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Article ; Online: Antibody verification of HLA class I and class II eplets by human monoclonal HLA antibodies.

Kramer, Cynthia S M / Bezstarosti, Suzanne / Franke-van Dijk, Marry E I / Vergunst, Manon / Roelen, Dave L / Uyar-Mercankaya, Merve / Voogt-Bakker, Kim H / Heidt, Sebastiaan

HLA

2024 Volume 103, Issue 1, Page(s) e15345

Abstract: In solid organ transplantation, formation of de novo donor-specific HLA antibodies is induced by mismatched eplets on donor HLA molecules. While several studies have shown a strong correlation between the number of eplet mismatches and inferior outcomes, ...

Abstract	In solid organ transplantation, formation of de novo donor-specific HLA antibodies is induced by mismatched eplets on donor HLA molecules. While several studies have shown a strong correlation between the number of eplet mismatches and inferior outcomes, not every eplet mismatch is immunogenic. Eplets are theoretically defined entities, necessitating formal proof that they can be recognised and bound by antibodies. This antibody verification is pivotal to ensure that clinically relevant eplets are considered in studies on molecular matching. Recombinant human HLA-specific monoclonal antibodies (mAbs) were generated from HLA-reactive B cell clones isolated from HLA immunised individuals using recombinant HLA molecules. Subsequently, the reactivity patterns of the mAbs obtained from single antigen bead assay were analysed using HLA-EMMA software to identify single or configurations of solvent accessible amino acids uniquely present on the reactive HLA alleles and were mapped to eplets. Two HLA class I and seven HLA class II-specific human mAbs were generated from four individuals. Extensive mAb reactivity analysis, led to antibody verification of three HLA-DR-specific eplets, and conversion of five eplets (one HLA-A, one HLA-B, two HLA-DR, and one HLA-DP), from provisionally verified to truly antibody-verified. Finally, one HLA-DQ-specific eplet was upgraded from level A2 to level A1 verification evidence. The generation of recombinant human HLA-specific mAbs with different specificities contributes significantly to the antibody verification of eplets and therefore is instrumental for implementation of eplet matching in the clinical setting.
MeSH term(s)	Humans ; Antibodies, Monoclonal ; Epitopes ; Alleles ; HLA-DR Antigens ; Tissue Donors ; HLA-B Antigens ; HLA Antigens ; Histocompatibility Testing ; Graft Rejection
Chemical Substances	Antibodies, Monoclonal ; Epitopes ; HLA-DR Antigens ; HLA-B Antigens ; HLA Antigens
Language	English
Publishing date	2024-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2845111-9
ISSN	2059-2310 ; 2059-2302
ISSN (online)	2059-2310
ISSN	2059-2302
DOI	10.1111/tan.15345
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Article ; Online: HLA-DQ-Specific Recombinant Human Monoclonal Antibodies Allow for In-Depth Analysis of HLA-DQ Epitopes.

Bezstarosti, Suzanne / Kramer, Cynthia S M / Franke-van Dijk, Marry E I / Vergunst, Manon / Bakker, Kim H / Uyar-Mercankaya, Merve / Buchli, Rico / Roelen, Dave L / de Fijter, Johan W / Claas, Frans H J / Heidt, Sebastiaan

Frontiers in immunology

2022 Volume 12, Page(s) 761893

Abstract: HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino ...

Abstract	HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino acids on HLA molecules that require verification to confirm that they can be recognized by alloantibodies and are therefore clinically relevant. In this study, we isolated HLA-DQ specific memory B cells from immunized individuals by using biotinylated HLA-DQ monomers to generate 15 recombinant human HLA-DQ specific monoclonal antibodies (mAb) with six distinct specificities. Single antigen bead reactivity patterns were analyzed with HLA-EMMA to identify amino acids that were uniquely shared by the reactive HLA alleles to define functional epitopes which were mapped to known eplets. The HLA-DQB103:01-specific mAb LB_DQB0301_A and the HLA-DQB103-specific mAb LB_DQB0303_C supported the antibody-verification of eplets 45EV and 55PP respectively, while mAbs LB_DQB0402_A and LB_DQB0602_B verified eplet 55R on HLA-DQB1*04/05/06. For three mAbs, multiple uniquely shared amino acid configurations were identified, warranting further studies to define the inducing functional epitope and corresponding eplet. Our unique set of HLA-DQ specific mAbs will be further expanded and will facilitate the in-depth analysis of HLA-DQ epitopes, which is relevant for further studies of HLA-DQ alloantibody pathogenicity in transplantation.
MeSH term(s)	Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Epitopes/chemistry ; Epitopes/genetics ; Epitopes/immunology ; HLA-DQ Antigens/chemistry ; HLA-DQ Antigens/genetics ; HLA-DQ Antigens/immunology ; Humans ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/immunology
Chemical Substances	Antibodies, Monoclonal ; Epitopes ; HLA-DQ Antigens ; Recombinant Proteins
Language	English
Publishing date	2022-01-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.761893
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Article ; Online: B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis.

Biewenga, Maaike / Heidt, Sebastiaan / Vergunst, Manon / Marijnissen, Camiel M J / de Man, Rob A / van der Eijk, Annemiek A / van der Meer, Adriaan J / Trouw, Leendert A / van Hoek, Bart

JHEP reports : innovation in hepatology

2022 Volume 4, Issue 5, Page(s) 100460

Abstract: Background & aims: Increased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B ...

Abstract	Background & aims: Increased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B cell populations in AIH and correlate these to treatment response. Methods: BAFF and IL-21 levels were determined in 66 patients with AIH before treatment and 10 healthy controls. Flow cytometry was performed on circulating B cells of 10 patients with AIH and 12 healthy controls. Results: Based on BAFF and IL-21 levels, untreated patients with AIH were divided into 3 groups: 27 (41%) patients with normal BAFF and IL-21 (normal BAFF), 27 (41%) patients with elevated BAFF but normal IL-21 (high BAFF), and 12 (18%) patients with elevated IL-21 (high IL-21). The high BAFF group presented with higher bilirubin compared with the normal BAFF and high IL-21 groups (159 Discussion: Using BAFF and IL-21, we identified different immunological phenotypes of AIH with a different presentation, treatment response, and outcome. Patients with high IL-21 had the poorest treatment response and a risk of developing PSC variant syndrome. BAFF level was related to shifts in circulating B-cell populations. Lay summary: In patients with untreated autoimmune hepatitis (AIH), circulating B-cell activating factor of the tumour necrosis family (BAFF), IL-21, and B-cell populations were determined. Three subgroups were identified: with (1) normal BAFF and IL-21, (2) elevated BAFF and normal IL-21, and (3) elevated IL-21. Remission after 1-year treatment occurred in 54, 34, and 0% in Groups 1, 2, and 3, respectively. Group 2 had higher bilirubin, indicating more liver dysfunction. In 25% of patients with high IL-21, AIH-PSC variant syndrome developed, but none in the other groups. Autoimmune-associated B cells were elevated and BAFF levels correlated with certain B cells.
Language	English
Publishing date	2022-02-22
Publishing country	Netherlands
Document type	Journal Article
ISSN	2589-5559
ISSN (online)	2589-5559
DOI	10.1016/j.jhepr.2022.100460
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Article ; Online: Proteasome inhibition profoundly affects activated human B cells.

Mulder, Arend / Heidt, Sebastiaan / Vergunst, Manon / Roelen, Dave L / Claas, Frans H J

Transplantation

2013 Volume 95, Issue 11, Page(s) 1331–1337

Abstract: Background: Proteasome inhibitors, although initially developed for the treatment of malignancies, have been found to affect normal plasma cells by efficaciously inducing apoptosis. One proteasome inhibitor, bortezomib, has been used in transplantation ... ...

Abstract	Background: Proteasome inhibitors, although initially developed for the treatment of malignancies, have been found to affect normal plasma cells by efficaciously inducing apoptosis. One proteasome inhibitor, bortezomib, has been used in transplantation settings to deplete human leukocyte antigen antibody-producing plasma cells to reverse humoral allograft rejection. Methods: To establish whether proteasome inhibitors are active on B cells, being plasma cell precursors, we examined a set of four proteasome inhibitors, including bortezomib, carfilzomib, ONX 0912, and ONX 0914, for their potential to impact the functionalities of activated B cells in vitro. Results: All proteasome inhibitors dose-dependently abrogated IgM and IgG production by activated B cells, as well as their proliferation, with varying efficiencies. The bortezomib-induced decline in immunoglobulin production was mainly due to a decrease in the number of B cells capable of immunoglobulin secretion, caused by apoptosis. Conclusions: The action of proteasome inhibitors is not confined to plasma cells but also has impact on activated naïve and memory B cells.
MeSH term(s)	Apoptosis/drug effects ; Apoptosis/physiology ; B-Lymphocytes/drug effects ; B-Lymphocytes/metabolism ; Boronic Acids/pharmacology ; Bortezomib ; Cell Proliferation/drug effects ; Cells, Cultured ; Humans ; Immunoglobulin G/metabolism ; Immunoglobulin M/metabolism ; In Vitro Techniques ; Oligopeptides/pharmacology ; Plasma Cells/drug effects ; Plasma Cells/physiology ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/physiology ; Pyrazines/pharmacology
Chemical Substances	Boronic Acids ; Immunoglobulin G ; Immunoglobulin M ; ONX 0912 ; Oligopeptides ; PR-957 ; Pyrazines ; Bortezomib (69G8BD63PP) ; carfilzomib (72X6E3J5AR) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2013-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0b013e3182911739
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 488: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: B Cell Markers of Operational Tolerance Can Discriminate Acute Kidney Allograft Rejection From Stable Graft Function.

Heidt, Sebastiaan / Vergunst, Manon / Anholts, Jacqueline D H / Reinders, Marlies E J / de Fijter, Johan W / Eikmans, Michael / Claas, Frans H J

Transplantation

2014

Abstract: Background: Recently, several B cell-related markers have been described to be upregulated during operational tolerance in kidney allograft recipients. Little data exist on these markers during allograft rejection.: Methods: In this study, we ... ...

Abstract	Background: Recently, several B cell-related markers have been described to be upregulated during operational tolerance in kidney allograft recipients. Little data exist on these markers during allograft rejection. Methods: In this study, we investigated regulation-associated B-cell phenotypes in peripheral blood mononuclear cells (PBMCs) of kidney transplant recipients with (n=21) and without (n=22) acute rejection (AR). We also determined expression levels of the B cell-related genes, MS4A1, TCL1A, and CD79B, in PBMCs and isolated B cells. Patient samples were analyzed before transplantation at discharge and at time of AR before initiation of antirejection therapy or at matching timepoints in patients with stable graft function. Results: On transplantation, the peripheral CD19CD24CD38 transitional B cell subset strongly declined, regardless of the subsequent occurrence of AR. In contrast, the CD19CD27CD24 subset remained stable after transplantation in both patients groups. MS4A1 gene expression levels in PBMC were comparable between patient groups at all timepoints. In contrast, TCL1A expression levels increased in stable patients, but decreased in patients at the time of AR in both PBMC and isolated B cells. CD79B expression levels in stable patients were unaltered after transplantation in PBMC but showed an increase in the B cell fraction at discharge. At the time of AR, CD79B gene expression was significantly lower compared to stable patients, being most apparent in the B-cell fraction. Conclusion: These results suggest that, in addition to being markers for immunologic unresponsiveness, gene expression levels of TCL1A and CD79B may also identify immune activation in the setting of kidney transplantation.
Language	English
Publishing date	2014-10-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000000465
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 488: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients.

Bank, Jonna R / Heidt, Sebastiaan / Moes, Dirk Jan A R / Roelen, Dave L / Mallat, Marko J K / van der Boog, Paul J M / Vergunst, Manon / Jol-van der Zijde, Cornelia M / Bredius, Robbert G M / Braat, Andries E / Ringers, Jan / van Tol, Maarten J D / Claas, Frans H J / Reinders, Marlies E J / de Fijter, Johannes W

Transplantation direct

2016 Volume 3, Issue 1, Page(s) e124

Abstract: Background: The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive.: Methods: This cohort study assessed incidence ... ...

Abstract	Background: The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. Methods: This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. Results: Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; Conclusions: Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients.
Language	English
Publishing date	2016-12-19
Publishing country	United States
Document type	Journal Article
ISSN	2373-8731
ISSN	2373-8731
DOI	10.1097/TXD.0000000000000634
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Article ; Online: The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome.

Transplantation

2012 Volume 94, Issue 5, Page(s) 478–485

Abstract: Background: Innate immunity plays a role in controlling adaptive immune responses.: Methods: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors ... ...

Abstract	Background: Innate immunity plays a role in controlling adaptive immune responses. Methods: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. Results: Polymorphisms in TLR-3 (rs3775296) in the recipients and in ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed ficolin-2. Donor grafts with the ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of ficolin-2 to N-acetylglucosamine. Conclusions: Presence of the ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.
MeSH term(s)	Apoptosis ; Biopsy ; Exons ; Gene Expression Regulation ; Genotype ; Graft Rejection/blood ; Graft Rejection/genetics ; Graft Rejection/immunology ; Graft Rejection/metabolism ; Graft Survival ; Humans ; Immunity, Innate/genetics ; Interleukin-1beta/genetics ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Jurkat Cells ; Kaplan-Meier Estimate ; Kidney Transplantation/adverse effects ; Kidney Transplantation/immunology ; Lectins/blood ; Lectins/genetics ; Logistic Models ; Multivariate Analysis ; Netherlands ; Odds Ratio ; Phenotype ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Risk Assessment ; Risk Factors ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology ; Time Factors ; Tissue Donors ; Treatment Outcome ; Tumor Necrosis Factor-alpha/genetics ; Ficolins
Chemical Substances	IL6 protein, human ; Interleukin-1beta ; Interleukin-6 ; Lectins ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2012-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0b013e31825c5967
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 488: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Antibody verification of HLA class I and class II eplets by human monoclonal HLA antibodies.

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Article ; Online: HLA-DQ-Specific Recombinant Human Monoclonal Antibodies Allow for In-Depth Analysis of HLA-DQ Epitopes.

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Article ; Online: B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis.

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Article ; Online: Proteasome inhibition profoundly affects activated human B cells.

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Article ; Online: B Cell Markers of Operational Tolerance Can Discriminate Acute Kidney Allograft Rejection From Stable Graft Function.

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Article: Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients.

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Article ; Online: The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome.

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In stock of ZB MED Cologne/Königswinter

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