Acute rejection of transplanted bone marrow cell (BMC) grafts can occur within 48 h in unsensitiz... more Acute rejection of transplanted bone marrow cell (BMC) grafts can occur within 48 h in unsensitized, lethally irradiated mice, and NK cells have been implicated as the effector cells. Recently, we observed that both CD8+ TCR-alpha beta+ T and NK cells of irradiated mice could rapidly reject allogeneic lymph node cell grafts. In this study, we evaluated the ability of NK and CD8+ T cells to mediate rejection of H2k or H2k/b BMC grafts by pretreating groups of mice with depleting mAbs. H2k BMC were transplanted into syngeneic, B6 (H2b), BALB/c (H2d), NZB (H2d), and (NZB x B6)F1 (NZB6F1, H2d/b) hosts. Proliferation measured 5 days after cell transfer indicated that syngeneic, B6, and BALB/c hosts accepted H2k BMC grafts. However, CD8+ T cells from NZB and poly I:C-treated BALB/c hosts, and NK cells from poly I:C-treated NZB6F1, hosts, rejected H2k BMC grafts. In NZB6F1 hosts, there was an added effect of anti-TCR-alpha beta and anti-NK1.1 mAbs. It is possible that T and NK cells cooperate in rejecting H2k or H2k/b BMC grafts in certain hosts. Transplantation of H2k/b, but not H2k/d, BMC into similar recipients had the same fate as H2k BMC. Thus, certain CD8+ T cells may share a similar recognition system with NK cells.
Lethally irradiated mice can reject H-2 allogeneic or parental strain stem cells in bone marrow c... more Lethally irradiated mice can reject H-2 allogeneic or parental strain stem cells in bone marrow cell (BMC) grafts within 48 h after transplantation. This rapid rejection of BMC grafts occurs without prior sensitization and is mediated by NK1.1+ NK cells. One hypothesis to account for the ability of host NK cells to mediate acute rejection of allogenic and parental stem cells is that these effector cells recognize hemopoietic histocompatibility (Hh-1) Ags on the donor stem cells. T cells present in the donor BMC can prevent NK cell-mediated rejection. However, lethally irradiated mice can also reject T cells present in lymph node cell preparations that respond to alloantigens of the host. T cell grafts from H-2k/Hh-1k, H-2r/Hh-1null, and H-2ia1/Hh-1null donors were rejected by CD8+ NK1.1- T cells. Ags other than Hh-1 Ags appeared to be recognized by these CD8+ T cells. In contrast, host NK cells rejected H-2d/Hh-1d T cell grafts, whereas both NK cells and CD8+ TCR-alpha beta + T cells rejected H-2b/Hh-1b T cell grafts. Therefore, both CD8+ TCR-alpha beta T cells and NK cells mediate allogeneic and hybrid resistance to T cell grafts.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 1997
T cells present in bone marrow cell (BMC) grafts promote engraftment in histoincompatible hosts, ... more T cells present in bone marrow cell (BMC) grafts promote engraftment in histoincompatible hosts, but they or other T cells may also initiate lethal graft-vs.-host disease (GVHD). The purpose of this study was to determine whether T cells from donors tolerant of host alloantigens were able to prevent natural killer (NK) cell-mediated rejection of BMC grafts without causing GVHD. Previous studies have shown that H2d C.B-17 SCID BMC grafts were rejected by (BALB/c x B6)F1 (CB6F1,H2d/b) host NK cells, and that this rejection was reversed by adding H2d T cells to the donor inoculum. T cells tolerant of H2d/b alloantigens were produced by irradiating (3 Gy) BALB/c newborn mice, and infusing CB6F1 BMCs. Tolerance was assessed by donor (H2b+) cell chimerism, acceptance of CB6F1 skin grafts, the inability of adoptively transferred lymphocytes to initiate GVHD in irradiated CB6F1 mice, and the inability of spleen or thymus cells to generate cytolytic T lymphocytes against H2b target cells in ...
Real-World Evidence (RWE), which has historically been used to support post approval safety studi... more Real-World Evidence (RWE), which has historically been used to support post approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review ...
Clinical and Experimental Pharmacology and Physiology, 1999
1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One... more 1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One major limitation in transplantation is chronic rejection involving the loss of the graft despite the use of immunosuppressive agents. Haematopoietic stem cell (HSC) chimerism, achieved through bone marrow transplantation (BMT), induces donor-specific tolerance to transplanted organs and prevents chronic rejection. 2. A second major limitation to organ transplantation is the donor shortage. Xenotransplantation, the transplantation of organs between different species, would have the ability to increase the availability of donor organs. 3. Current immunosuppressive therapies do not prevent the rejection of xenografts. Therefore, the only reliable method for achieving donor-specific tolerance to xenografts may require HSC chimerism. 4. In order to justify the use of BMT to induce transplantation tolerance in patients with non-life-threatening diseases, the morbidity and mortality associated with current conditioning regimens must be addressed. 5. The use of partial conditioning regimens to promote engraftment of xenogeneic HSC and the development of donor-specific tolerance may eventually make xenotransplantation in humans a clinical reality. 6. Additional advantages of xenotransplantation are the ability to genetically engineer the donor xenograft and resistance of some xenografts to infection by human viruses because of the species specificity of most viruses. 7. The clinical application of disease resistance for HIV and hepatitis B virus is the focus of the present review.
Natural killer (NK) cells of inbred mice reject allogeneic bone-marrow cells, and NK cells of F1 ... more Natural killer (NK) cells of inbred mice reject allogeneic bone-marrow cells, and NK cells of F1 hybrid mice can reject parental bone-marrow cells (hybrid resistance). In some cases these patterns of rejection can be mimicked in vitro by utilizing IL-2 cultured NK effector cells and allogeneic or parental T-lymphoblasts as target cells. Lysis of allogeneic and parental targets in vitro can be explained on the basis of the missing self hypothesis. Subsets of NK cells that bear non-overlapping MHC class I inhibitory receptors belonging to the Ly49 family lyse allogeneic targets because they do not express self class I molecules of the NK cell donor. Parental strain targets are lysed because they do not express all of the self class I antigens of the F1 hybrid, and hence fail to deliver inhibitory signals to all subsets of F1 NK cells. The expression of Ly49 receptors on NK cells is regulated by host MHC to ensure maximal sensitivity to alterations in self class I molecules and to prevent autoreactivity. In many instances, however, the rejection of allogeneic bone marrow cells in vivo cannot be readily explained by the missing self hypothesis. In these instances, it appears that rejection is initiated by class I MHC receptors on NK cells that recognize allogeneic class I molecules as non-self, and activate rather than inhibit NK cell function.
The studies of hybrid resistance (HR) to murine bone marrow cell (BMC) grafts have been helpful i... more The studies of hybrid resistance (HR) to murine bone marrow cell (BMC) grafts have been helpful in elucidating the biology and genetics of natural killer (NK) cell mediated recognition of incompatible cells (1). The discovery and claim for HR is contrary to the laws of ...
“Disease has long been the deadliest enemy of mankind, infectious diseases make no distinctions a... more “Disease has long been the deadliest enemy of mankind, infectious diseases make no distinctions among people and recognize no borders. We have fought the causes and consequences of disease throughout history and must continue to do so with every available means. All civilized nations reject as intolerable the use of disease and biological weapons as instruments of war and terror.” (President George W. Bush; November 1, 2001)Successful biodefense will require the coordination of efforts between government, academic, medical, and industrial agencies focusing on improving the nation's infrastructure, response efforts, and scientific capability for dealing with bioterrorist agents. The United States Department of Health and Human Services will play a critical role in strengthening the currently available anti-bioterrorism programs as well as working with all sectors of the nation to improve state, local, and federal capabilities and medical tools needed to combat bioterrorism. The Food and Drug Administration (FDA), in particular, may need to develop new regulatory models that will allow expeditious approval of drugs, biologics, and vaccines with potential to combat the currently identified bioterrorism agents, without compromising standards of safety and efficacy. This review provides an overview of the types of select agents identified as potential candidates for use in a bioterrorist attack, the government agencies and systems already in place to respond in the event of an emergency, and the role of FDA and regulatory affairs professionals in furthering the nation's defense against bioterrorism.
Gastroenterology, Volume 120, Issue 5, Pages A688, April 2001, Authors:Holly A. McAdams; Alemsege... more Gastroenterology, Volume 120, Issue 5, Pages A688, April 2001, Authors:Holly A. McAdams; Alemseged Truneh; Jen P. Kou; Christopher Eichman; Colleen M. Davenport; SmithKline Beecham. ...
Acute rejection of transplanted bone marrow cell (BMC) grafts can occur within 48 h in unsensitiz... more Acute rejection of transplanted bone marrow cell (BMC) grafts can occur within 48 h in unsensitized, lethally irradiated mice, and NK cells have been implicated as the effector cells. Recently, we observed that both CD8+ TCR-alpha beta+ T and NK cells of irradiated mice could rapidly reject allogeneic lymph node cell grafts. In this study, we evaluated the ability of NK and CD8+ T cells to mediate rejection of H2k or H2k/b BMC grafts by pretreating groups of mice with depleting mAbs. H2k BMC were transplanted into syngeneic, B6 (H2b), BALB/c (H2d), NZB (H2d), and (NZB x B6)F1 (NZB6F1, H2d/b) hosts. Proliferation measured 5 days after cell transfer indicated that syngeneic, B6, and BALB/c hosts accepted H2k BMC grafts. However, CD8+ T cells from NZB and poly I:C-treated BALB/c hosts, and NK cells from poly I:C-treated NZB6F1, hosts, rejected H2k BMC grafts. In NZB6F1 hosts, there was an added effect of anti-TCR-alpha beta and anti-NK1.1 mAbs. It is possible that T and NK cells cooperate in rejecting H2k or H2k/b BMC grafts in certain hosts. Transplantation of H2k/b, but not H2k/d, BMC into similar recipients had the same fate as H2k BMC. Thus, certain CD8+ T cells may share a similar recognition system with NK cells.
Lethally irradiated mice can reject H-2 allogeneic or parental strain stem cells in bone marrow c... more Lethally irradiated mice can reject H-2 allogeneic or parental strain stem cells in bone marrow cell (BMC) grafts within 48 h after transplantation. This rapid rejection of BMC grafts occurs without prior sensitization and is mediated by NK1.1+ NK cells. One hypothesis to account for the ability of host NK cells to mediate acute rejection of allogenic and parental stem cells is that these effector cells recognize hemopoietic histocompatibility (Hh-1) Ags on the donor stem cells. T cells present in the donor BMC can prevent NK cell-mediated rejection. However, lethally irradiated mice can also reject T cells present in lymph node cell preparations that respond to alloantigens of the host. T cell grafts from H-2k/Hh-1k, H-2r/Hh-1null, and H-2ia1/Hh-1null donors were rejected by CD8+ NK1.1- T cells. Ags other than Hh-1 Ags appeared to be recognized by these CD8+ T cells. In contrast, host NK cells rejected H-2d/Hh-1d T cell grafts, whereas both NK cells and CD8+ TCR-alpha beta + T cells rejected H-2b/Hh-1b T cell grafts. Therefore, both CD8+ TCR-alpha beta T cells and NK cells mediate allogeneic and hybrid resistance to T cell grafts.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 1997
T cells present in bone marrow cell (BMC) grafts promote engraftment in histoincompatible hosts, ... more T cells present in bone marrow cell (BMC) grafts promote engraftment in histoincompatible hosts, but they or other T cells may also initiate lethal graft-vs.-host disease (GVHD). The purpose of this study was to determine whether T cells from donors tolerant of host alloantigens were able to prevent natural killer (NK) cell-mediated rejection of BMC grafts without causing GVHD. Previous studies have shown that H2d C.B-17 SCID BMC grafts were rejected by (BALB/c x B6)F1 (CB6F1,H2d/b) host NK cells, and that this rejection was reversed by adding H2d T cells to the donor inoculum. T cells tolerant of H2d/b alloantigens were produced by irradiating (3 Gy) BALB/c newborn mice, and infusing CB6F1 BMCs. Tolerance was assessed by donor (H2b+) cell chimerism, acceptance of CB6F1 skin grafts, the inability of adoptively transferred lymphocytes to initiate GVHD in irradiated CB6F1 mice, and the inability of spleen or thymus cells to generate cytolytic T lymphocytes against H2b target cells in ...
Real-World Evidence (RWE), which has historically been used to support post approval safety studi... more Real-World Evidence (RWE), which has historically been used to support post approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review ...
Clinical and Experimental Pharmacology and Physiology, 1999
1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One... more 1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One major limitation in transplantation is chronic rejection involving the loss of the graft despite the use of immunosuppressive agents. Haematopoietic stem cell (HSC) chimerism, achieved through bone marrow transplantation (BMT), induces donor-specific tolerance to transplanted organs and prevents chronic rejection. 2. A second major limitation to organ transplantation is the donor shortage. Xenotransplantation, the transplantation of organs between different species, would have the ability to increase the availability of donor organs. 3. Current immunosuppressive therapies do not prevent the rejection of xenografts. Therefore, the only reliable method for achieving donor-specific tolerance to xenografts may require HSC chimerism. 4. In order to justify the use of BMT to induce transplantation tolerance in patients with non-life-threatening diseases, the morbidity and mortality associated with current conditioning regimens must be addressed. 5. The use of partial conditioning regimens to promote engraftment of xenogeneic HSC and the development of donor-specific tolerance may eventually make xenotransplantation in humans a clinical reality. 6. Additional advantages of xenotransplantation are the ability to genetically engineer the donor xenograft and resistance of some xenografts to infection by human viruses because of the species specificity of most viruses. 7. The clinical application of disease resistance for HIV and hepatitis B virus is the focus of the present review.
Natural killer (NK) cells of inbred mice reject allogeneic bone-marrow cells, and NK cells of F1 ... more Natural killer (NK) cells of inbred mice reject allogeneic bone-marrow cells, and NK cells of F1 hybrid mice can reject parental bone-marrow cells (hybrid resistance). In some cases these patterns of rejection can be mimicked in vitro by utilizing IL-2 cultured NK effector cells and allogeneic or parental T-lymphoblasts as target cells. Lysis of allogeneic and parental targets in vitro can be explained on the basis of the missing self hypothesis. Subsets of NK cells that bear non-overlapping MHC class I inhibitory receptors belonging to the Ly49 family lyse allogeneic targets because they do not express self class I molecules of the NK cell donor. Parental strain targets are lysed because they do not express all of the self class I antigens of the F1 hybrid, and hence fail to deliver inhibitory signals to all subsets of F1 NK cells. The expression of Ly49 receptors on NK cells is regulated by host MHC to ensure maximal sensitivity to alterations in self class I molecules and to prevent autoreactivity. In many instances, however, the rejection of allogeneic bone marrow cells in vivo cannot be readily explained by the missing self hypothesis. In these instances, it appears that rejection is initiated by class I MHC receptors on NK cells that recognize allogeneic class I molecules as non-self, and activate rather than inhibit NK cell function.
The studies of hybrid resistance (HR) to murine bone marrow cell (BMC) grafts have been helpful i... more The studies of hybrid resistance (HR) to murine bone marrow cell (BMC) grafts have been helpful in elucidating the biology and genetics of natural killer (NK) cell mediated recognition of incompatible cells (1). The discovery and claim for HR is contrary to the laws of ...
“Disease has long been the deadliest enemy of mankind, infectious diseases make no distinctions a... more “Disease has long been the deadliest enemy of mankind, infectious diseases make no distinctions among people and recognize no borders. We have fought the causes and consequences of disease throughout history and must continue to do so with every available means. All civilized nations reject as intolerable the use of disease and biological weapons as instruments of war and terror.” (President George W. Bush; November 1, 2001)Successful biodefense will require the coordination of efforts between government, academic, medical, and industrial agencies focusing on improving the nation's infrastructure, response efforts, and scientific capability for dealing with bioterrorist agents. The United States Department of Health and Human Services will play a critical role in strengthening the currently available anti-bioterrorism programs as well as working with all sectors of the nation to improve state, local, and federal capabilities and medical tools needed to combat bioterrorism. The Food and Drug Administration (FDA), in particular, may need to develop new regulatory models that will allow expeditious approval of drugs, biologics, and vaccines with potential to combat the currently identified bioterrorism agents, without compromising standards of safety and efficacy. This review provides an overview of the types of select agents identified as potential candidates for use in a bioterrorist attack, the government agencies and systems already in place to respond in the event of an emergency, and the role of FDA and regulatory affairs professionals in furthering the nation's defense against bioterrorism.
Gastroenterology, Volume 120, Issue 5, Pages A688, April 2001, Authors:Holly A. McAdams; Alemsege... more Gastroenterology, Volume 120, Issue 5, Pages A688, April 2001, Authors:Holly A. McAdams; Alemseged Truneh; Jen P. Kou; Christopher Eichman; Colleen M. Davenport; SmithKline Beecham. ...
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