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  1. Article ; Online: In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation.

    Shatry, Alwi / Levy, Robert B

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2009  Volume 15, Issue 7, Page(s) 785–794

    Abstract: Host antidonor effector T cells represent a major barrier to the successful engraftment of allogeneic donor hematopoietic progenitor and stem cells. Here, administration of a complex of IL-2 and anti-IL 2 antibodies (IAC) significantly enhanced donor ... ...

    Abstract Host antidonor effector T cells represent a major barrier to the successful engraftment of allogeneic donor hematopoietic progenitor and stem cells. Here, administration of a complex of IL-2 and anti-IL 2 antibodies (IAC) significantly enhanced donor chimerism early as well as long-term engraftment following reduced-intensity conditioning (RIC) and allogeneic major histocompatibility complex (MHC)-matched hematopoietic cell transplantion (HCT). Timing of administration of this complex was crucial: administration of IAC post-HCT more efficiently facilitated marrow engraftment than pre-HCT treatment. Donor chimerism persisted to >6 months post-HCT. Importantly, this approach clearly suppressed the emergence of host antidonor CD8 T cells 2 to 3 weeks post-HCT as assessed by tetramer staining. Following in vivo reactivation of IAC-treated and control recipients at >5 months post-HCT with donor antigen, only PBS-treated control marrow allograft recipients responded with tetramer-binding CD8 cells. In total, the present findings support the notion that the transient activation and expansion of host Tregs in situ post-HCT can be explored as a new approach to regulate host alloreactivity posttransplant. Interestingly, direct stimulation of recipient Treg cells in RIC recipients obviated a requirement for exogenous Treg cell transfusion in this model and may represent a viable alternative to, and/or complement the adaptive transfer of Treg populations in clinical HCT.
    MeSH term(s) Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; Graft Survival/drug effects ; Graft Survival/immunology ; Hematopoietic Stem Cell Transplantation ; Histocompatibility Antigens/immunology ; Host vs Graft Reaction/drug effects ; Host vs Graft Reaction/immunology ; Interleukin-2/immunology ; Interleukin-2/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Mice ; T-Lymphocytes, Regulatory/immunology ; Time Factors ; Transplantation Chimera/immunology ; Transplantation, Homologous
    Chemical Substances Antibodies, Monoclonal ; Histocompatibility Antigens ; Interleukin-2
    Language English
    Publishing date 2009-05-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1474865-4
    ISSN 1523-6536 ; 1083-8791
    ISSN (online) 1523-6536
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2009.03.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Engraftment of splenic tissue as a method to investigate repopulation by hematopoietic cells from host and donor marrow.

    Shatry, Alwi M / Levy, Robert B

    Stem cells and development

    2004  Volume 13, Issue 4, Page(s) 390–399

    Abstract: The lymphohematopoietic function of the spleen in mice varies dependent on age and hematopoietic requirements. A method was developed to study splenic repopulation of mature and progenitor cell populations by grafting neonatal or adult spleen tissue ... ...

    Abstract The lymphohematopoietic function of the spleen in mice varies dependent on age and hematopoietic requirements. A method was developed to study splenic repopulation of mature and progenitor cell populations by grafting neonatal or adult spleen tissue under the renal capsule of splenectomized mice. Two weeks following implant of irradiated syngeneic neonatal spleens into B6-Ly 5.1 or B6-gfp recipients, host lymphoid (B220(+), CD4/8(+)) and myeloid cells (CD11b(+)) had repopulated the splenic grafts and constituted the majority of cells contained in these heterotopic implants. Notably, the percentage of lymphoid and myeloid cells approximated adult levels in contrast to preimplant neonatal spleen levels. This observation indicated relatively rapid repopulation of the grafted tissue by adult host cells and suggests that the repopulation patterns were regulated by the host. Three months post-implantation, the cell composition in the graft remained comparable to adult levels. Microscopic examination demonstrated normal splenic architecture including follicles and red pulp. Lymphocytes within the graft were functional as indicated by their proliferation in response to lipopolysaccharide (LPS) and concanavalin A (ConA) stimulation. Progenitor cell activity determined by colony-forming unit interleukin-3 (CFU-IL-3) levels was also present in these grafts. Splenic implants were then assessed in transplant models following lethal irradiation and syngeneic or allogeneic bone marrow transplantation (BMT). Two weeks post-BMT, adult splenic tissue implants contained donor-derived B cells, T cells, and myeloid cell populations. As typically detected in the host spleen post-BMT, the grafted tissue also contained elevated levels of donor progenitor cells. By 3 months post-BMT, CFU-IL3 levels in the graft reflected the decreased levels characteristic of adult levels. The functional integrity of post-transplant splenocytes in the implants was also demonstrated by mitogenic responsiveness. In summary, this method should provide a useful model for the transfer of the splenic microenvironment to study the biology of the spleen in non-transplant and BMT settings.
    MeSH term(s) Animals ; Bone Marrow Cells/cytology ; Bone Marrow Transplantation/physiology ; Cell Division ; Female ; Hematopoietic Stem Cells/cytology ; Interleukin-3/analysis ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Spleen/transplantation ; Splenectomy ; Subrenal Capsule Assay/methods ; Transplantation, Homologous/physiology
    Chemical Substances Interleukin-3
    Language English
    Publishing date 2004-08
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2142214-X
    ISSN 1557-8534 ; 1547-3287
    ISSN (online) 1557-8534
    ISSN 1547-3287
    DOI 10.1089/scd.2004.13.390
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Survival and function of MiHA epitope-specific host CD8 TM cells following ablative conditioning and HCT.

    Shatry, Alwi M / Roopenian, Derry C / Levy, Robert B

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2007  Volume 13, Issue 3, Page(s) 293–298

    Abstract: Memory T cell (TM) populations specific for transplantation Ags may arise from sensitization due to blood transfusions, tissue transplants, or in multiparous females. In each of these scenarios, TM cells are likely generated, and have been shown to ... ...

    Abstract Memory T cell (TM) populations specific for transplantation Ags may arise from sensitization due to blood transfusions, tissue transplants, or in multiparous females. In each of these scenarios, TM cells are likely generated, and have been shown to persist in such individuals for extended time periods. Heightened resistance to allogeneic marrow engraftment in certain individuals is therefore consistent with the presence of antidonor TM. CD8 TM were generated against a single minor H Ag (MiHA) epitope to determine if such cells could inhibit allogeneic marrow engraftment. The present results demonstrate that B6 mice sensitized to a single immunodominant (H60) epitope efficiently reject donor marrow allografts expressing this MiHA alone or together with multiple minor transplantation antigens, even following ablative TBI conditioning. To further address the survival and function of these CD8 TM, sensitized mice were ablatively conditioned and administered a syngeneic HCT. CD8(+)H60(TCR+) TM were clearly detected up to 2 weeks later in such recipients. Additionally, the memory cells present were capable of mediating effector responses as evidenced by their ability to resist a second, allogeneic HCT. In summary, these observations highlight the increased risk of resistance in the presence of antidonor antigen-specific CD8 TM due to their ability to survive and function even following rigorous conditioning and HCT.
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes/immunology ; Cell Survival/immunology ; Graft Survival/immunology ; Hematopoietic Stem Cell Transplantation/methods ; Immunologic Memory/immunology ; Mice ; Minor Histocompatibility Antigens/immunology ; Transplantation Conditioning/methods ; Transplantation, Homologous
    Chemical Substances Minor Histocompatibility Antigens ; minor H antigen H60
    Language English
    Publishing date 2007-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474865-4
    ISSN 1083-8791
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2006.12.440
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The effect of the spleen on compartmental levels and distribution of donor progenitor cells after syngeneic and allogeneic bone marrow transplants.

    Shatry, Alwi M / Jones, Monica / Levy, Robert B

    Stem cells and development

    2004  Volume 13, Issue 1, Page(s) 51–62

    Abstract: These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and "cross-talk" with the marrow compartment following syngeneic or allogeneic bone marrow transplantation (BMT) in sham or fully splenectomized mice. Intact ... ...

    Abstract These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and "cross-talk" with the marrow compartment following syngeneic or allogeneic bone marrow transplantation (BMT) in sham or fully splenectomized mice. Intact recipient B6 mice were lethally irradiated prior to transplant with T cell-depleted bone marrow (BM-TCD). The kinetics of PC reconstitution following i.v. transplant consistently revealed a dramatic increase in splenic colony-forming unit interleukin-3 (CFU IL-3) and CFU (high proliferative potential-(HPP) levels between days 5 and 12 post-BMT. Direct injection of TCD-BM into the recipient marrow cavity did not alter this pattern of reconstitution in the splenic compartment. In contrast to spleens from normal adult B6 mice containing 0.9% and 0.6% of the total combined splenic and marrow committed (CFU IL-3) and primitive (CFU-HPP) progenitors, respectively, spleens of syngeneic BMT recipients at day 12 contained a 10-fold increase (p < 0.001) over the progenitor levels in normal spleens. These splenic numbers decreased to normal, homeostatic levels by day 28 post-BMT. In contrast, the level of marrow CFU IL-3 progenitors continued to increase post-transplant, reaching near homeostatic levels by day 28 post-BMT. Interestingly, early seeding of 5- (and -6)carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled or green fluorescent protein (GFP) donor bone marrow cells (BMC) to the marrow compartment was not different in sham splenectomies or recipients splenectomized 14 days earlier. However, recipient splenectomy consistently resulted in significantly higher numbers of CFU IL-3 in the bone marrow during the first 2 weeks post-transplant compared to sham controls. These elevated levels exceeded the combined progenitor numbers of the splenic and marrow compartments of intact recipients. Notably, this increase in marrow progenitor activity in splenectomized recipients was observed after syngeneic as well as allogeneic BMT. Allogeneic transplants across major, or those limited to minor, histocompatibility antigen differences exhibited this increased marrow progenitor activity. Splenectomy performed 2 h post-transplant to assure "normal" marrow seeding also resulted in higher marrow progenitor activity. Thus, this "marrow response" to splenectomy is not induced by early "shunting" of infused BM cells to the marrow compartment. These results suggest that communication between the splenic and marrow compartments following syngeneic and allogeneic BMT exists during early hematopoietic reconstitution, one effect of which is to impact the compartmental distribution of donor progenitor cells. The role of the spleen on engraftment, chimerism, and tolerance in allogeneic BMT models are now under investigation.
    MeSH term(s) Animals ; Bone Marrow/metabolism ; Bone Marrow Transplantation/methods ; Colony-Forming Units Assay ; Female ; Flow Cytometry ; Green Fluorescent Proteins ; Hematopoiesis ; Interleukin-3/metabolism ; Kinetics ; Luminescent Proteins/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Spleen/cytology ; Spleen/metabolism ; Stem Cells/cytology ; T-Lymphocytes/metabolism ; Time Factors ; Transplantation, Homologous
    Chemical Substances Interleukin-3 ; Luminescent Proteins ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2004-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2142214-X
    ISSN 1557-8534 ; 1547-3287
    ISSN (online) 1557-8534
    ISSN 1547-3287
    DOI 10.1089/154732804773099254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Targeting Treg cells in situ: emerging expansion strategies for (CD4(+)CD25(+)) regulatory T cells.

    Shatry, Alwi / Chirinos, Jackeline / Gorin, Michael A / Jones, Monica / Levy, Robert B

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2009  Volume 15, Issue 10, Page(s) 1239–1243

    Abstract: Recognition of the ability of CD4(+)FoxP3(+) T cells (Treg) to influence the generation of peripheral immune responses has engendered enthusiasm for the development of strategies utilizing these cells to regulate immune responses in clinically important ... ...

    Abstract Recognition of the ability of CD4(+)FoxP3(+) T cells (Treg) to influence the generation of peripheral immune responses has engendered enthusiasm for the development of strategies utilizing these cells to regulate immune responses in clinically important settings including transplantation, autoimmunity and cancer. A number of studies have reported effective regulation utilizing ex-vivo expansion approaches and subsequent transfer of Treg populations in experimental models. This commentary discusses recently emerging strategies to activate and expand Treg cells in situ which include antibodies, antigen presenting cells and the use of IL2 / anti-IL2 antibody complex. The development of reagents which can stimulate and / or remove Treg cells in situ would represent an important advance towards facilitating new opportunities to harness this compartment for the augmentation of 'wanted' or suppression of 'unwanted' immune responses. Simultaneous targeting of multiple molecules on Treg cells may ultimately enable more effective control of this regulatory sector.
    MeSH term(s) Animals ; Antibodies/immunology ; Antigen-Presenting Cells/immunology ; Autoimmunity/immunology ; Cell Proliferation ; Humans ; Interleukin-2/immunology ; Neoplasms/immunology ; Organ Transplantation ; T-Lymphocytes, Regulatory/immunology ; Transplantation Immunology/immunology
    Chemical Substances Antibodies ; Interleukin-2
    Language English
    Publishing date 2009-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1474865-4
    ISSN 1523-6536 ; 1083-8791
    ISSN (online) 1523-6536
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2009.06.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Cytolytic pathways used by effector cells derived from recipient naive and memory T cells and natural killer cells in resistance to allogeneic hematopoietic cell transplantation.

    Zimmerman, Zachary / Jones, Monica / Shatry, Alwi / Komatsu, Masanobu / Mammolenti, Michele / Levy, Robert

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2005  Volume 11, Issue 12, Page(s) 957–971

    MeSH term(s) Animals ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunologic Memory/immunology ; Killer Cells, Natural/immunology ; Signal Transduction/immunology ; T-Lymphocytes/immunology ; Transplantation Immunology ; Transplantation, Homologous
    Language English
    Publishing date 2005-12
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1474865-4
    ISSN 1083-8791
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2005.07.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated.

    Torroella-Kouri, Marta / Silvera, Risset / Rodriguez, Dayron / Caso, Raul / Shatry, Alwi / Opiela, Shannon / Ilkovitch, Dan / Schwendener, Reto A / Iragavarapu-Charyulu, Vijaya / Cardentey, Yoslayma / Strbo, Natasa / Lopez, Diana M

    Cancer research

    2009  Volume 69, Issue 11, Page(s) 4800–4809

    Abstract: Systemic and local immune deficiency is associated with cancer, and the role of M2 tumor-associated macrophages in this phenomenon is well recognized. However, the immune status of macrophages from peripheral compartments in tumor hosts is unclear. ... ...

    Abstract Systemic and local immune deficiency is associated with cancer, and the role of M2 tumor-associated macrophages in this phenomenon is well recognized. However, the immune status of macrophages from peripheral compartments in tumor hosts is unclear. Peritoneal macrophages (PEM) are derived from circulating monocytes and recruited to the peritoneal cavity where they differentiate into macrophages. We have previously shown that PEMs from mice bearing D1-DMBA-3 mammary tumors (T-PEM) are deficient in inflammatory functions and that this impairment is associated with diminished expression of transcription factors nuclear factor kappaB and CAAT/enhancer-binding protein. We now provide evidence that T-PEMs display neither M1 nor M2 phenotypes, yet exhibit deficiencies in the expression of several inflammatory cytokines and various proinflammatory signaling pathways. Moreover, due to nuclear factor kappaB down-regulation, increased apoptosis was observed in T-PEMs. We report for the first time that macrophage depletion is associated with increased macrophage progenitors in bone marrow. Furthermore, T-PEMs have a lower expression of macrophage differentiation markers F4/80, CD68, CD115, and CD11b, whereas Gr-1 is up-regulated. Our results suggest that T-PEMs are less differentiated and represent a newly derived population from blood monocytes. Lastly, we show that transforming growth factor-beta and prostaglandin E(2), two immunosuppressive tumor-derived factors, may be involved in this phenomenon.
    MeSH term(s) 3T3 Cells ; Animals ; CCAAT-Enhancer-Binding Proteins/genetics ; CCAAT-Enhancer-Binding Proteins/metabolism ; Carcinoma/genetics ; Carcinoma/immunology ; Carcinoma/metabolism ; Carcinoma/pathology ; Cell Differentiation/immunology ; Cell Separation ; Clodronic Acid/pharmacology ; Cytokines/metabolism ; Dinoprostone/metabolism ; Dinoprostone/physiology ; Female ; Gene Expression Regulation, Neoplastic ; Inflammation Mediators/metabolism ; Macrophages/classification ; Macrophages/metabolism ; Macrophages/pathology ; Mammary Neoplasms, Animal/genetics ; Mammary Neoplasms, Animal/immunology ; Mammary Neoplasms, Animal/metabolism ; Mammary Neoplasms, Animal/pathology ; Mice ; Mice, Inbred BALB C ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/physiology ; Tumor Cells, Cultured
    Chemical Substances CCAAT-Enhancer-Binding Proteins ; Cytokines ; Inflammation Mediators ; NF-kappa B ; Transforming Growth Factor beta ; Clodronic Acid (0813BZ6866) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2009-05-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-08-3427
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Effector cells derived from host CD8 memory T cells mediate rapid resistance against minor histocompatibility antigen-mismatched allogeneic marrow grafts without participation of perforin, Fas ligand, and the simultaneous inhibition of 3 tumor necrosis factor family effector pathways.

    Zimmerman, Zachary / Shatry, Alwi / Deyev, Vadim / Podack, Eckhard / Mammolenti, Michele / Blazar, Bruce R / Yagita, Hideo / Levy, Robert B

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

    2005  Volume 11, Issue 8, Page(s) 576–586

    Abstract: Reduced-intensity conditioning regimens for transplant recipients have heightened awareness of immunologic resistance to allogeneic bone marrow transplants (BMT). Although T cell-mediated cytotoxicity has been assumed to play a role in the resistance ... ...

    Abstract Reduced-intensity conditioning regimens for transplant recipients have heightened awareness of immunologic resistance to allogeneic bone marrow transplants (BMT). Although T cell-mediated cytotoxicity has been assumed to play a role in the resistance against donor allogeneic hematopoietic stem and progenitor cell grafts, several studies have reported relatively unimpaired resistance by recipients who lack perforin, Fas ligand (FasL), and other cytotoxic mediators. This study compared the early kinetics of T cell-mediated resistance in B6 (H2b) cytotoxically normal versus deficient recipients after transplantation with major histocompatibility complex-matched, minor histocompatibility antigen (MiHA)-mismatched allogeneic marrow grafts. Wild-type B6 or cytotoxic double-deficient perforin-/-/gld+/+ (B6-cdd) mice were sensitized against major histocompatibility complex-matched BALB.B or C3H.SW (H2b) MiHA and transplanted with a high dose (1 x 10(7)) of T cell-depleted bone marrow. CD8 T memory cells were shown to be present in recipients before BMT, and anti-CD8 monoclonal antibody infusion abolished resistance, thus demonstrating that CD8 T cells are the host effector population. Donor-committed and high proliferative potential progenitor numbers were markedly diminished by 48 hours after transplantation in both wild-type B6 and B6-cdd anti-donor MiHA-sensitized recipients. These observations indicate that the resistance pathway used in the cytotoxic deficient mice was both potent and rapidly induced--consistent with a CD8 memory T-cell response. To examine the role of Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)- and TL1A-mediated cytotoxicity in this strong resistance, newly generated monoclonal antibodies specific for these ligands were administered to B6-cdd recipients sensitized to donor antigens. Recipients of syngeneic B6-gfp bone marrow exhibited significant donor colony-forming unit numbers after BMT. In contrast, low or absent colony-forming unit levels were detected in allogeneic recipients, including those that lacked perforin and FasL and that received anti-TWEAK, anti-tumor necrosis factor-related apoptosis-inducing ligand, and anti-TL1A monoclonal antibodies. These findings extend previous observations by demonstrating the existence of a rapidly effected resistance pathway mediated by memory CD8 effector T cells independent of the 2 major pathways of cytotoxicity. Together with previous findings, these results support the notion that effector cells derived from memory CD8 T-cell populations can mediate strong resistance against donor allogeneic MiHA-disparate hematopoietic engraftment by using a mechanism that is independent of the contribution of perforin, FasL, and the known death ligand receptor pathways.
    MeSH term(s) Animals ; Apoptosis Regulatory Proteins ; Bone Marrow Transplantation/immunology ; CD8-Positive T-Lymphocytes/immunology ; Carrier Proteins/immunology ; Cell Line ; Cytokine TWEAK ; Fas Ligand Protein ; Graft Survival/immunology ; Immunologic Memory/genetics ; Immunologic Memory/immunology ; Membrane Glycoproteins/immunology ; Membrane Proteins/immunology ; Mice ; Mice, Knockout ; Minor Histocompatibility Antigens/immunology ; Pore Forming Cytotoxic Proteins ; Signal Transduction/immunology ; Transplantation Immunology ; Transplantation, Homologous ; Tumor Necrosis Factors
    Chemical Substances Apoptosis Regulatory Proteins ; Carrier Proteins ; Cytokine TWEAK ; Fas Ligand Protein ; Fasl protein, mouse ; Membrane Glycoproteins ; Membrane Proteins ; Minor Histocompatibility Antigens ; Pore Forming Cytotoxic Proteins ; Tnfsf12 protein, mouse ; Tumor Necrosis Factors ; perforin, mouse
    Language English
    Publishing date 2005-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1474865-4
    ISSN 1083-8791
    ISSN 1083-8791
    DOI 10.1016/j.bbmt.2005.05.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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