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Suzanne van Dorp,
Henrike Resemann,
Liane te Boome,
Floor Pietersma,
Debbie van Baarle,
Frits Gmelig-Meyling,
Roel de Weger,
Eefke Petersen,
Monique Minnema,
Henk Lokhorst, Saskia Ebeling,
Scott J P Beijn,
Edward F Knol,
Marijke van Dijk,
Ellen Meijer,
Jürgen Kuball
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ABSTRACT: Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8(+) T cells, suggesting that host B cells play a role in maintaining pathological CD8(+) T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42).
Haematologica 05/2011; 96(9):1380-4. · 6.42 Impact Factor
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ABSTRACT: Chronic graft-versus-host disease is a serious complication in long-term survivors of allogeneic hematopoietic stem cell transplantation, with several organ systems affected. Chronic graft-versus-host disease is an important cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. This article reviews the pathogenesis of chronic graft-versus-host disease. In particularly, the role of B cells in chronic graft-versus-host disease is evaluated, as is evident from several studies which have investigated the presence of antibodies as well as studies which have analyzed B cells as a target for immunotherapy. Thirty autoantibodies and 5 alloantibodies have been identified in chronic graft-versus-host disease patients in 24 studies, and 8 autoantibodies and 5 alloantibodies seemed to be strongly associated with chronic graft-versus-host disease. In addition, various studies have observed significant improvements in chronic graft-versus-host disease using the anti-CD20(+) antibody rituximab. However, it appears to be highly likely that both B cells as well as T cells are of major importance in chronic graft-versus-host disease. Further research is required to clarify the pathogenesis of chronic graft-versus-host disease.
Haematologica 09/2008; 93(11):1702-11. · 6.42 Impact Factor
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Jessica L Teeling,
Wendy J M Mackus,
Luus J J M Wiegman,
Jeroen H N van den Brakel,
Stephen A Beers,
Ruth R French,
Tom van Meerten, Saskia Ebeling,
Tom Vink,
Jerry W Slootstra,
Paul W H I Parren,
Martin J Glennie,
Jan G J van de Winkel
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ABSTRACT: We have previously defined a panel of fully human CD20 mAb. Most of these were unexpectedly efficient in their ability to recruit C1q to the surface of CD20-positive cells and mediate tumor lysis via activation of the classical pathway of complement. This complement-dependent cytotoxicity (CDC) potency appeared to relate to the unusually slow off-rate of these human Abs. However, we now present epitope-mapping data, which indicates that all human mAb bind a novel region of CD20 that may influence CDC potency. Epitope mapping, using both mutagenesis studies and overlapping 15-mer peptides of the extracellular loops of CD20, defined the amino acids required for binding by an extensive panel of mouse and human mAb. Binding by rituximab and mouse CD20 mAb, had an absolute requirement for alanine and proline at positions 170 and 172, respectively, within the large extracellular loop of CD20. Surprisingly, however, all of the human CD20 mAb recognize a completely novel epitope located N-terminally of this motif, also including the small extracellular loop of CD20. Thus, although off-rate may influence biological activity of mAb, another critical factor for determining CDC potency by CD20 mAb appears to be the region of the target molecule they recognize. We conclude that recognition of the novel epitope cooperates with slow off-rate in determining the activity of CD20 Ab in activation of complement and induction of tumor cell lysis.
The Journal of Immunology 08/2006; 177(1):362-71. · 5.79 Impact Factor
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Experimental Hematology 04/2006; 34(3):251-63. · 2.90 Impact Factor
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ABSTRACT: Immunotherapeutic approaches that target antigens that are differentially recognized on haematopoietic and non-haematopoietic cells may specifically enhance the graft-versus-leukaemia (GVL) effect of donor lymphocyte infusion. In this study, we have characterized a new HLA-B*5201-restricted epitope of the UTY gene. Unusually, presentation of this epitope was restricted to lymphoblasts. As a result, a T cell clone specific to this epitope recognized normal and malignant male B and T lymphoblasts, while showing little reactivity towards male HLA-B*5201+ fibroblasts. Transfer of its T cell receptor (TCR) into donor T cells led to the generation of large numbers of T cells, which acquired the specificity of the original clone, its avidity and the differential pattern of reactivity towards lymphoblasts and fibroblasts. Remarkably, the specific response of TCR-transferred T cells was significantly higher than that of the original clone. This is the first demonstration of the possibility to preserve the specific pattern of a T cell response to a differentially expressed antigen after TCR-transfer and to augment the amplitude of this response concomitantly. These results indicate that it may be feasible to enhance the GVL effect of donor lymphocyte infusions in lymphoproliferative malignancies by the transfer of TCRs specific to epitopes that are differentially recognized on lymphoblasts.
British Journal of Haematology 06/2005; 129(3):392-402. · 4.94 Impact Factor
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ABSTRACT: The superior graft-versus-leukemia (GVL) effect of the female-to-male stem cell transplantation is partially independent from the concomitant graft-versus-host reactivity. However, the antigenic basis of this selective GVL response remains enigmatic, because no H-Y antigens with hematopoietic-restricted expression were identified. In this study, we report a novel H-Y epitope that is preferentially recognized on activated proliferating lymphocytes.
We generated a CTL clone YKIII.8 that showed reactivity toward male B*5201+ CD40-activated B cells, EBV-lymphoblastoid cell lines, and phytohemagglutinin-activated T-cell blasts but little or no reactivity toward fibroblasts, CD14+ cells, or unstimulated B and T cells. The antigen recognized by YKIII.8 was identified by screening of a cDNA expression library, and its pattern of expression was investigated.
cDNA of the male isoform of 40S ribosomal protein S4 was found to encode the antigenic peptide TIRYPDPVI, which was recognized by YKIII.8. Western blot analysis showed that rapidly proliferating cells overexpress the RPS4 protein in comparison with nonrecognized cell subsets. Retroviral transfer of YKIII.8 T-cell receptor resulted in preservation of the lymphoblast-specific reactivity pattern.
Our findings suggest that CTL specific to certain epitopes of ubiquitously expressed H-Y antigens may specifically target lymphoblasts, contributing to the selective GVL effect of female-to-male stem cell transplantation.
Clinical Cancer Research 04/2005; 11(5):1694-703. · 7.74 Impact Factor
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Suzanne Van Dorp,
Henrike Resemann,
Liane Te Boome,
Floor Pietersma,
Debbie Van Baarle,
Frits H Gmelig-Meyling,
Roel De Weger,
Eefke Petersen,
Monique Minnema,
Henk Lokhorst, Saskia Ebeling,
Scott J P Beijn,
Edward F Knoll,
Marijke R Van Dijk,
Ellen Meijer,
Jürgen Kuball
[show abstract]
[hide abstract]
ABSTRACT: Haematologica 2011 [Epub ahead of print] Citation: van Dorp S, Resemann H, te Boome L, Pietersma F, van Baarle D, Gmelig-Meyling FH, de Weger R, Petersen E, Minnema M, Lokhorst H, Ebeling S, Beijn SJP, Knoll EF, van Dijk MR, Meijer E, and Kuball J. The immunological phenotype of rituximab-sensitive chronic GVHD: a phase II study. Haematologica. 2011; 96:xxx doi:10.3324/haematol.2011.041814 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.
