Werner Krenger
Boston Children's Hospital
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Featured researches published by Werner Krenger.
Stem Cells | 1996
James L.M. Ferrara; Kenneth R. Cooke; Luying Pan; Werner Krenger
The major complication after allogeneic bone marrow transplantation (BMT) is the development of graft‐versus‐host‐disease (GVHD). This disease is initiated during the conditioning of the recipient, when host tissues are damaged. During the afferent phase of the disease, alloreactive donor T cells recognize foreign major and minor histocompatibility antigens of host tissues. The efferent phase includes activation of inflammatory effector cells as well as the secretion of cytopathic molecules which induce pathology in skin, gastrointestinal tract, liver, lung, and the immune system. Substantial experimental and clinical evidence now indicates a central role of cytokines in the immunopathophysiology of acute GVHD, which forms the basis of this review. The balance between cytokines released by T helper 1 (Th1) cells (interleukin 2, interferon‐γ) or by T helper 2 (Th2) cells (interleukin 4, interleukin 10) after allogeneic BMT is hypothesized to govern the extent of the systemic inflammatory response. Because Th2 cytokines can inhibit the production of proinflammatory cytokines such as interleukin 1 and tumor necrosis factor‐α, a Th1→Th2 shift in the initial response of donor T cells may interrupt the cytokine cascade and thus offer a new approach to the prevention and treatment of acute GVHD. Successful interventions to modify the response of donor T cells may obviate the need for T cell depletion and thereby avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.
Immunologic Research | 1996
Werner Krenger; James L.M. Ferrara
Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation (BMT) and is initiated by alloreactive donor T cells recognizing foreign histocompatibility antigens of the host. There is now substantial experimental and clinical evidence to implicate a dysregulation of cytokine networks as a primary cause for the induction and maintenance of GVHD. In this article, current knowledge of the involvement of cytokines in GVHD is reviewed. The balance between type 1 cytokines (interleukin-2, interferon-γ) and type 2 cytokines (interleukin-4, interleukin-10) is hypothesized to govern the extent to which a cell-mediated immune response and a systemic inflammatory response develop after allogeneic BMT. Because type 2 cytokines can inhibit the production of the proinflammatory cytokines interleukin-1 and tumor necrosis factor-α, a type 1 to type 2 shift in the initial response of donor T cells to host alloantigens may interrupt the cytokine cascade after allogeneic BMT and may offer a new approach to the prevention and treatment of acute GVHD. Interventions to specifically eliminate or modify the response of donor T cells to alloantigens in order to reduce GVHD may obviate the need for T cell depletion in clinical BMT and thus avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.
Blood | 2011
Werner Krenger; Bruce R. Blazar; Georg A. Holländer
Cytoreductive conditioning regimens used in the context of allogeneic hematopoietic cell transplantation (HCT) elicit deficits in innate and adaptive immunity, which predispose patients to infections. As such, transplantation outcomes depend vitally on the successful reconstruction of immune competence. Restoration of a normal peripheral T-cell pool after HCT is a slow process that requires the de novo production of naive T cells in a functionally competent thymus. However, there are several challenges to this regenerative process. Most notably, advanced age, the cytotoxic pretransplantation conditioning, and posttransplantation alloreactivity are risk factors for T-cell immune deficiency as they independently interfere with normal thymus function. Here, we discuss preclinical allogeneic HCT models and clinical observations that have contributed to a better understanding of the transplant-related thymic dysfunction. The identification of the cellular and molecular mechanisms that control regular thymopoiesis but are altered in HCT patients is expected to provide the basis for new therapies that improve the regeneration of the adaptive immune system, especially with functionally competent, naive T cells.
Transplantation | 1994
Werner Krenger; Kurt Snyder; Sidney Smith; James L.M. Ferrara
IL-10 is a regulatory cytokine of both T cells and monocytes. We have investigated the ability of IL-10 to regulate responses to alloantigens in vitro and in vivo. Addition of IL-10 to mixed lymphocyte cultures profoundly decreased the proliferation and IL-2 production by donor B10.BR cells stimulated with CBA cells expressing minor histocompatibility antigens. Administration of IL-10 for a period of 2 weeks after bone marrow transplantation decreased the expansion of CD4+ and CD8+ donor T cells. In addition, splenocytes from BMT mice treated with IL-10 secreted less IFN-γ after stimulation with Con A in vitro. The suppression of the mitogen-driven proliferative response of lymphocytes from the IL-10-treated group could also be reversed with significantly less anti-IFN-γ antibody than for saline-treated controls. However, treatment with IL-10 was not sufficient to alter significantly the clinical course of graft-versus-host disease in CBA recipient mice as assessed by survival, weight loss, and splenomegaly. The results suggest that exogenous IL-10 suppresses the afferent Th1 response in a graftversus-host reaction but does not significantly diminish the effector stage of graft-versus-host disease.
Transplantation | 1996
Werner Krenger; Kenneth R. Cooke; James M. Crawford; Stephen T. Sonis; Ray Simmons; Luying Pan; John Delmonte; Mahesh Karandikar; James L.M. Ferrara
Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage.
Transfusion Medicine Reviews | 1998
James L.M. Ferrara; Werner Krenger
G RAFT-VERSUS-HOST DISEASE (GVHD) has been associated with the infusion of unirradiated cellular blood products. ~ Manifestations of GVHD usually occur several weeks after the transfusion, and include rash, diarrhea, fever, liver abnormalities, and eventually pancytopenia. There is an extremely high fatality rate for transfusion-associated GVHD. 2 Transfusion from HLA homozygous donors into HLA heterozygous recipients who share one HLA haplotype with the donor are at particular risk for this complication. The development of GVHD in this setting is almost invariably fatal, despite therapy with high-dose corticosteroids and cyclosporine. GVHD is initiated by alloreactive donor T cells recognizing foreign major histocompatibility complex (MHC) antigens and/or minor histocompatibility antigens (minor HA) of the host. The subsequent induction of inflammatory effector mechanisms ultimately culminates in a complex syndrome in which specific host tissues, including the skin, liver, lung, gastrointestinal tract, and the immune system itself, are severely damaged. There is now substantial evidence to implicate the inappropriate production of cytokines, which are the central regulatory molecules of the immune system, as a primary cause for the induction and maintenance of experimental and clinical GVHD. 3-5 Dysregulation of complex cytokine networks occurring at different steps in the sequence is thought to be responsible for the manifestations of this disease. Because of the central role of cytokines in the pathophysiology of GVHD, advances in the understanding of cytokine networks should enable us to optimize preventive and therapeutic strategies. As will be discussed later in more detail, several protocols that include the intervention in cytokinemediated processes during the effector phase of GVHD have been initiated with varying success. The nature of the cytokine cascade makes it difficult to intervene in GVHD once clinical signs appear. Recent breakthroughs in the understanding of T-cell cytokine networks, particularly with the emergence of the Thl/Th2 paradigm, may provide valuable new tools for the directed intervention in
Current Opinion in Pharmacology | 2010
Georg A. Holländer; Werner Krenger; Bruce R. Blazar
The thymus constitutes the primary lymphoid organ for the generation of T cells. Its function is particularly susceptible to various negative influences ranging from age-related involution to atrophy as a consequence of malnutrition, infection or harmful iatrogenic influences such as chemotherapy and radiation. The loss of regular thymus function significantly increases the risk for infections and cancer because of a restricted capacity for immune surveillance. In recent years, thymus-stimulatory, thymus-regenerative, and thymus-protective strategies have been developed to enhance and repair thymus function in the elderly and in individuals undergoing hematopoietic stem cell transplantation. These strategies include the use of sex steroid ablation, the administration of growth and differentiation factors, the inhibition of p53, and the transfer of T cell progenitors to alleviate the effects of thymus dysfunction and consequent T cell deficiency.
Journal of Immunology | 2009
Saulius Zuklys; Jason Gill; Marcel P. Keller; Mathias Hauri-Hohl; Saule Zhanybekova; Gina Balciunaite; Kyung Jae Na; Lukas T. Jeker; Katrin Hafen; Noriyuki Tsukamoto; Takashi Amagai; Makoto M. Taketo; Werner Krenger; Georg A. Holländer
Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation of the canonical Wnt signaling pathway by a stabilizing mutation of β-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function.
Seminars in Immunopathology | 2008
Werner Krenger; Georg A. Holländer
The clinical success of allogeneic hematopoietic stem cell transplantation (HSCT) depends on the appropriate reconstitution of the host’s immune system. While recovery of T-cell immunity may occur in transplant recipients via both thymus-dependent and thymus-independent pathways, the regeneration of a population of phenotypically naive T cells with a broad receptor repertoire relies entirely on the de novo generation of T-cells in the thymus. Preclinical models and clinical studies of allogeneic HSCT have identified the thymus as a target of graft-versus-host disease (GVHD), thus limiting T-cell regeneration. The present review focuses on recent insight into how GVHD affects thymic structure and function and how this knowledge may aid in the design of new strategies to improve T-cell reconstitution following allogeneic HSCT.
Transplantation | 2000
Werner Krenger; Rossi S; Georg A. Holländer
BACKGROUND Elimination of immature thymocytes resulting in thymic atrophy is characteristic of acute graft-versus-host disease (aGVHD). Because aGVHD has been associated with elevated glucocorticoid (GC) production, and CD4,CD8 double-positive thymocytes undergo rapid apoptosis in response to GCs, we hypothesized that administration of the GC receptor antagonist RU486 (mifepristone) should alter aGVHD-mediated thymocyte apoptosis. METHODS Thymic development in the presence of aGVHD was studied in a haploidentical nonirradiated murine transplantation model (C57BL/6-->B6D2F1). Recipients were treated with RU486 or vehicle alone. Thymic development was analyzed by flow cytometry at different times post transplant. RESULTS Acute thymic GVHD was characterized (1) by infiltration of mature donor-derived T cells and (2) by increased apoptosis of immature CD4+CD8+ thymocytes between 1 and 2 weeks after allogeneic transplantation. Contrary to expectations, administration of RU486 had no effect on these two parameters. CONCLUSIONS Our data suggest that thymic pathology during aGVHD is mediated via a glucocorticoid-independent mechanism of apoptosis as blockade of glucocorticoid receptors did not alter the GVHD-induced thymic phenotype.