23 results on '"van Balen, Peter"'
Search Results
2. Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM
- Author
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Meurer, Thuja, Crivello, Pietro, Metzing, Maximilian, Kester, Michel, Megger, Dominik A., Chen, Weiqiang, van Veelen, Peter A., van Balen, Peter, Westendorf, Astrid M., Homa, Georg, Layer, Sophia E., Turki, Amin T., Griffioen, Marieke, Horn, Peter A., Sitek, Barbara, Beelen, Dietrich W., Falkenburg, J. H. Frederik, Arrieta-Bolaños, Esteban, and Fleischhauer, Katharina
- Published
- 2021
- Full Text
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3. Risk factors for graft-versus-host- disease after donor lymphocyte infusion following T-cell depleted allogeneic stem cell transplantation.
- Author
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Koster, Eva A. S., von dem Borne, Peter A., van Balen, Peter, Marijt, Erik W. A., Tjon, Jennifer M. L., Snijders, Tjeerd J. F., van Lammeren, Daniëlle, Veelken, Hendrik, Falkenburg, J. H. Frederik, Halkes, Constantijn J. M., and de Wreede, Liesbeth C.
- Subjects
STEM cell transplantation ,DISEASE risk factors ,LYMPHOPENIA ,LYMPHOCYTES ,T cells ,MYELODYSPLASTIC syndromes - Abstract
Introduction: Unmodified donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (alloSCT) can boost the beneficial Graft-versus- Leukemia (GvL) effect but may also induce severe Graft-versus-Host-Disease (GvHD). To improve the balance between GvL and GvHD, it is crucial to identify factors that influence the alloreactivity of DLI. Methods: We investigated the effects of the presence of patient-derived antigen-presenting cells at time of DLI as estimated by the bone marrow (BM) chimerism status, lymphopenia as measured by the absolute lymphocyte count (ALC) at time of DLI, and the presence of a viral infection (de novo or reactivation) close to DLI on the risk of GvHD after DLI. The cohort consisted of patients with acute leukemia or myelodysplastic syndrome who prophylactically or pre-emptively received DLI as standard care after alemtuzumab-based alloSCT. In patients at high risk for relapse, DLI was administered at 3 months after alloSCT (n=88) with a dose of 0.3x10
6 or 0.15x106 T cells/kg in case of a related or unrelated donor, respectively. All other patients (n=76) received 3x106 or 1.5x106 T cells/kg, respectively, at 6 months after alloSCT. Results: For both DLIs, patients with reduced-intensity conditioning and an unrelated donor had the highest risk of GvHD. For DLI given at three months, viral infection within 1 week before and 2 weeks after DLI was an additional significant risk factor (hazard ratio (HR) 3.66 compared to no viral infection) for GvHD. At six months after alloSCT, viral infections were rare and not associated with GvHD. In contrast, mixed BM chimerism (HR 3.63 for ≥5% mixed chimerism compared to full donor) was an important risk factor for GvHD after DLI given at six months after alloSCT. ALC of <1000x106/l showed a trend for association with GvHD after this DLI (HR 2.05 compared to ≥1000x106/l, 95% confidence interval 0.94-4.45). Furthermore, the data suggested that the presence of a viral infection close to the DLI at three months or ≥5% mixed chimerism at time of the DLI at six months correlated with the severity of GvHD, thereby increasing their negative impact on the current GvHD-relapse-free survival. Conclusion: These data demonstrate that the risk factors for GvHD after DLI depend on the setting of the DLI. [ABSTRACT FROM AUTHOR]- Published
- 2024
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4. Competitive Repopulation and Allo-Immunologic Pressure Determine Chimerism Kinetics after T Cell-Depleted Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion
- Author
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Koster, Eva A.S., von dem Borne, Peter A., van Balen, Peter, van Egmond, Esther H.M., Marijt, Erik W.A., Veld, Sabrina A.J., Jedema, Inge, Snijders, Tjeerd J.F., van Lammeren, Daniëlle, Veelken, Hendrik, Falkenburg, J.H. Frederik, de Wreede, Liesbeth C., and Halkes, Constantijn J.M.
- Published
- 2023
- Full Text
- View/download PDF
5. Joint models quantify associations between immune cell kinetics and alloimmunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion.
- Author
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Koster, Eva A. S., Bonneville, Edouard F., von dem Borne, Peter A., van Balen, Peter, Marijt, Erik W. A., Tjon, Jennifer M. L., Snijders, Tjeerd J. F., van Lammeren, Daniëlle, Veelken, Hendrik, Putter, Hein, Falkenburg, J. H. Frederik, Halkes, Constantijn J. M., and de Wreede, Liesbeth C.
- Subjects
STEM cell transplantation ,HEMATOPOIETIC stem cell transplantation ,KILLER cells ,LYMPHOCYTES - Abstract
Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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6. Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response
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van Bergen, Cornelis A.M., van Luxemburg-Heijs, Simone A.P., de Wreede, Liesbeth C., Eefting, Matthijs, von dem Borne, Peter A., van Balen, Peter, Heemskerk, Mirjam H.M., Mulder, Arend, Claas, Fransiscus H.J., Navarrete, Marcelo A., Honders, Wilhelmina M., Rutten, Caroline E., Veelken, Hendrik, Jedema, Inge, Halkes, Constantijn J.M., Griffioen, Marieke, and Falkenburg, J.H. Frederik
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T cells -- Health aspects ,Leukemia -- Care and treatment -- Development and progression ,Immune response -- Regulation ,Stem cells -- Transplantation ,Health care industry - Abstract
Patients with leukemia who receive a T cell-depleted allogeneic stem cell graft followed by postponed donor lymphocyte infusion (DLI) can experience graft-versus-leukemia (GVL) reactivity, with a lower risk of graft-versus-host disease (GVHD). Here, we have investigated the magnitude, diversity, and specificity of alloreactive CD8 T cells in patients who developed GVL reactivity after DLI in the absence or presence of GVHD. We observed a lower magnitude and diversity of CD8 T cells for minor histocompatibility antigens (MiHAs) in patients with selective GVL reactivity without GVHD. Furthermore, we demonstrated that MiHA-specific T cell clones from patients with selective GVL reactivity showed lower reactivity against nonhematopoietic cells, even when pretreated with inflammatory cytokines. Expression analysis of MiHA-encoding genes showed that similar types of antigens were recognized in both patient groups, but in patients who developed GVHD, T cell reactivity was skewed to target broadly expressed MiHAs. As an inflammatory environment can render nonhematopoietic cells susceptible to T cell recognition, prevention of such circumstances favors induction of selective GVL reactivity without development of GVHD., Introduction The curative effect of allogeneic stem cell transplantation (allo-SCT) as a treatment modality for hematological malignancies is based on the capacity of donor T cells to effectively induce graft-versus-leukemia [...]
- Published
- 2017
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7. Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity.
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Laghmouchi, Aicha, Kester, Michel G. D., Hoogstraten, Conny, Hageman, Lois, de Klerk, Wendy, Huisman, Wesley, Koster, Eva A. S., de Ru, Arnoud H., van Balen, Peter, Klobuch, Sebastian, van Veelen, Peter A., Falkenburg, J. H. Frederik, and Jedema, Inge
- Subjects
HISTOCOMPATIBILITY antigens ,IMMUNE response ,PEPTIDES ,T cells ,STEM cell transplantation ,CROSS reactions (Immunology) - Abstract
In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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8. Effects of HLA Mismatches on Cytokine Release Syndrome and Associated Non-Relapse Mortality in Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide
- Author
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Von Dem Borne, Peter A., Kemps-Mols, Berit M., de Wreede, Liesbeth C., van Beek, Adriaan A., Snijders, Tjeerd J.F., van Lammeren, Danielle, Tijmensen, Janneke, Sijs-Szabo, Aniko, Nering Bögel, Theo L., Oudshoorn, Mirjam A., Halkes, Constantijn J.M., van Balen, Peter, Marijt, Erik W.A.F., Tjon, Jennifer M.L., Vermaat, Joost S.P., and Veelken, Hendrik
- Published
- 2022
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9. Immunotherapy By Targeting CD45 in Mismatched HLA-DP to Treat Patients after Allogeneic Stem Cell Transplantation
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Struckman, Nadine E., Klobuch, Sebastian, Kester, Michel G.D., de Klerk, Wendy, de Ru, Arnoud H., Heemskerk, Mirjam H.M., van Veelen, Peter A., van Balen, Peter, Falkenburg, J.H.Frederik, and Griffioen, Marieke
- Published
- 2022
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10. Prophylactic Donor Lymphocyte Infusion in Patients after Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Is Associated with Low Relapse Risk and Excellent Survival in Patients below 65 Years with Acute Myeloid Leukemia and High-Risk Myelodysplasia
- Author
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Von Dem Borne, Peter A., Snijders, Tjeerd J.F., van Lammeren, Danielle, Tijmensen, Janneke, Planken, Erwin V., Levenga, Henriette, van den Berg, Yascha, Marijt, Erik WAF, van Balen, Peter, Tjon, Jennifer M., Vermaat, Joost S.P., Nering Bögel, Theo L., Oudshoorn, Mirjam A., Halkes, Constantijn J.M., and Veelken, Hendrik
- Published
- 2022
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11. HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study.
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van Balen, Peter, Jedema, Inge, van Loenen, Marleen M., de Boer, Renate, van Egmond, H. M., Hagedoorn, Renate S., Hoogstaten, Conny, Veld, Sabrina A. J., Hageman, Lois, van Liempt, P. A. G., Zwaginga, Jaap-Jan, Meij, Pauline, Veelken, H., Falkenburg, J. H. F., and Heemskerk, Mirjam H. M.
- Subjects
T-cell receptor genes ,STEM cell transplantation ,GENETIC transformation ,HEMATOLOGIC malignancies ,T cells - Abstract
Graft-vs.-leukemia (GVL) reactivity after HLA-matched allogeneic stem cell transplantation (alloSCT) is mainly mediated by donor T cells recognizing minor histocompatibility antigens (MiHA). If MiHA are targeted that are exclusively expressed on hematopoietic cells of recipient origin, selective GVL reactivity without severe graft-vs.-host-disease (GVHD) may occur. In this phase I study we explored HA-1H TCR gene transfer into T cells harvested from the HA-1H negative stem-cell donor to treat HA-1H positive HLA-A
* 02:01 positive patients with high-risk leukemia after alloSCT. HA-1H is a hematopoiesis-restricted MiHA presented in HLA-A* 02:01. Since we previously demonstrated that donor-derived virus-specific T-cell infusions did not result in GVHD, we used donor-derived EBV and/or CMV-specific T-cells to be redirected by HA-1H TCR. EBV and/or CMV-specific T-cells were purified, retrovirally transduced with HA-1H TCR, and expanded. Validation experiments illustrated dual recognition of viral antigens and HA-1H by HA-1H TCR-engineered virus-specific T-cells. Release criteria included products containing more than 60% antigen-specific T-cells. Patients with high risk leukemia following T-cell depleted alloSCT in complete or partial remission were eligible. HA-1H TCR T-cells were infused 8 and 14 weeks after alloSCT without additional pre-conditioning chemotherapy. For 4/9 included patients no appropriate products could be made. Their donors were all CMV-negative, thereby restricting the production process to EBV-specific T-cells. For 5 patients a total of 10 products could be made meeting the release criteria containing 3–280 × 106 virus and/or HA-1H TCR T-cells. No infusion-related toxicity, delayed toxicity or GVHD occurred. One patient with relapsed AML at time of infusions died due to rapidly progressing disease. Four patients were in remission at time of infusion. Two patients died of infections during follow-up, not likely related to the infusion. Two patients are alive and well without GVHD. In 2 patients persistence of HA-1H TCR T-cells could be illustrated correlating with viral reactivation, but no overt in-vivo expansion of infused T-cells was observed. In conclusion, HA-1H TCR-redirected virus-specific T-cells could be made and safely infused in 5 patients with high-risk AML, but overall feasibility and efficacy was too low to warrant further clinical development using this strategy. New strategies will be explored using patient-derived donor T-cells isolated after transplantation transduced with HA-1H-specific TCR to be infused following immune conditioning. [ABSTRACT FROM AUTHOR]- Published
- 2020
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12. Alloreactivity to HLA-DP is modulated by selft-cell epitopes in the responder
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Arrieta-Bolanos, Esteban, Crivello, Pietro, Van Bergen, Kees, Metzing, Maximilian, van Balen, Peter, Horn, Peter A., Falkenburg, Frederick, and Fleischhauer, Katharina
- Subjects
Medizin - Published
- 2016
13. HLA-DM Mediates Permissiveness of HLA-DPB1 T Cell Epitope Mismatches in Unrelated HCT
- Author
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Metzing, Maximilian, Crivello, Pietro, Meurer, Thuja, Kester, Michel G.D., Megger, Dominik, Chen, Weiqiang, Van Balen, Peter, Griffioen, Marieke, Horn, Peter A., Sitek, Barbara, Falkenburg, J.H.Frederik, Arrieta-Bolaños, Esteban, and Fleischhauer, Katharina
- Published
- 2019
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14. Tissue Damage Caused by Myeloablative, but Not Non-Myeloablative, Conditioning before Allogeneic Stem Cell Transplantation Results in Dermal Macrophage Recruitment without Active T-Cell Interaction.
- Author
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van Balen, Peter, van der Zouwen, Boris, Kruisselbrink, Alwine B., Eefting, Matthijs, Szuhai, Karoly, Jordanova, Ekaterina S., Falkenburg, J. H. F., and Jedema, Inge
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STEM cell transplantation ,T cells ,GRAFT versus host disease - Abstract
Introduction: Conditioning regimens preceding allogeneic stem cell transplantation (alloSCT) can cause tissue damage and acceleration of the development of graft-versus-host disease (GVHD). T-cell-depleted alloSCT with postponed donor lymphocyte infusion (DLI) may reduce GVHD, because tissue injury can be restored at the time of DLI. In this study, we investigated the presence of tissue injury and inflammation in skin during the period of hematologic recovery and immune reconstitution after alloSCT. Methods: Skin biopsies were immunohistochemically stained for HLA class II, CD1a, CD11c, CD40, CD54, CD68, CD86, CD206, CD3, and CD8. HLA class II-expressing cells were characterized as activated T-cells, antigen-presenting cells (APCs), or tissue repairing macrophages. In sex-mismatched patient and donor couples, origin of cells was determined by multiplex analysis combining XY-FISH and fluorescent immunohistochemistry. Results: No inflammatory environment due to pretransplant conditioning was detected at the time of alloSCT, irrespective of the conditioning regimen. An increase in HLA class II-positive macrophages and CD3 T-cells was observed 12-24 weeks after myeloablative alloSCT, but these macrophages did not show signs of interaction with the co-localized T-cells. In contrast, during GVHD, an increase in HLA class II-expressing cells coinciding with T-cell interaction was observed, resulting in an overt inflammatory reaction with the presence of activated APC, activated donor T-cells, and localized upregulation of HLA class II expression on epidermal cells. In the absence of GVHD, patient derived macrophages were gradually replaced by donor-derived macrophages although patient- derived macrophages were detectable even 24 weeks after alloSCT. Conclusion: Conditioning regimens cause tissue damage in the skin, but this does not result in a local increase of activated APC. In contrast to the inflamed situation in GVHD, when interaction takes place between activated APC and donor T-cells, the tissue damage caused by myeloablative alloSCT results in dermal recruitment of HLA class II-positive tissue repairing macrophages co-existing with increased numbers of patient- and donor-derived T-cells, but without signs of specific interaction and initiation of an immune response. Thus, the local skin damage caused by the conditioning regimen appears to be insufficient as single factor to provoke GVHD induction. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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15. Accurate prediction of HLA class II antigen presentation across all loci using tailored data acquisition and refined machine learning.
- Author
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Nilsson, Jonas B., Kaabinejadian, Saghar, Yari, Hooman, Kester, Michel G. D., van Balen, Peter, Hildebrand, William H., and Nielsen, Morten
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ANTIGEN presentation , *HLA histocompatibility antigens , *MACHINE learning , *T cells , *ACQUISITION of data , *PEPTIDES - Abstract
Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules is crucial for rational development of immunotherapies and vaccines targeting CD4+ T cell activation. So far, most prediction methods for HLA class II antigen presentation have focused on HLA-DR because of limited availability of immunopeptidomics data for HLA-DQ and HLA-DP while not taking into account alternative peptide binding modes. We present an update to the NetMHCIIpan prediction method, which closes the performance gap between all three HLA class II loci. We accomplish this by first integrating large immunopeptidomics datasets describing the HLA class II specificity space across all loci using a refined machine learning framework that accommodates inverted peptide binders. Next, we apply targeted immunopeptidomics assays to generate data that covers additional HLA-DP specificities. The final method, NetMHCIIpan-4.3, achieves high accuracy and molecular coverage across all HLA class II allotypes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
16. Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion.
- Author
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Koster EAS, Bonneville EF, Borne PAVD, van Balen P, Marijt EWA, Tjon JML, Snijders TJF, van Lammeren D, Veelken H, Putter H, Falkenburg JHF, Halkes CJM, and de Wreede LC
- Subjects
- Humans, Kinetics, CD8-Positive T-Lymphocytes, CD4-Positive T-Lymphocytes, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control
- Abstract
Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Koster, Bonneville, Borne, van Balen, Marijt, Tjon, Snijders, van Lammeren, Veelken, Putter, Falkenburg, Halkes and de Wreede.)
- Published
- 2023
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17. Treatment patterns and clinical outcomes of asciminib in a real-world multiresistant chronic myeloid leukemia patient population.
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Kockerols CCB, Janssen JJWM, Blijlevens NMA, Klein SK, Van Hussen-Daenen LGM, Van Gorkom GGY, Smit WM, Van Balen P, Biemond BJ, Cruijsen MJ, Corsten MF, Te Boekhorst PAW, Koene HR, Van Sluis GL, Cornelissen JJ, and Westerweel PE
- Subjects
- Humans, Pyrazoles therapeutic use, Niacinamide therapeutic use, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid drug therapy
- Published
- 2023
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18. Human T cells recognize HLA-DP-bound peptides in two orientations.
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Klobuch S, Lim JJ, van Balen P, Kester MGD, de Klerk W, de Ru AH, Pothast CR, Jedema I, Drijfhout JW, Rossjohn J, Reid HH, van Veelen PA, Falkenburg JHF, and Heemskerk MHM
- Subjects
- Humans, Amino Acids, Cytomegalovirus, Histocompatibility Antigens Class II, HLA-DP Antigens immunology, T-Lymphocytes immunology, Cytomegalovirus Infections, Peptides
- Abstract
Human leukocyte antigen (HLA) molecules present small peptide antigens to T cells, thereby allowing them to recognize pathogen-infected and cancer cells. A central dogma over the last 50+ y is that peptide binding to HLA molecules is mediated by the docking of side chains of particular amino acids in the peptide into pockets in the HLA molecules in a conserved N- to C-terminal orientation. Whether peptides can be presented in a reversed C- to N-terminal orientation remains unclear. Here, we performed large-scale identification of peptides bound to HLA-DP molecules and observed that in addition to peptide binding in an N- to C-terminal orientation, in 9 out of 14 HLA-DP allotypes, reverse motifs are found, compatible with C- to N-terminal peptide binding. Moreover, we isolated high-avidity human cytomegalovirus (CMV)-specific HLA-DP-restricted CD4
+ T cells from the memory repertoire of healthy donors and demonstrate that such T cells recognized CMV-derived peptides bound to HLA-DPB1*01:01 or *05:01 in a reverse C- to N-terminal manner. Finally, we obtained a high-resolution HLA-DPB1*01:01-CMVpp65(142-158) peptide crystal structure, which is the molecular basis for C- to N-terminal peptide binding to HLA-DP. Our results point to unique features of HLA-DP molecules that substantially broaden the HLA class II bound peptide repertoire to combat pathogens and eliminate cancer cells.- Published
- 2022
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19. B-cell lymphoblastic lymphoma with cutaneous involvement and a KMT2A gene rearrangement.
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Kemps PG, Cleven AHG, van Wezel T, van Eijk R, Bot FJ, Veelken H, van Balen P, and Kerkhoffs JH
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- Adult, Humans, Male, Gene Rearrangement, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology
- Published
- 2020
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20. The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells.
- Author
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Laghmouchi A, Hoogstraten C, van Balen P, Falkenburg JHF, and Jedema I
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- Adult, Dendritic Cells pathology, Female, Graft vs Host Disease pathology, Hematologic Neoplasms pathology, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Humans, T-Lymphocytes pathology, Transplantation, Homologous, Dendritic Cells immunology, Graft vs Host Disease immunology, Graft vs Leukemia Effect immunology, HLA-DP Antigens immunology, Hematologic Neoplasms immunology, T-Lymphocytes immunology
- Abstract
Stem cell grafts from 10/10 HLA-matched unrelated donors are often mismatched for HLA-DP. In some patients, donor T-cell responses targeting the mismatched HLA-DP allele(s) have been found to induce a specific graft- versus -leukemia effect without coinciding graft- versus -host disease, whereas in other cases significant graft- versus -host disease occurred. Cell-lineage-specific recognition patterns within the allogeneic HLA-DP-specific donor T-cell repertoire could explain the differential clinical effects mediated by donor T cells after HLA-DP-mismatched allogeneic stem cell transplantation. To unravel the composition of the HLA-DP T-cell repertoire, donor T-cell responses were provoked by in vitro stimulation with allogeneic HLA-DP-mismatched monocyte-derived dendritic cells. A strategy including depletion of reactivity against autologous dendritic cells allowed efficient identification and enrichment of allo-reactive T cells upon stimulation with HLA-DP-mismatched dendritic cells. In this study we elucidated that the allogeneic HLA-DP-restricted T-cell repertoire contained T cells with differential cell-lineage-specific recognition profiles. As expected, some of the allogeneic HLA-DP-restricted T cells showed broad recognition of a variety of hematopoietic and non-hematopoietic cell types expressing the targeted mismatched HLA-DP allele. However, a significant proportion of the allogeneic HLA-DP-restricted T cells showed restricted recognition of hematopoietic cells, including primary malignant cells, or even restricted recognition of only myeloid cells, including dendritic cells and primary acute myeloid leukemia samples, but not of other hematopoietic and non-hematopoietic cell types. These data demonstrate that the allogeneic HLA-DP-specific T-cell repertoire contains T cells that show restricted recognition of hematopoietic cells, which may contribute to the specific graft- versus -leukemia effect without coinciding graft- versus -host disease., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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21. CD4 Donor Lymphocyte Infusion Can Cause Conversion of Chimerism Without GVHD by Inducing Immune Responses Targeting Minor Histocompatibility Antigens in HLA Class II.
- Author
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van Balen P, van Bergen CAM, van Luxemburg-Heijs SAP, de Klerk W, van Egmond EHM, Veld SAJ, Halkes CJM, Zwaginga JJ, Griffioen M, Jedema I, and Falkenburg JHF
- Subjects
- CD4-Positive T-Lymphocytes immunology, Chimerism, Female, Graft vs Host Disease immunology, Graft vs Leukemia Effect immunology, Histocompatibility Antigens Class II immunology, Humans, Living Donors, Male, Middle Aged, Minor Histocompatibility Antigens immunology, Myeloablative Agonists therapeutic use, Siblings, Transplantation, Homologous, Treatment Outcome, CD4-Positive T-Lymphocytes transplantation, Graft vs Host Disease prevention & control, Leukemia therapy, Peripheral Blood Stem Cell Transplantation adverse effects, Transplantation Conditioning methods
- Abstract
Under non-inflammatory conditions HLA class II is predominantly expressed on hematopoietic cells. Therefore, donor CD4 T-cells after allogeneic stem cell transplantation (alloSCT) may mediate graft-vs.-leukemia reactivity without graft-vs.-host disease (GVHD). We analyzed immune responses in four patients converting from mixed to full donor chimerism without developing GVHD upon purified CD4 donor lymphocyte infusion (DLI) from their HLA-identical sibling donor after T-cell depleted alloSCT. In vivo activated T-cells were clonally isolated after CD4 DLI. Of the alloreactive T-cell clones, 96% were CD4 positive, illustrating the dominant role of CD4 T-cells in the immune responses. We identified 9 minor histocompatibility antigens (MiHA) as targets for alloreactivity, of which 8 were novel HLA class II restricted MiHA. In all patients, MiHA specific CD4 T-cells were found that were capable to lyse hematopoietic cells and to recognize normal and malignant cells. No GVHD was induced in these patients. Skin fibroblasts forced to express HLA class II, were recognized by only two MiHA specific CD4 T-cell clones. Of the 7 clones that failed to recognize fibroblasts, two targeted MiHA were encoded by genes not expressed in fibroblasts, presentation of one MiHA was dependent on HLA-DO, which is absent in fibroblasts, and T-cells recognizing the remaining 4 MiHA had an avidity that was apparently too low to recognize fibroblasts, despite clear recognition of hematopoietic cells. In conclusion, purified CD4 DLI from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with graft-vs.-malignancy reactivity, but without GVHD, by targeting HLA class II restricted MiHA.
- Published
- 2018
- Full Text
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22. Dissecting Genetic Control of HLA-DPB1 Expression and Its Relation to Structural Mismatch Models in Hematopoietic Stem Cell Transplantation.
- Author
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Meurer T, Arrieta-Bolaños E, Metzing M, Langer MM, van Balen P, Falkenburg JHF, Beelen DW, Horn PA, Fleischhauer K, and Crivello P
- Subjects
- 3' Untranslated Regions genetics, Alleles, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cells, Cultured, Epitopes, T-Lymphocyte chemistry, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Gene Frequency, Graft vs Host Disease etiology, Graft vs Host Disease genetics, HLA-DP beta-Chains genetics, Haplotypes, HeLa Cells, Hematopoietic Stem Cell Transplantation adverse effects, Humans, T-Lymphocytes immunology, T-Lymphocytes metabolism, 3' Untranslated Regions immunology, Gene Expression Regulation immunology, Graft vs Host Disease immunology, HLA-DP beta-Chains immunology, Hematopoietic Stem Cell Transplantation methods, Polymorphism, Single Nucleotide immunology
- Abstract
HLA expression levels have been suggested to be genetically controlled by single nucleotide polymorphisms (SNP) in the untranslated regions (UTR), and expression variants have been associated with the outcome of chronic viral infection and hematopoietic stem cell transplantation (HSCT). In particular, the 3'UTR rs9277534-G/A SNP in HLA-DPB1 has been associated with graft-versus-host-disease after HSCT (Expression model); however its relevance in different immune cells and its mode of action have not been systematically addressed. In addition, there is a strong though not complete overlap between the rs9277534-G/A SNP and structural HLA-DPB1 T cell epitope (TCE) groups which have also been associated with HSCT outcome (TCE Structural model). Here we confirm and extend previous findings of significantly higher HLA-DPB1 expression in B cell lines, unstimulated primary B cells, and monocytes homozygous for rs9277534-G compared to those homozygous for rs9277534-A. However, these differences were abrogated by interferon-γ stimulation or differentiation into dendritic cells. We identify at least seven 3'UTR rs9277534-G/A haplotypes differing by a total of 37 SNP, also characterized by linkage to length variants of a short tandem repeat (STR) in intron 2 and TCE group assignment. 3'UTR mapping did not show any significant differences in post-transcriptional regulation assessed by luciferase assays between two representative rs9277534-G/A haplotypes for any of eight overlapping fragments. Moreover, no evidence for alternative splicing associated with the intron 2 STR was obtained by RT-PCR. In an exemplary cohort of 379 HLA-DPB1 mismatched donor-recipient pairs, risk prediction by the Expression model and the Structural TCE model was 36.7% concordant, with the majority of discordances due to non-applicability of the Expression model. HLA-DPB1 from different TCE groups expressed in the absence of the 3'UTR at similar levels by transfected HeLa cells elicited significantly different mean alloreactive CD4+ T-cell responses, as assessed by CD137 upregulation assays in 178 independent cultures. Taken together, our data provide new insights into the cell type-specific and mechanistic basis of the association between the rs9277534-G/A SNP and HLA-DPB1 expression, and show that, despite partial overlap between both models in HSCT risk-prediction, differential alloreactivity determined by the TCE structural model occurs independently from HLA-DPB1 differential expression.
- Published
- 2018
- Full Text
- View/download PDF
23. Alloreactive T Cell Receptor Diversity against Structurally Similar or Dissimilar HLA-DP Antigens Assessed by Deep Sequencing.
- Author
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Arrieta-Bolaños E, Crivello P, Metzing M, Meurer T, Ahci M, Rytlewski J, Vignali M, Yusko E, van Balen P, Horn PA, Falkenburg JHF, and Fleischhauer K
- Subjects
- Alleles, Clonal Selection, Antigen-Mediated, Genetic Variation, HeLa Cells, High-Throughput Nucleotide Sequencing, Humans, Immunophenotyping, Autoantigens immunology, CD4-Positive T-Lymphocytes physiology, HLA-DP Antigens immunology, Isoantigens immunology, Receptors, Antigen, T-Cell, alpha-beta genetics
- Abstract
T cell alloreactivity is mediated by a self-human leukocyte antigen (HLA)-restricted T cell receptor (TCR) repertoire able to recognize both structurally similar and dissimilar allogeneic HLA molecules (i.e., differing by a single or several amino acids in their peptide-binding groove). We hypothesized that thymic selection on self-HLA molecules could have an indirect impact on the size and diversity of the alloreactive response. To test this possibility, we used TCR Vβ immunophenotyping and immunosequencing technology in a model of alloreactivity between self-HLA selected T cells and allogeneic HLA-DPB1 (DPB1) differing from self-DPB1*04:02 by a single (DPB1*02:01) or several (DPB1*09:01) amino acids in the peptide-binding groove. CD4+ T cells from three different self-DPB1*04:01,*04:02 individuals were stimulated with HeLa cells stably transduced with the relevant peptide processing machinery, co-stimulatory molecules, and HLA-DP. Flow cytometric quantification of the DPB1-specific T cell response measured as upregulation of the activation marker CD137 revealed significantly lower levels of alloreactivity against DPB1*02:01 compared with DPB1*09:01 (mean CD4+CD137+ frequency 35.2 ± 9.9 vs. 61.5 ± 7.7%, respectively, p < 0.0001). These quantitative differences were, however, not reflected by differences in the breadth of the alloreactive response at the Vβ level, with both alloantigens eliciting specific responses from all TCR-Vβ specificities tested by flow cytometry, albeit with higher levels of reactivity from most Vβ specificities against DPB1*09:01. In line with these observations, TCRB -CDR3 immunosequencing showed no significant differences in mean clonality of sorted CD137+CD4+ cells alloreactive against DPB1*02:01 or DPB1*09:01 [0.39 (0.36-0.45) and 0.39 (0.30-0.46), respectively], or in the cumulative frequencies of the 10 most frequent responding clones (55-67 and 58-62%, respectively). Most of the clones alloreactive against DPB1*02:01 (68.3%) or DPB1*09:01 (75.3%) were characterized by low-abundance (i.e., they were not appreciable among the pre-culture T cells). Interestingly, however, their cumulative frequency was lower against DPB1*02:01 compared with DPB1*09:01 (mean cumulative frequency 35.3 vs. 50.6%, respectively). Our data show that, despite lower levels of alloreactivity, a similar clonal diversity can be elicited by structurally similar compared with structurally dissimilar HLA-DPB1 alloantigens and demonstrate the power of TCRB immunosequencing in unraveling subtle qualitative changes not appreciable by conventional methods.
- Published
- 2018
- Full Text
- View/download PDF
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