentiation. Moreover, Treg treatment allowed human HSCs to localize preferentially in the epiphyseal areas of the femurs, where donor cells started to engraft (p<.04). When looking at donor B cell reconstitution, we found HSC-derived mature B cells rapidly abundant and easily detectable starting 30 days after HSC infusion in PB of Treg-treated animals (p<.05). To further assess whether HSC-derived B cells were functional in patients that received Treg/Tcon haplo-HCT, we analysed total Ig production and specific responses to CMV reactivation. Post-transplant hypogammaglobulinemia was rapidly corrected in Treg/Tcon haplo-HCT patients. Total IgM were higher compared to other haplo-HCT protocols and reached normal levels by 3 months after transplant (96±155 mg/dL, Fig.1B). CMV reactivation rate was lower (47% vs 79%) and it occurred later after Treg/Tcon immunotherapy (51±19 vs 40±48 days). New production of anti-CMV specific IgM was documented in 43% of CMV seropositive patients 98±48 days after Treg/Tcon haplo-HCT, while anti-CMV specific IgM were almost undetectable after other haplo-HCT protocols within the first 6 months after transplant (Fig.1C). Such potent B cell responses coupled with T cell reconstitution resulted in a reduction of CMV second reactivations (Fig.1D p<.05) with no patient that died with CMV disease. Conclusions: Adoptive transfer of human Tregs boosts donor HSC engraftment and facilitates the reconstitution of functional HSC-derived donor B cells. Such results suggest that Treg/Tcon haplo-HCT patients could be early vaccinated after transplant. Treg/Tcon immunotherapy promotes control of infections and B cell immunity in patients undergoing haplo-HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Human neonatal B cell immunity differs from the adult version by conserved Ig repertoires and rapid, but transient response dynamics

2020 ◽  
Author(s):  
Bettina Budeus ◽  
Artur Kibler ◽  
Martina Brauser ◽  
Ekaterina Homp ◽  
Kevin Bronischewski ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Cord Blood ◽  
B Cell ◽  
Transient Response ◽  
Cell System ◽  
Response Dynamics ◽  
Vaccination Strategies ◽  
Cell Immunity ◽  
B Cell Immunity

AbstractThe human infant B cell system is considered premature or impaired. Here we show that most cord blood B cells are mature and functional as seen in adults, albeit with distinct transcriptional programs providing accelerated responsiveness to T cell-independent and T cell-dependent stimulation and facilitated IgA class switching. Stimulation drives extensive differentiation into antibody-secreting cells, thereby presumably limiting memory B cell formation. The neonatal Ig-repertoire is highly variable, but conserved, showing recurrent B cell receptor (BCR) clonotypes frequently shared between neonates. Our study demonstrates that cord blood B cells are not impaired but differ from their adult counterpart in a conserved BCR repertoire and rapid but transient response dynamics. These properties may account for the sensitivity of neonates to infections and limited effectivity of vaccination strategies. Humanized mice suggest that the distinctness of cord blood versus adult B cells is already reflected by the developmental program of hematopoietic precursors, arguing for a layered B-1/B-2 lineage system as in mice. Still, our findings reveal overall limited comparability of human cord blood B cells and murine B-1 cells.Significance StatementNeonates and infants suffer from enhanced susceptibility to infections. Our study contrasts with the current concept of a premature or impaired B cell system in neonates, by showing that most cord blood B cells are mature and functional. However, their responses are rapid but provide only short-term protection, which may help to improve infant vaccination strategies. We propose an altered perspective on the early human B cell system, which looks similar to but functions differently from the adult counterpart. Finally, our analysis indicates that cord blood- and adult B cell development occur layered as in mice, but certain mouse models still may offer a limited view on human neonatal B cell immunity.

Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

2021 ◽  
Vol 118 (46) ◽  
pp. e2108157118
Author(s):  
Kerstin Narr ◽  
Yusuf I. Ertuna ◽  
Benedict Fallet ◽  
Karen Cornille ◽  
Mirela Dimitrova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Memory B Cells ◽  
Type I ◽  
Clonal Deletion ◽  
Cell Immunity ◽  
B Cell Immunity

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

T-cell and B-cell immunity in celiac disease

2015 ◽  
Vol 29 (3) ◽  
pp. 413-423 ◽  
Author(s):  
M. Fleur du Pré ◽  
Ludvig M. Sollid
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
B Cell ◽  
Cell Immunity ◽  
B Cell Immunity

Helper T-cell-regulated B-cell immunity

2003 ◽  
Vol 5 (3) ◽  
pp. 205-212 ◽  
Author(s):  
Michael McHeyzer-Williams ◽  
Louise McHeyzer-Williams ◽  
Joanne Panus ◽  
Rebecca Pogue-Caley ◽  
Gabriel Bikah ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Helper T Cell ◽  
Cell Immunity ◽  
B Cell Immunity

Conditioning Intensity and T Cell Dose Determine Efficacy of CD19-Targeted T Cell-Mediated Tumor Eradication in an Immunocompetent Mouse Model of B-ALL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2613-2613
Author(s):  
Marco L Davila ◽  
Christopher Kloss ◽  
Renier J Brentjens ◽  
Michel Sadelain
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immunocompetent Mouse ◽  
Cell Dose ◽  
Conditioning Intensity

Abstract Abstract 2613 Recent work by our group and others demonstrates the therapeutic potential of CD19-targeted T cells to treat patients with indolent B cell malignancies. These studies make use of T cells that are genetically engineered with chimeric antigen receptors (CARs) comprising an scFv fused to various T cell activating elements. Whereas firs-generation CARs only direct T cell activation, second-generation CARs include two signal elements, such as CD3z and CD28 signaling domains (19–28z). We and our colleagues at MSKCC are currently evaluating the safety of 19–28z-transduced T cells in patients with acute leukemia (B-ALL) in a Phase I protocol (NCT01044069). Pre-clinical studies performed to date have mostly relied on xenogeneic models utilizing immunodeficient animals, which enable the evaluation of human engineered T cells but do not recapitulate all the interactions that may affect tumor eradication by CAR-modified T cells. We have therefore developed a pre-clinical immunocompetent mouse model of B-ALL, and addressed therein the impact of conditioning and T cell dose on the eradication of leukemia by syngeneic, CAR-targeted T cells. To establish an immunocompetent mouse model of B cell leukemia, we generated a clone from the lymph node of an Eμ-myc B6 transgenic mouse. The immunophenotype and gene-expression profile of clone Eμ-ALL01 is consistent with a progenitor B cell origin. Syngeneic B6 mice inoculated with this clone develop florid acute leukemia and die approximately 2–4 weeks after injection from progressive bone marrow infiltration. We created an anti-mouse CD19 CAR comprising all murine elements, including the CD8 signal peptide, a CD19-specific single chain variable fragment, the CD8 transmembrane region, and the CD28 and CD3z signaling domains. Transduction of the murine 19–28z CAR into mouse T cells was robust and successfully retargeted the T cells to B cells. In vitro assays demonstrated that m19–28 z transduced T cells mediated effective killing of CD19-expressing target cells and the production of effector cytokines such as IFNγ and TNFα. Cyclophosphamide either alone or in combination with control syngeneic T cells is insufficient to eradicate established Eμ-ALL01 in B6 mice. However, treatment with cyclophosphamide and m19–28z-transduced T cells cured nearly all mice. Mice sacrificed six months after treatment exhibited a dramatic reduction of B cells in the bone marrow (BM), blood, and spleen. The few remaining B lineage cells found in the BM had a phenotype consistent with early pro-B cells, suggesting that endogenous reconstitution of the B cell compartment was thwarted by persisting, functional m19–28z+ T cells. Thus, T cells are retained at the site of antigen expression, which is maintained through regeneration of progenitor B cells. The persisting CD19-targeted T cells in the BM exhibited a cell surface phenotype consistent with effector and central memory cells. Using B cell aplasia as a surrogate endpoint for assessing in vivo T cell function and persistence, we evaluated how conditioning chemotherapy and T cell dose determine the level of B cell depletion induced by adoptively transferred CD19-targeted T cells. Overall, increasing the cyclophosphamide or T cell dose, increased the degree and duration of B cell depletion and the number of persisting CAR-modified T cells. Significantly, increasing the T cell dose at a set cyclophosphamide level had a lesser impact than increasing the conditioning intensity for a given T cell dose. In summary, the new Eμ-ALL01 syngeneic, immunocompetent B-ALL model we describe here is a valuable tool for modeling CD19 CAR therapies. Our results indicate that m19–28z transduced T cells are effective at eradicating B-ALL tumor cells and persist long-term, preferentially in bone marrow. Our findings further establish that conditioning intensity and T cell dose directly determine B cell elimination and long-term T cell persistence. These studies in mice will serve as an important framework to further model and perfect our studies in patients with B-ALL. Disclosures: No relevant conflicts of interest to declare.

Rituximab Administration before Allogeneic HSCT Is Associated with Accelerated T Cell Reconstitution after Transplantation: Kinetic Evidence for a Graft-Versus-Leukemia Effect

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3905-3905
Author(s):  
Sakura Hosoba ◽  
Christopher R. Flowers ◽  
Catherine J Wu ◽  
Jens R. Wrammert ◽  
Edmund K. Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Post Transplant ◽  
T Cell Reconstitution ◽  
Relative Value ◽  
History Of

Abstract Introduction: Rituximab (R) administration results in depletion of blood B cells and suppression of B cell reconstitution for several months after, with suggestions that T cell reconstitution may also be impaired. We hypothesized that pre-transplant R would be associated with delayed B and T cell reconstitution after allo-HSCT compared with non-R-treated allo-HSCT recipients. Methods: We conducted a retrospective analysis of 360 patients who underwent allo-HSCT using BM or G-CSF mobilized PB. Recipients of cord blood, T cell depleted grafts and 2nd allo-HSCT were excluded. Analysis of lymphocyte subsets in at least one blood at 1, 3, 6, 12, and 24 months post-allo-HSCT was available for 255 eligible patients. Data on lymphocyte recovery was censored after DLI or post-transplant R therapy. Post-HSCT lymphocyte recovery in 217 patients who never received R (no-R) was compared to 38 patients who had received R before allo-HSCT (+R) including 12 CLL, 19 NHL, and 7 B-cell ALL patients. +R patients received a median of 9 doses of R with the last dose of R at a median of 45 days pre-transplant. Results: Mean lymphocyte numbers in the blood at 1, 3, 6, 12, and 24 months were B-cells: 55 ± 465/µL, 82 ± 159/µL, 150 ± 243/µL, 255 ± 345/µL, and 384 ± 369/µL (normal range 79-835); and T-cells: 65 ± 987/µL, 831 ± 667/µL, 1058 ± 788/µL, 1291 ± 985/µL, and 1477 ± 1222/µL (normal range 675-3085). Lymphocyte reconstitution kinetics did not vary significantly based upon the intensity of the conditioning regimen or related vs. unrelated donors allowing aggregation of patients in the +R and no-R groups (Figure). B cell reconstitution in the +R patients was higher at 1 month post-allo-HSCT (relative value of 143% p=0.008) and lower at 3 months post-transplant (19.2%, p=0.069) compared to no-R patients. Blood B cells in the +R group rebounded by the 6th month post-allo-HSCT and remained higher than the no-R group through the 24th month post-HSCT (197% at the 6th month, p=0.037). Higher levels of B-cells at 1 month in the +R group was due to higher blood B-cells at 1 month post-HSCT among 12 CLL patients compared with no-R patients (423%, p<0.001; Figure), while B-cell counts in the remaining +R patients (B-cell NHL and B-cell ALL) were lower than the no-R patients at both 1 and 3 months. Reconstitution of CD4+ and CD8+ T cells among +R patients were similar to no-R patients in the first month post-allo-HSCT and then rebounded to higher levels than the no-R group of patients (relative value 194%, p=0.077 at the 24th month for CD4+ T cell subset, and 224%, p=0.020 for CD8+ T cell subset; Figure). CLL patients had a striking increase in blood levels of donor-derived CD4+ and CD8+ T cells at 3 months post-transplant concomitant with the disappearance of blood B cells compared with no-R patients (relative value of 178% and 372%, p=0.018 and p=0.003, respectively; Figure). Long term T cell reconstitution remained higher for +R patients compared with no-R patients, even when CLL patients were excluded (relative value of 203%, p=0.005 at 24 months post-HSCT; Figure). Conclusions: We observed higher levels of blood B cells and T cells ³ 6 months post-allo-HSCT in +R patients compared with no-R patients. B cell recovery at 6 months post-transplant is consistent with clearance of residual plasma R given the 1-2 months half-life of R, and the median of 1.5 months between the last dose of R and allo-HSCT. The increased blood CD8+ T cells in the blood of CLL patients at 3 months post-allo-HSCT associated with clearance of the B-cells seen 1 month post-HSCT is consistent with a donor T cell-mediated GVL effect. Pre-transplant R therapy does not appear to have any long-term deleterious effect on immune reconstitution, indicating that post-allo-HSCT vaccination at ≥6 months may be efficacious. Figure: Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Figure:. Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Disclosures No relevant conflicts of interest to declare.

scholarly journals Adoptive Transfer of Tumor Reactive B Cells Confers Host T-Cell Immunity and Tumor Regression

2011 ◽  
Vol 17 (15) ◽  
pp. 4987-4995 ◽  
Author(s):  
Qiao Li ◽  
Xiangming Lao ◽  
Qin Pan ◽  
Ning Ning ◽  
Ji Yet ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Adoptive Transfer ◽  
Tumor Regression ◽  
T Cell Immunity ◽  
Cell Immunity

scholarly journals Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice

2018 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Alexis Saintamand ◽  
Amandine David ◽  
Mehdi Alizadeh ◽  
François Boyer ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immune Suppression ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma

AbstractTransformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.Summary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

scholarly journals α4-integrin deficiency in B cells does not affect disease in a T-cell–mediated EAE disease model

2019 ◽  
Vol 6 (4) ◽  
pp. e563
Author(s):  
Rehana Z. Hussain ◽  
Petra D. Cravens ◽  
William A. Miller-Little ◽  
Richard Doelger ◽  
Valerie Granados ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Adoptive Transfer ◽  
Lymphoid Organs ◽  
Pathogenic Role ◽  
Genetic Ablation ◽  
Secondary Lymphoid Organs ◽  
The Brain

ObjectiveThe goal of this study was to investigate the role of CD 19+ B cells within the brain and spinal cord during CNS autoimmunity in a peptide-induced, primarily T-cell–mediated experimental autoimmune encephalomyelitis (EAE) model of MS. We hypothesized that CD19+ B cells outside the CNS drive inflammation in EAE.MethodsWe generated CD19.Cre+/− α4-integrinfl/fl mice. EAE was induced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOGp35-55). Multiparameter flow cytometry was used to phenotype leukocyte subsets in primary and secondary lymphoid organs and the CNS. Serum cytokine levels and Ig levels were assessed by bead array. B-cell adoptive transfer was used to determine the compartment-specific pathogenic role of antigen-specific and non–antigen-specific B cells.ResultsA genetic ablation of α4-integrin in CD19+/− B cells significantly reduced the number of CD19+ B cells in the CNS but does not affect EAE disease activity in active MOGp35-55-induced disease. The composition of B-cell subsets in the brain, primary lymphoid organs, and secondary lymphoid organs of CD19.Cre+/− α4-integrinfl/fl mice was unchanged during MOGp35-55-induced EAE. Adoptive transfer of purified CD19+ B cells from CD19.Cre+/− α4-integrinfl/fl mice or C57BL/6 wild-type (WT) control mice immunized with recombinant rMOG1-125 or ovalbumin323-339 into MOGp35-55-immunized CD19.Cre+/− α4-integrinfl/fl mice caused worse clinical EAE than was observed in MOGp35-55-immunized C57BL/6 WT control mice that did not receive adoptively transferred CD19+ B cells.ConclusionsObservations made in CD19.Cre+/− α4-integrinfl/fl mice in active MOGp35-55-induced EAE suggest a compartment-specific pathogenic role of CD19+ B cells mostly outside of the CNS that is not necessarily antigen specific.

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