Publications by authors named "Jörn Albring"

20 Publications

  • Page 1 of 1

Blinatumomab or Inotuzumab Ozogamicin as Bridge to Allogeneic Stem Cell Transplantation for Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia: A Retrospective Single-Center Analysis.

Clin Lymphoma Myeloma Leuk 2020 10 3;20(10):e724-e733. Epub 2020 Jun 3.

Department of Medicine A - Hematology, Hemostaseology, Oncology, Pulmonology, University Hospital Münster, Münster, Germany. Electronic address:

Background: Blinatumomab and inotuzumab ozogamicin are now widely used to treat relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

Patients And Methods: We have reported the clinical course of 34 adult patients with r/r B-ALL receiving blinatumomab or inotuzumab ozogamicin at our institution from 2009 to 2019.

Results: Blinatumomab-based salvage therapy was applied for overt r/r B-ALL (n = 13) or minimal residual disease (MRD) positivity (n = 5). Of the 13 patients with r/r B-ALL, 9 (69%; 95% confidence interval [CI], 39%-91%) achieved complete remission (CR), with 78% of CR patients (95% CI, 40%-97%) reaching MRD negativity. MRD negativity was also achieved in all 5 patients treated for MRD positivity. The 1-year overall survival of patients receiving blinatumomab for r/r B-ALL and MRD positivity was 54% (n = 13; 95% CI, 26%-81%) and 80% (n = 5; 95% CI, 44-100), respectively. In the inotuzumab ozogamicin group, all 16 patients were treated for overt r/r B-ALL. The rate of CR was 94% (95% CI, 70%-100%), with 67% (95% CI, 38%-88%) of CR patients reaching MRD negativity. The 1-year OS after the first application of inotuzumab ozogamicin was 46% (95% CI, 18%-74%). Of those patients receiving blinatumomab and inotuzumab ozogamicin as a bridge-to-transplant strategy, 79% and 80%, respectively, proceeded to allogeneic stem cell transplantation. The most frequent drug-specific adverse events were similar to those previously reported, including cytokine release syndrome, capillary leak syndrome, and neurotoxicity for blinatumomab and transplant-associated veno-occlusive disease of the liver for inotuzumab ozogamicin.

Conclusion: Together with previous observations from phase III clinical trials, these data suggest that blinatumomab and inotuzumab ozogamicin are highly effective salvage regimens in r/r B-ALL.
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http://dx.doi.org/10.1016/j.clml.2020.05.022DOI Listing
October 2020

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction.

Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts.

Results: MTD was 3 mg/m tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t of 8 to 9 h without accumulation in daily administrations.

Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
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http://dx.doi.org/10.3390/cancers12061488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352358PMC
June 2020

Monitoring minimal residual/relapsing disease after allogeneic haematopoietic stem cell transplantation in adult patients with acute lymphoblastic leukaemia.

Bone Marrow Transplant 2020 07 30;55(7):1410-1420. Epub 2020 Jan 30.

Department of Medicine A/Haematology and Oncology, University of Muenster, Muenster, Germany.

Relapse after allogeneic haematopoietic stem cell transplantation (SCT) is a major cause of death in patients with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed the contributions of lineage-sorted donor cell chimerism (sDCC) and quantitative PCR (qPCR) targeting disease-specific genetic rearrangements to detect minimal residual/relapsing disease (MRD) and predict impending relapse in 94 adult ALL patients after SCT. With a median follow-up of surviving patients (n = 61) of 3.3 years, qPCR and/or sDCC measurements turned positive in 38 patients (40%). Of these, 22 patients relapsed and 16 remained in complete remission. At 3 years, qPCR and/or sDCC positive patients showed an increased incidence of relapse (50% vs. 4%, p < 0.0001), decreased relapse-free survival (RFS, 40% vs. 85%, p < 0.0001), and decreased overall survival (OS, 47% vs. 87%, p 0.004). Both, qPCR and sDCC pre-detected 11 of 21 relapses occurring within the first two years after SCT and, overall, complemented for each other method in four of the relapsing and four of the non-relapsing cases. Patients receiving pre-emptive MRD-driven interventions (n = 11) or not (n = 10) showed comparable median times until relapse, RFS, and OS. In our single centre cohort, qPCR and sDCC were similarly effective and complementary helpful to indicate haematological relapse of ALL after SCT.
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http://dx.doi.org/10.1038/s41409-020-0801-0DOI Listing
July 2020

Alloantigen expression on malignant cells and healthy host tissue influences graft-versus-tumor reactions after allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2018 07 23;53(7):807-819. Epub 2018 Jan 23.

Department of Medicine A, University Hospital of Muenster, Muenster, Germany.

Durable remissions of hematological malignancies regularly observed following allogeneic hematopoietic stem cell transplantation (aHSCT) are due to the conditioning regimen, as well as an immunological phenomenon called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. The development of GVL is closely linked to graft-versus-host disease (GVHD), the main side effect associated with aHSCT. Both, GVHD and GVL are mediated by donor T cells that are initially activated by antigen-presenting cells that present recipient-derived alloantigens in the context of either matched or mismatched MHC class I molecules. Using murine models of aHSCT we show that ubiquitously expressed minor histocompatibility alloantigens (mHAg) are no relevant target for GVT effects. Interestingly, certain ubiquitously expressed MHC alloantigens augmented GVT effects early after transplantation, while others did not. The magnitude of GVT effects correlated with tumor infiltration by CD8+ cytotoxic T cells and tumor cell apoptosis. Furthermore, the immune response underlying GVHD and GVT was oligoclonal, highlighting that immunodominance is an important factor during alloimmune responses. These results emphasize that alloantigen expression on non-hematopoietic tissues can influence GVT effects in a previously unrecognized fashion. These findings bear significance for harnessing optimal GVL effects in patients receiving aHSCT.
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http://dx.doi.org/10.1038/s41409-017-0071-7DOI Listing
July 2018

RAB43 facilitates cross-presentation of cell-associated antigens by CD8α+ dendritic cells.

J Exp Med 2016 12 29;213(13):2871-2883. Epub 2016 Nov 29.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

In this study, to examine cross-presentation by classical dendritic cells (DCs; cDCs), we evaluated the role of RAB43, a protein found to be selectively expressed by Batf3-dependent CD8α and CD103 compared with other DC subsets and immune lineages. Using a specific monoclonal antibody, we localized RAB43 expression to the Golgi apparatus and LAMP1 cytoplasmic vesicles. Mice with germline or conditional deletion of Rab43 are viable and fertile and have normal development of cDCs but show a defect for in vivo and in vitro cross-presentation of cell-associated antigen. This defect is specific to cDCs, as Rab43-deficient monocyte-derived DCs showed no defect in cross-presentation of cell-associated antigen. These results suggest that RAB43 provides a specialized activity used in cross-presentation selectively by CD8α DCs but not other antigen-presenting cells.
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http://dx.doi.org/10.1084/jem.20160597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154939PMC
December 2016

Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells.

J Exp Med 2016 11 17;213(12):2553-2565. Epub 2016 Oct 17.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Current systems for conditional gene deletion within mouse macrophage lineages are limited by ectopic activity or low efficiency. In this study, we generated a Mafb-driven Cre strain to determine whether any dendritic cells (DCs) identified by Zbtb46-GFP expression originate from a Mafb-expressing population. Lineage tracing distinguished macrophages from classical DCs, neutrophils, and B cells in all organs examined. At steady state, Langerhans cells (LCs) were lineage traced but also expressed Zbtb46-GFP, a phenotype not observed in any other population. After exposure to house dust mite antigen, Zbtb46-negative CD64 inflammatory cells infiltrating the lung were substantially lineage traced, but Zbtb46-positive CD64 cells were not. These results provide new evidence for the unique identity of LCs and challenge the notion that some inflammatory cells are a population of monocyte-derived DCs.
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http://dx.doi.org/10.1084/jem.20160600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110021PMC
November 2016

Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor.

Nat Immunol 2015 Jul 8;16(7):708-17. Epub 2015 Jun 8.

1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

The transcription factors Batf3 and IRF8 are required for the development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α(+) cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(-/-) mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α(+) cDCs due to decay of Irf8 autoactivation and diverted to the CD4(+) cDC lineage.
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http://dx.doi.org/10.1038/ni.3197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507574PMC
July 2015

L-Myc expression by dendritic cells is required for optimal T-cell priming.

Nature 2014 Mar 9;507(7491):243-7. Epub 2014 Feb 9.

1] Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA [2] Howard Hughes Medical Institute, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA.

The transcription factors c-Myc and N-Myc--encoded by Myc and Mycn, respectively--regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.
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http://dx.doi.org/10.1038/nature12967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954917PMC
March 2014

Re(de)fining the dendritic cell lineage.

Nat Immunol 2012 Dec 16;13(12):1145-54. Epub 2012 Nov 16.

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.

Dendritic cells (DCs) are essential mediators of innate and adaptive immune responses. Study of these critical cells has been complicated by their similarity to other hematopoietic lineages, particularly monocytes and macrophages. Progress has been made in three critical areas of DC biology: the characterization of lineage-restricted progenitors in the bone marrow, the identification of cytokines and transcription factors required during differentiation, and the development of genetic tools for the visualization and depletion of DCs in vivo. Collectively, these advances have clarified the nature of the DC lineage and have provided novel insights into their function during health and disease.
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http://dx.doi.org/10.1038/ni.2467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644874PMC
December 2012

Compensatory dendritic cell development mediated by BATF-IRF interactions.

Nature 2012 Oct 19;490(7421):502-7. Epub 2012 Sep 19.

Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8α(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.
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http://dx.doi.org/10.1038/nature11531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832PMC
October 2012

Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation.

Blood 2012 Jul 4;120(2):335-46. Epub 2012 Jun 4.

Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St Louis, MO 63110, USA.

Myeloid ecotropic viral integration site 1 (Meis1) forms a heterodimer with Pbx1 that augments Hox-dependent gene expression and is associated with leukemogenesis and HSC self-renewal. Here we identified 2 independent actions of Meis1 in hematopoietic development: one regulating cellular proliferation and the other involved in megakaryocyte lineage development. First, we found that endogenous Mesp1 indirectly induces Meis1 and Meis2 in endothelial cells derived from embryonic stem cells. Overexpression of Meis1 and Meis2 greatly enhanced the formation of hematopoietic colonies from embryonic stem cells, with the exception of erythroid colonies, by maintaining hematopoietic progenitor cells in a state of proliferation. Second, overexpression of Meis1 repressed the development of early erythroid progenitors, acting in vivo at the megakaryocyte-erythroid progenitor stage to skew development away from erythroid generation and toward megakaryocyte development. This previously unrecognized action of Meis1 may explain the embryonic lethality observed in Meis1(-/-) mice that arises from failure of lymphatic-venous separation and can result as a consequence of defective platelet generation. These results show that Meis1 exerts 2 independent functions, with its role in proliferation of hematopoietic progenitors acting earlier in development from its influence on the fate choice at the megakaryocyte-erythroid progenitor between megakaryocytic and erythroid development.
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http://dx.doi.org/10.1182/blood-2012-01-403139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628121PMC
July 2012

Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages.

J Exp Med 2012 Jun 21;209(6):1135-52. Epub 2012 May 21.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.

Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages.
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http://dx.doi.org/10.1084/jem.20120030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371733PMC
June 2012

Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.

J Exp Med 2010 Nov 15;207(12):2551-9. Epub 2010 Nov 15.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4(+) forkhead box P3(-) (Foxp3(-)) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4(+) Foxp3(+) regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.
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http://dx.doi.org/10.1084/jem.20102017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989771PMC
November 2010

Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells.

J Exp Med 2010 Apr 29;207(4):823-36. Epub 2010 Mar 29.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8alpha+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3(-/-) mice also lack CD103+CD11b- DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3(-/-) mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b- DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3(-/-) mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8alpha+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ-resident CD8alpha+ cDCs and nonlymphoid CD103+ DCs.
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http://dx.doi.org/10.1084/jem.20091627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856032PMC
April 2010

Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation.

Nat Immunol 2008 Jun 27;9(6):603-12. Epub 2008 Apr 27.

Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Calcineurin is required for B cell receptor (BCR)-induced proliferation of mature B cells. Paradoxically, loss of NFAT transcription factors, themselves calcineurin targets, induces hyperactivity, which suggests that calcineurin targets other than NFAT are required for BCR-induced proliferation. Here we demonstrate a function for the calcineurin-regulated transcription factor Mef2c in B cells. BCR-induced calcium mobilization was intact after Mef2c deletion, but loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo. Mef2c activity was specific to BCR stimulation, as Toll-like receptor and CD40 signaling induced normal responses in Mef2c-deficient B cells. Mef2c-dependent targets included the genes encoding cyclin D2 and the prosurvival factor Bcl-x(L). Our results emphasize an unrecognized but critical function for Mef2c in BCR signaling.
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http://dx.doi.org/10.1038/ni.1609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518613PMC
June 2008

Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography.

Blood 2008 Mar 5;111(5):2909-18. Epub 2007 Dec 5.

Department of Medicine/Hematology and Oncology, University of Muenster, Albert-Schweitzer-Strasse 33, Muenster, Germany.

Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHD-associated inflammation in an allogeneic murine transplantation model by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in vivo. A predominant localization of intestinal GVHD to the colon was verified by histology and fluorescence reflectance imaging of enhanced green fluorescent protein (EGFP)-expressing donor cells. Colonic infiltration by EGFP(+) donor lymphocytes matched increased FDG uptake in PET examinations. These preclinical data were prospectively translated into 30 patients with suspected intestinal GVHD beyond 20 days after transplantation. A total of 14 of 17 patients with a diagnostic histology showed significant FDG uptake of the gut, again predominantly in the colon. No increased FDG uptake was detected in 13 patients without histologic evidence of intestinal GVHD. Our findings indicate that FDG-PET is a sensitive and specific noninvasive imaging technique to assess intestinal GVHD, map its localization, and predict and monitor treatment responsiveness. Novel targeted tracers for PET may provide new insights into the pathophysiology of GVHD and bear the potential to further improve GVHD diagnosis.
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http://dx.doi.org/10.1182/blood-2007-10-119164DOI Listing
March 2008

Differential requirement for a cellular type-1 immune response in tumor-associated versus alloantigen-targeted GvT effects.

Transplantation 2007 Feb;83(3):314-22

Department of Medicine/Hematology and Oncology, University of Muenster, Germany.

Background: The major obstacles that impair successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies remain graft-versus-host disease (GvHD) and tumor relapse. Improved survival after allogeneic HSCT therefore requires more effective control of GvHD while preserving graft-versus-tumor (GvT) effects.

Methods: Allogeneic parent-into-F1 murine transplant models (BALB/c or C57BL/6 --> F1[BALB/cxC57BL/6]) were used to evaluate the interrelation of GvHD and GvT effects targeting tumor-specific antigens or alloantigens on MethA tumor cells.

Results: Compared with syngeneic F1-into-F1 controls (F1[H-2(b/d)] --> F1: MethA[H-2d]), significant T cell-mediated GvT effects occurred in both allogeneic transplant models, even in the absence of histoincompatibilities between donor cells and host tumor (BALB/c[H-2d] --> F1: MethA[H-2d]). Selective inhibition of type-1 (Th-1/Tc1) immune responses with TAK-603 after HSCT nearly abolished GvHD in both allogeneic transplant models. While GvT effects directed against alloantigens (C57BL/6[H-2b] --> F1: MethA[H-2d]) remained unaffected during type-1-immune suppression, GvT effects targeted against tumor-associated antigens (BALB/c[H-2d] --> F1: MethA[H-2d]) were not evident. CONCLUSIONS.: Our data show that GvHD and GvT effects are in principle separable from each other by selective type-1 inhibition in transplantation models with major histocompatibility complex disparities between tumor, host, and donor. In contrast, in situations that only allow for GvT effects that exclusively target tumor-associated antigens (TAAs), type-1 inhibition results in complete abrogation not only of GvHD but also desired GvT reactions. These differences in GvT effects targeting alloantigens or TAAs and their interrelation to GvHD should be considered in future studies aimed at separating GvT reactions from GvHD.
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http://dx.doi.org/10.1097/01.tp.0000250725.95074.f1DOI Listing
February 2007

Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets.

Blood 2004 Aug 15;104(4):1210-6. Epub 2004 Apr 15.

Department of Medicine/Hematology and Oncology, University of Münster, Albert-Schweitzer-Str 33, D-48129 Münster, Germany.

Cure of hematologic malignancies after allogeneic hematopoietic stem cell transplantation is partially attributable to immunocellular antitumor reactions termed graft-versus-tumor (GvT) effect. GvT effects are heterogeneous with respect to effector cell populations, target antigens, and their interrelation with graft-versus-host disease (GvHD). In the present study, allogeneic parent-into-F1 murine transplantation models (BALB/c or C57BL/6 --> [C57BL/6 x BALB/c]F1) with different tumors derived from either parental strain were used to evaluate tumor-specific GvT effects. Compared with syngeneic F1-into-F1 controls, significant CD8+ T cell-mediated GvT effects occurred in both allogeneic transplantation models, even in the absence of histoincompatibilities between donor cells and host tumor. Identical genetic background of donor and tumor precluded allorecognition of tumor cells, indicating that tumor-associated antigens (TAAs) were targeted. With allowance made for selective major histocompatibility complex (MHC) disparities between donor cells and normal host tissue, GvHD was identified as a driving force for TAA-specific GvT effects. Adoptive transfer of the effector cells into secondary tumor-bearing recipients confirmed sustained antitumor activity and specificity of the T-cell response. The results provide experimental proof of a donor CD8+ T cell-mediated TAA-specific antitumor response in vivo that is driven by GvHD. It may represent one of the mechanisms contributing to GvT effects observed in allogeneic transplant recipients.
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http://dx.doi.org/10.1182/blood-2003-10-3387DOI Listing
August 2004

Retrotranslocation of MHC class I heavy chain from the endoplasmic reticulum to the cytosol is dependent on ATP supply to the ER lumen.

Mol Immunol 2004 Jan;40(10):733-41

Division of Molecular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

MHC class I heavy chains (HC) that fail to acquire a mature conformation in the endoplasmic reticulum (ER) as a result of defective folding or assembly with beta2-microglobulin, or lack of appropriate peptide cargo are retrotranslocated through the Sec61 channel to the cytosol for degradation by proteasomes. The mechanisms involved in ER retrotranslocation of HC are as yet incompletely understood. Using a microsomal system, we characterized the molecular requirements for the release of HC into the soluble fraction. Extraction of ubiquitinated HC was facilitated by cytosol, or by addition of proteins that stabilized the membrane association of the cytoplasmic ATPase p97. Functional proteasomes were not needed for HC mobilization. ATP supply to the ER lumen was found to be an essential factor since an inhibitor of the ATP importing pump in the ER membrane blocked HC release. Also non-hydrolyzable ATP analogs delivered to the ER lumen facilitated HC export suggesting that ATP binding by ER chaperones rather than ATP hydrolysis is involved.
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http://dx.doi.org/10.1016/j.molimm.2003.08.008DOI Listing
January 2004