Werner Krenger | University of Basel, Switzerland (original) (raw)
Papers by Werner Krenger
Blood
The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound ... more The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound deficits in immune function that lead to increased morbidity and mortality after bone marrow transplantation (BMT). We investigated a mechanism of T-cell immunodeficiency in response to mitogen or alloantigen in an experimental model of acute GVHD by analyzing the roles of two immunosuppressive moieties: interferon gamma (IFN-gamma) and nitric oxide (NO). Splenocytes from mice with GVHD did not proliferate either to the T-cell mitogen, concanavalin A (Con A), or to host alloantigens, but only mitogen-activated cultures produced increased levels of NO. The abrogation of NO synthesis with LG-mono-methyl-arginine (NMMA) restored mitogen-induced proliferation but not the response to host antigens. The mechanism of impared proliferation to mitogen was dependent on IFN-gamma because blockade of this cytokine in culture inhibited NO production and restored proliferation to Con A to levels simil...
Blood
Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated th... more Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as important effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (slg+) B cells was observed in GVHD spleens isolated 2 weeks after transplant. However, proliferation of these cells in response to LPS was suppressed by more than 35-fold. Activated GVHD splenocytes secreted large amounts of TNF-alpha and NO in culture. Neutralization of TNF-alpha with anti-TNF-alpha antibody (Ab) both abrogated NO production and restored LPS-induced proliferation of B cells to levels found in non-GVHD control mice. The specific inhibition of NO synthesis with LG-monomethyl-arginine (NMMA) restored splenocyte respo...
Cytokines Cellular & Molecular Therapy
Graft-versus-host disease (GVHD) remains the principal complication limiting the wider applicatio... more Graft-versus-host disease (GVHD) remains the principal complication limiting the wider application of allogeneic bone marrow transplantation (BMT). Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. This article reviews current evidence that dysregulated cytokine production can be considered a cascade of sequential monocyte and T-cell activation that is responsible for many of the manifestations of acute GVHD. We suggest that cytokine dysregulation can be conceptualized in three phases. Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in phase 2 is facilitated by the consequences of phase 1. The T-cell-derived cytokines of phase 2 activate...
Blood
We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice ca... more We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-gamma. Cytotoxic T lymphocyte (CTL)...
Blood
Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone ... more Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was ...
The Journal of Immunology
Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type ... more Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice ...
Blood, 2000
Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone ... more Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was ...
Blood, Jan 17, 2015
During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de ... more During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus, implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that medullary thymic epithelial cells expressing the autoimmune regulator (Aire(+)mTEC(high)) are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during aGVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data therefore indicate that a functional compromise of the medullary mTEC compartment may link alloimmunity to the development of autoimmunity...
Swiss medical weekly, Jan 10, 2006
Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus be... more Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus before they exit into the periphery as functional T lymphocytes. Thymic stroma cells, the majority being of epithelial origin, provide the functional partners for the maturational progression along this differentiation pathway. Here we review some of the molecular and cellular mechanisms that account for thymus organogenesis and discuss a strategy to use thymic epithelial precursor cells for the regeneration of the thymic microenvironment.
Transplantation, Jan 15, 1999
Costimulation through CD40-CD154 plays an important role in T-cell activation. Although systemic ... more Costimulation through CD40-CD154 plays an important role in T-cell activation. Although systemic administration of anti-CD154 antibody prevents or delays rejection of organ allografts in animal models, the molecular mechanisms responsible for this effect are not well defined. We have previously demonstrated that priming of mice (H2d) with CD40-/- but not with wildtype naive B cells (H2b) leads to alloantigen-specific T-cell hyporesponsiveness in vitro. In the present study, we investigated whether such priming modifies allograft rejection in a major histocompatibility complex-mismatched murine cardiac transplantation model. Priming of hosts with donor-specific CD40-/- B cells delayed rejection of subsequently transplanted wild-type cardiac allografts by 8.0 days (P<0.001). The lack of CD40 on the cardiac graft delayed rejection in unprimed or primed hosts by 3-5 days. Prolongation of graft survival correlated with the failure of infused CD40-/- B cells to express B7.2 and ICAM-1 ...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 1996
Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplanta... more Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated dono...
Transfusion, 2013
Scientific progress in the biology of hematopoietic stem cells (HSCs) provides opportunities for ... more Scientific progress in the biology of hematopoietic stem cells (HSCs) provides opportunities for advances in therapy for different diseases. While stem cell sources such as umbilical cord blood (UCB) are unproblematic, other sources such as human embryonic stem cells (hESCs) raise ethical concerns. In a prospective survey we established the ethical acceptability of collection, research, and therapy with UCB HSCs versus hESCs among health care professionals, pregnant women, patients undergoing in vitro fertilization therapy, parents, and HSC donors and recipients in Switzerland. There was overall agreement about an ethical justification for the collection of UCB for research and therapy in the majority of participants (82%). In contrast, research and therapy with hESCs was acceptable only by a minority (38% of all responders). The collection of hESCs solely created for HSC collection purposes met overall with the lowest approval rates. Hematologists displayed among the participants t...
Transplantation, 1996
Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells ... more 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&amp;lt;0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR--&amp;gt;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.
Transplantation, 1997
Transplantation. Wolters Kluwer Health Logo. All Issues. ...
Transplantation, 2000
Elimination of immature thymocytes resulting in thymic atrophy is characteristic of acute graft-v... more 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. 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. 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. 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.
Transplantation, 1994
IL-10 is a regulatory cytokine of both T cells and monocytes. We have investigated the ability of... more 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-gamma 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-gamma 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 graft-versus-host reaction but does not significantly diminish the effector stage of graft-versus-host disease.
Transfusion Medicine Reviews, 1998
Transfusion, 2013
BACKGROUND: Two competitive concepts of umbilical cord blood (UCB) banking are currently availabl... more BACKGROUND: Two competitive concepts of umbilical cord blood (UCB) banking are currently available: either allogeneic UCB is donated to a public bank or autologous cells are stored in a private bank. Allogeneicautologous hybrid banking is a new concept that combines these two approaches. However, acceptance of hybrid UCB banking among potential donors is unknown to date. STUDY DESIGN AND METHODS: In a prospective survey, we aimed to establish the acceptance of the hybrid banking model among actual and potential UCB donors in Switzerland. The study groups consisted of parents and pregnant women with or without children. As control group, women at reproductive ages were investigated. RESULTS: The majority of participants agreed fundamentally with UCB donation, and overall acceptance of private banking was 47%. If a possibility for hybrid banking were to be made available, 49% would opt for such a public-private model and only 13% would choose private banking alone. Among the proponents of hybrid banking, a majority of participants chose donor cell splitting over the sequential banking mode. Fifty-six percent of responders wished prior notification before the release of their donated UCB to a foreign recipient. CONCLUSIONS: This is the first study which compared the acceptance of allogeneic, autologous, and hybrid allogeneic-autologous UCB banking in different target groups. We demonstrated that hybrid cord blood banking is the preferred model of banking among actual and potential UCB donors. With increasing demand for UCB in the future, health care providers should therefore consider offering hybrid banking as a viable storage option. ABBREVIATION: UCB = umbilical cord blood.
Blood
The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound ... more The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound deficits in immune function that lead to increased morbidity and mortality after bone marrow transplantation (BMT). We investigated a mechanism of T-cell immunodeficiency in response to mitogen or alloantigen in an experimental model of acute GVHD by analyzing the roles of two immunosuppressive moieties: interferon gamma (IFN-gamma) and nitric oxide (NO). Splenocytes from mice with GVHD did not proliferate either to the T-cell mitogen, concanavalin A (Con A), or to host alloantigens, but only mitogen-activated cultures produced increased levels of NO. The abrogation of NO synthesis with LG-mono-methyl-arginine (NMMA) restored mitogen-induced proliferation but not the response to host antigens. The mechanism of impared proliferation to mitogen was dependent on IFN-gamma because blockade of this cytokine in culture inhibited NO production and restored proliferation to Con A to levels simil...
Blood
Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated th... more Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as important effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (slg+) B cells was observed in GVHD spleens isolated 2 weeks after transplant. However, proliferation of these cells in response to LPS was suppressed by more than 35-fold. Activated GVHD splenocytes secreted large amounts of TNF-alpha and NO in culture. Neutralization of TNF-alpha with anti-TNF-alpha antibody (Ab) both abrogated NO production and restored LPS-induced proliferation of B cells to levels found in non-GVHD control mice. The specific inhibition of NO synthesis with LG-monomethyl-arginine (NMMA) restored splenocyte respo...
Cytokines Cellular & Molecular Therapy
Graft-versus-host disease (GVHD) remains the principal complication limiting the wider applicatio... more Graft-versus-host disease (GVHD) remains the principal complication limiting the wider application of allogeneic bone marrow transplantation (BMT). Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. This article reviews current evidence that dysregulated cytokine production can be considered a cascade of sequential monocyte and T-cell activation that is responsible for many of the manifestations of acute GVHD. We suggest that cytokine dysregulation can be conceptualized in three phases. Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in phase 2 is facilitated by the consequences of phase 1. The T-cell-derived cytokines of phase 2 activate...
Blood
We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice ca... more We have previously shown in a murine acute myelogenous leukemia (AML) model that leukemic mice can be cured with a B7 vaccine if immunized early in the disease and that CD8+ T cells are necessary for tumor rejection. However, when B7 vaccine is administered 2 weeks after leukemia inoculation, the effect is only prolonged survival, ending in death virtually of all the mice. To distinguish between tumor kinetics and tumor-induced immunosuppression as potential mechanisms eliminating the therapeutic potential of late B7 vaccines, we performed in vitro T-cell studies during leukemia progression and in vivo studies on the clinical outcome of late B7 vaccines in combination with prior cytoreductive chemotherapy. Our results show that CD8+ T cells from leukemic mice 1 and 2 weeks after leukemia inoculation proliferate more vigorously in response to in vitro activation than cells from normal mice and produce Th1-type cytokines interleukin-2 and interferon-gamma. Cytotoxic T lymphocyte (CTL)...
Blood
Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone ... more Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was ...
The Journal of Immunology
Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type ... more Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice ...
Blood, 2000
Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone ... more Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was ...
Blood, Jan 17, 2015
During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de ... more During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus, implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that medullary thymic epithelial cells expressing the autoimmune regulator (Aire(+)mTEC(high)) are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during aGVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data therefore indicate that a functional compromise of the medullary mTEC compartment may link alloimmunity to the development of autoimmunity...
Swiss medical weekly, Jan 10, 2006
Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus be... more Haematopoietic precursors have to undergo a complex series of maturational steps in the thymus before they exit into the periphery as functional T lymphocytes. Thymic stroma cells, the majority being of epithelial origin, provide the functional partners for the maturational progression along this differentiation pathway. Here we review some of the molecular and cellular mechanisms that account for thymus organogenesis and discuss a strategy to use thymic epithelial precursor cells for the regeneration of the thymic microenvironment.
Transplantation, Jan 15, 1999
Costimulation through CD40-CD154 plays an important role in T-cell activation. Although systemic ... more Costimulation through CD40-CD154 plays an important role in T-cell activation. Although systemic administration of anti-CD154 antibody prevents or delays rejection of organ allografts in animal models, the molecular mechanisms responsible for this effect are not well defined. We have previously demonstrated that priming of mice (H2d) with CD40-/- but not with wildtype naive B cells (H2b) leads to alloantigen-specific T-cell hyporesponsiveness in vitro. In the present study, we investigated whether such priming modifies allograft rejection in a major histocompatibility complex-mismatched murine cardiac transplantation model. Priming of hosts with donor-specific CD40-/- B cells delayed rejection of subsequently transplanted wild-type cardiac allografts by 8.0 days (P<0.001). The lack of CD40 on the cardiac graft delayed rejection in unprimed or primed hosts by 3-5 days. Prolongation of graft survival correlated with the failure of infused CD40-/- B cells to express B7.2 and ICAM-1 ...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 1996
Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplanta... more Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated dono...
Transfusion, 2013
Scientific progress in the biology of hematopoietic stem cells (HSCs) provides opportunities for ... more Scientific progress in the biology of hematopoietic stem cells (HSCs) provides opportunities for advances in therapy for different diseases. While stem cell sources such as umbilical cord blood (UCB) are unproblematic, other sources such as human embryonic stem cells (hESCs) raise ethical concerns. In a prospective survey we established the ethical acceptability of collection, research, and therapy with UCB HSCs versus hESCs among health care professionals, pregnant women, patients undergoing in vitro fertilization therapy, parents, and HSC donors and recipients in Switzerland. There was overall agreement about an ethical justification for the collection of UCB for research and therapy in the majority of participants (82%). In contrast, research and therapy with hESCs was acceptable only by a minority (38% of all responders). The collection of hESCs solely created for HSC collection purposes met overall with the lowest approval rates. Hematologists displayed among the participants t...
Transplantation, 1996
Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells ... more 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&amp;lt;0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR--&amp;gt;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.
Transplantation, 1997
Transplantation. Wolters Kluwer Health Logo. All Issues. ...
Transplantation, 2000
Elimination of immature thymocytes resulting in thymic atrophy is characteristic of acute graft-v... more 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. 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. 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. 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.
Transplantation, 1994
IL-10 is a regulatory cytokine of both T cells and monocytes. We have investigated the ability of... more 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-gamma 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-gamma 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 graft-versus-host reaction but does not significantly diminish the effector stage of graft-versus-host disease.
Transfusion Medicine Reviews, 1998
Transfusion, 2013
BACKGROUND: Two competitive concepts of umbilical cord blood (UCB) banking are currently availabl... more BACKGROUND: Two competitive concepts of umbilical cord blood (UCB) banking are currently available: either allogeneic UCB is donated to a public bank or autologous cells are stored in a private bank. Allogeneicautologous hybrid banking is a new concept that combines these two approaches. However, acceptance of hybrid UCB banking among potential donors is unknown to date. STUDY DESIGN AND METHODS: In a prospective survey, we aimed to establish the acceptance of the hybrid banking model among actual and potential UCB donors in Switzerland. The study groups consisted of parents and pregnant women with or without children. As control group, women at reproductive ages were investigated. RESULTS: The majority of participants agreed fundamentally with UCB donation, and overall acceptance of private banking was 47%. If a possibility for hybrid banking were to be made available, 49% would opt for such a public-private model and only 13% would choose private banking alone. Among the proponents of hybrid banking, a majority of participants chose donor cell splitting over the sequential banking mode. Fifty-six percent of responders wished prior notification before the release of their donated UCB to a foreign recipient. CONCLUSIONS: This is the first study which compared the acceptance of allogeneic, autologous, and hybrid allogeneic-autologous UCB banking in different target groups. We demonstrated that hybrid cord blood banking is the preferred model of banking among actual and potential UCB donors. With increasing demand for UCB in the future, health care providers should therefore consider offering hybrid banking as a viable storage option. ABBREVIATION: UCB = umbilical cord blood.