The Experts below are selected from a list of 1515 Experts worldwide ranked by ideXlab platform
Yair Reisner - One of the best experts on this subject based on the ideXlab platform.
-
human colon adenocarcinoma in the scid cb6 Radiation Chimera is susceptible to adoptive transfer of allogeneic human peripheral blood mononuclear cells
Journal of Hematotherapy & Stem Cell Research, 2002Co-Authors: Fabian D. Arditti, Benjamin Dekel, Alain Berrebi, Hadar Marcus, Ron Greenberg, Arnon Nagler, Y Skornick, Yair ReisnerAbstract:The aim of this study was to develop a murine model of human colon carcinoma (hCC) and to ascertain the potential of cellular immunotherapy in this model. Fragments of hCC obtained at surgery from 6 patients were transplanted under the kidney capsule of lethally irradiated CB6 mice radioprotected with severe combined immunodeficient (SCID) mice bone marrow. Tumor xenografts conserved their malignant behavior in the new environment, invading the mouse kidney parenchyma and expanding into the peritoneal cavity and adjacent tissues. Their growth was typically exponential, and they expanded to dimensions that allowed their subsequent fragmentation and passage to further preconditioned mice. Human carcinoembryonic antigen (hCEA) was detected on the implanted tumor and at occasionally spontaneous lung metastases. Most significantly, high levels of this tumor marker were detected in the sera of tumor-bearing mice, providing a useful tool, which allowed long-term experiments, monitoring of tumor progression, and ...
-
intranasal administration of peptide vaccine protects human mouse Radiation Chimera from influenza infection
International Immunology, 1999Co-Authors: Tamar Benyedidia, Yair Reisner, Hadar Marcus, Ruth ArnonAbstract:Influenza virus is characterized by frequent and unpredictable changes of the surface glycoproteins which enable the virus to escape the immune system. Approved vaccines which consist of the whole virus or the surface glycoproteins fail to induce broad specificity protection. We have previously reported that a peptide-based experimental recombinant vaccine which includes conserved epitopes of B and T lymphocytes was efficient in mice, leading to cross-strain, long-term protection. In the present study, this approach was adapted for the design of a human vaccine, based on epitopes recognized by the prevalent HLAs. These epitopes were expressed in Salmonella flagellin and tested for their efficacy in human/mouse Radiation Chimera in which human peripheral blood mononuclear cells (PBMC) are functionally engrafted. The vaccinated mice demonstrated clearance of the virus after challenge and resistance to lethal infection. The production of virus-specific human antibodies was also higher in this group. Control groups of either non-vaccinated, or vaccinated mice which had not been engrafted with the human PBMC, did not exhibit the protective immune response. FACS analysis showed that most human cells in the transplanted mice are CD8(+) and CD4(+). Hence, it may be concluded: (i) that the protection involves cellular mechanisms, but is most probably accomplished without direct lysis of influenza-infected pulmonary cells by cytotoxic T lymphocytes, but rather via a cytokine-mediated mechanism, (ii) that the human/mouse Radiation Chimera model may be of some value in the investigation of new vaccines, as an additional tool prior to clinical trials, and (iii) that the synthetic recombinant vaccine can induce a response in the human immune system and confers protection against influenza infection. Further investigation is needed to establish the efficacy of such a peptide vaccine in human subjects.
-
antigen specific b and t cells in human mouse Radiation Chimera following immunization in vivo
Immunology, 1999Co-Authors: Wulf O Bocher, Benjamin Dekel, Hadar Marcus, Daniel Shouval, E Galun, R Shakarchy, Yair ReisnerAbstract:SUMMARY Adoptive transfer of human peripheral blood mononuclear cells (PBMC ) into mice with severe combined immunodeficiency (SCID) or into lethally irradiated BALB/c mice radioprotected with SCID bone marrow, leads to marked engraftment of human T and B cells. In such Chimeras, human serum antibody responses can be stimulated readily by vaccination with recall antigens, but the detection of antigen-specific functional T or B cells has been extremely diYcult. In the present study, we were able to detect by Elispot analysis high frequencies of immunoglobulin G (IgG)-secreting B cells and mitogen-responsive interferon-c (IFN-c) or interleukin-4 (IL-4)secreting T cells in peritoneum and spleen of human/BALB/c chimeric mice during the first 3 weeks after PBMC transfer. Moreover, specific memory responses were elicited by vaccination with tetanus toxoid (TT ) or hepatitis B virus (HBV ) surface (HBs) antigen of chimeric mice transplanted with PBMC derived from TT- or HBV-immune donors. Substantially higher TT-specific B-cell frequencies were found during the first 3 weeks after vaccination in mice challenged with the specific antigen compared to the levels found in control animals. High numbers of TT-specific IFN-c-secreting T cells persisted in the peritoneum of vaccinated, but not of unvaccinated, animals during the entire observation period, but only low numbers of specific IL-4-secreting T cells were found in vaccinated mice. Similar results were achieved following vaccination with HBs antigen of chimeric mice, transplanted with PBMC of HBV immunized donors. Thus, TT or HBsAg-specific antibody responses in our model correlate closely with the existence of specific IFN-c-secreting T helper 1/0 cells. Furthermore, these results show that adoptive transfer of human PBMC into lethally irradiated mice provides an eYcient approach to generate specific B-cell fusion partners for the production of human monoclonal antibodies and specific T-cell lines for adoptive cell therapy of malignant or infectious diseases.
-
Intranasal administration of peptide vaccine protects human/mouse Radiation Chimera from influenza infection
International immunology, 1999Co-Authors: Tamar Ben-yedidia, Yair Reisner, Hadar Marcus, Ruth ArnonAbstract:Influenza virus is characterized by frequent and unpredictable changes of the surface glycoproteins which enable the virus to escape the immune system. Approved vaccines which consist of the whole virus or the surface glycoproteins fail to induce broad specificity protection. We have previously reported that a peptide-based experimental recombinant vaccine which includes conserved epitopes of B and T lymphocytes was efficient in mice, leading to cross-strain, long-term protection. In the present study, this approach was adapted for the design of a human vaccine, based on epitopes recognized by the prevalent HLAs. These epitopes were expressed in Salmonella flagellin and tested for their efficacy in human/mouse Radiation Chimera in which human peripheral blood mononuclear cells (PBMC) are functionally engrafted. The vaccinated mice demonstrated clearance of the virus after challenge and resistance to lethal infection. The production of virus-specific human antibodies was also higher in this group. Control groups of either non-vaccinated, or vaccinated mice which had not been engrafted with the human PBMC, did not exhibit the protective immune response. FACS analysis showed that most human cells in the transplanted mice are CD8(+) and CD4(+). Hence, it may be concluded: (i) that the protection involves cellular mechanisms, but is most probably accomplished without direct lysis of influenza-infected pulmonary cells by cytotoxic T lymphocytes, but rather via a cytokine-mediated mechanism, (ii) that the human/mouse Radiation Chimera model may be of some value in the investigation of new vaccines, as an additional tool prior to clinical trials, and (iii) that the synthetic recombinant vaccine can induce a response in the human immune system and confers protection against influenza infection. Further investigation is needed to establish the efficacy of such a peptide vaccine in human subjects.
-
human balb Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
Benjamin Dekel - One of the best experts on this subject based on the ideXlab platform.
-
human colon adenocarcinoma in the scid cb6 Radiation Chimera is susceptible to adoptive transfer of allogeneic human peripheral blood mononuclear cells
Journal of Hematotherapy & Stem Cell Research, 2002Co-Authors: Fabian D. Arditti, Benjamin Dekel, Alain Berrebi, Hadar Marcus, Ron Greenberg, Arnon Nagler, Y Skornick, Yair ReisnerAbstract:The aim of this study was to develop a murine model of human colon carcinoma (hCC) and to ascertain the potential of cellular immunotherapy in this model. Fragments of hCC obtained at surgery from 6 patients were transplanted under the kidney capsule of lethally irradiated CB6 mice radioprotected with severe combined immunodeficient (SCID) mice bone marrow. Tumor xenografts conserved their malignant behavior in the new environment, invading the mouse kidney parenchyma and expanding into the peritoneal cavity and adjacent tissues. Their growth was typically exponential, and they expanded to dimensions that allowed their subsequent fragmentation and passage to further preconditioned mice. Human carcinoembryonic antigen (hCEA) was detected on the implanted tumor and at occasionally spontaneous lung metastases. Most significantly, high levels of this tumor marker were detected in the sera of tumor-bearing mice, providing a useful tool, which allowed long-term experiments, monitoring of tumor progression, and ...
-
Autologous t cells control b-chronic lymphocytic leukemia tumor progression in human →mouse Radiation Chimera
Cancer research, 1999Co-Authors: Avichai Shimoni, Benjamin Dekel, Hadar Marcus, Allon Canaan, Rachel Shkarchi, Fabian D. Arditti, Lev Shvidel, Mordechai Shtalrid, Wulf Bucher, David ErgasAbstract:B-chronic lymphocytic leukemia (B-CLL) is characterized by the clonal accumulation of CD5+ B cells. It has been suggested that CLL cells may be regulated by inhibitory and growth-promoting signals exerted by autologous T cells. We have recently described a model for human B-CLL in which peripheral blood mononuclear cells (PBMCs) are transplanted into the peritoneal cavity of lethally irradiated mice radioprotected with bone marrow from mice with severe combined immunedeficiency. In this model, adoptive transfer of low-stage PBMCs leads to marked engraftment of T cells or combined T and CLL cell engraftment, whereas infusion of high-stage PBMCs leads to dominance of CLL cells with a miniscule level of T-cell engraftment. This mutual exclusive pattern of engraftment indicated that T cells might control the expansion of tumor cells in the peritoneum of recipient BALB/c mice. In the present study, we further investigated this question and we demonstrate that in vivo T-cell depletion, using OKT3 antibody, markedly enhances the engraftment of B-CLL cells from patients with early-stage disease. In mice receiving PBMCs from 11 donors with advanced-stage disease, the results were more heterogeneous. In five patients the results were similar to those observed in early stage, whereas in two cases no CLL cell engraftment was found in the absence of T cells. The addition of purified T cells to PBMCs led to a substantial decrease of CLL engraftment in three advanced-stage cases. These results strengthen the working hypothesis that autologous T cells can actively suppress the expansion of the pathological cells in human→mouse Radiation Chimera. This effect is prominent in early-stage disease, whereas in advanced stage suppresive and/or stimulatory effects may occur in different patients. The interaction of T cells with tumor cells and the potential of autologous T cell/immune-therapy in CLL can be further explored in this model.
-
antigen specific b and t cells in human mouse Radiation Chimera following immunization in vivo
Immunology, 1999Co-Authors: Wulf O Bocher, Benjamin Dekel, Hadar Marcus, Daniel Shouval, E Galun, R Shakarchy, Yair ReisnerAbstract:SUMMARY Adoptive transfer of human peripheral blood mononuclear cells (PBMC ) into mice with severe combined immunodeficiency (SCID) or into lethally irradiated BALB/c mice radioprotected with SCID bone marrow, leads to marked engraftment of human T and B cells. In such Chimeras, human serum antibody responses can be stimulated readily by vaccination with recall antigens, but the detection of antigen-specific functional T or B cells has been extremely diYcult. In the present study, we were able to detect by Elispot analysis high frequencies of immunoglobulin G (IgG)-secreting B cells and mitogen-responsive interferon-c (IFN-c) or interleukin-4 (IL-4)secreting T cells in peritoneum and spleen of human/BALB/c chimeric mice during the first 3 weeks after PBMC transfer. Moreover, specific memory responses were elicited by vaccination with tetanus toxoid (TT ) or hepatitis B virus (HBV ) surface (HBs) antigen of chimeric mice transplanted with PBMC derived from TT- or HBV-immune donors. Substantially higher TT-specific B-cell frequencies were found during the first 3 weeks after vaccination in mice challenged with the specific antigen compared to the levels found in control animals. High numbers of TT-specific IFN-c-secreting T cells persisted in the peritoneum of vaccinated, but not of unvaccinated, animals during the entire observation period, but only low numbers of specific IL-4-secreting T cells were found in vaccinated mice. Similar results were achieved following vaccination with HBs antigen of chimeric mice, transplanted with PBMC of HBV immunized donors. Thus, TT or HBsAg-specific antibody responses in our model correlate closely with the existence of specific IFN-c-secreting T helper 1/0 cells. Furthermore, these results show that adoptive transfer of human PBMC into lethally irradiated mice provides an eYcient approach to generate specific B-cell fusion partners for the production of human monoclonal antibodies and specific T-cell lines for adoptive cell therapy of malignant or infectious diseases.
-
human balb Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
-
Human/BALB Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
Hadar Marcus - One of the best experts on this subject based on the ideXlab platform.
-
human colon adenocarcinoma in the scid cb6 Radiation Chimera is susceptible to adoptive transfer of allogeneic human peripheral blood mononuclear cells
Journal of Hematotherapy & Stem Cell Research, 2002Co-Authors: Fabian D. Arditti, Benjamin Dekel, Alain Berrebi, Hadar Marcus, Ron Greenberg, Arnon Nagler, Y Skornick, Yair ReisnerAbstract:The aim of this study was to develop a murine model of human colon carcinoma (hCC) and to ascertain the potential of cellular immunotherapy in this model. Fragments of hCC obtained at surgery from 6 patients were transplanted under the kidney capsule of lethally irradiated CB6 mice radioprotected with severe combined immunodeficient (SCID) mice bone marrow. Tumor xenografts conserved their malignant behavior in the new environment, invading the mouse kidney parenchyma and expanding into the peritoneal cavity and adjacent tissues. Their growth was typically exponential, and they expanded to dimensions that allowed their subsequent fragmentation and passage to further preconditioned mice. Human carcinoembryonic antigen (hCEA) was detected on the implanted tumor and at occasionally spontaneous lung metastases. Most significantly, high levels of this tumor marker were detected in the sera of tumor-bearing mice, providing a useful tool, which allowed long-term experiments, monitoring of tumor progression, and ...
-
Autologous t cells control b-chronic lymphocytic leukemia tumor progression in human →mouse Radiation Chimera
Cancer research, 1999Co-Authors: Avichai Shimoni, Benjamin Dekel, Hadar Marcus, Allon Canaan, Rachel Shkarchi, Fabian D. Arditti, Lev Shvidel, Mordechai Shtalrid, Wulf Bucher, David ErgasAbstract:B-chronic lymphocytic leukemia (B-CLL) is characterized by the clonal accumulation of CD5+ B cells. It has been suggested that CLL cells may be regulated by inhibitory and growth-promoting signals exerted by autologous T cells. We have recently described a model for human B-CLL in which peripheral blood mononuclear cells (PBMCs) are transplanted into the peritoneal cavity of lethally irradiated mice radioprotected with bone marrow from mice with severe combined immunedeficiency. In this model, adoptive transfer of low-stage PBMCs leads to marked engraftment of T cells or combined T and CLL cell engraftment, whereas infusion of high-stage PBMCs leads to dominance of CLL cells with a miniscule level of T-cell engraftment. This mutual exclusive pattern of engraftment indicated that T cells might control the expansion of tumor cells in the peritoneum of recipient BALB/c mice. In the present study, we further investigated this question and we demonstrate that in vivo T-cell depletion, using OKT3 antibody, markedly enhances the engraftment of B-CLL cells from patients with early-stage disease. In mice receiving PBMCs from 11 donors with advanced-stage disease, the results were more heterogeneous. In five patients the results were similar to those observed in early stage, whereas in two cases no CLL cell engraftment was found in the absence of T cells. The addition of purified T cells to PBMCs led to a substantial decrease of CLL engraftment in three advanced-stage cases. These results strengthen the working hypothesis that autologous T cells can actively suppress the expansion of the pathological cells in human→mouse Radiation Chimera. This effect is prominent in early-stage disease, whereas in advanced stage suppresive and/or stimulatory effects may occur in different patients. The interaction of T cells with tumor cells and the potential of autologous T cell/immune-therapy in CLL can be further explored in this model.
-
intranasal administration of peptide vaccine protects human mouse Radiation Chimera from influenza infection
International Immunology, 1999Co-Authors: Tamar Benyedidia, Yair Reisner, Hadar Marcus, Ruth ArnonAbstract:Influenza virus is characterized by frequent and unpredictable changes of the surface glycoproteins which enable the virus to escape the immune system. Approved vaccines which consist of the whole virus or the surface glycoproteins fail to induce broad specificity protection. We have previously reported that a peptide-based experimental recombinant vaccine which includes conserved epitopes of B and T lymphocytes was efficient in mice, leading to cross-strain, long-term protection. In the present study, this approach was adapted for the design of a human vaccine, based on epitopes recognized by the prevalent HLAs. These epitopes were expressed in Salmonella flagellin and tested for their efficacy in human/mouse Radiation Chimera in which human peripheral blood mononuclear cells (PBMC) are functionally engrafted. The vaccinated mice demonstrated clearance of the virus after challenge and resistance to lethal infection. The production of virus-specific human antibodies was also higher in this group. Control groups of either non-vaccinated, or vaccinated mice which had not been engrafted with the human PBMC, did not exhibit the protective immune response. FACS analysis showed that most human cells in the transplanted mice are CD8(+) and CD4(+). Hence, it may be concluded: (i) that the protection involves cellular mechanisms, but is most probably accomplished without direct lysis of influenza-infected pulmonary cells by cytotoxic T lymphocytes, but rather via a cytokine-mediated mechanism, (ii) that the human/mouse Radiation Chimera model may be of some value in the investigation of new vaccines, as an additional tool prior to clinical trials, and (iii) that the synthetic recombinant vaccine can induce a response in the human immune system and confers protection against influenza infection. Further investigation is needed to establish the efficacy of such a peptide vaccine in human subjects.
-
antigen specific b and t cells in human mouse Radiation Chimera following immunization in vivo
Immunology, 1999Co-Authors: Wulf O Bocher, Benjamin Dekel, Hadar Marcus, Daniel Shouval, E Galun, R Shakarchy, Yair ReisnerAbstract:SUMMARY Adoptive transfer of human peripheral blood mononuclear cells (PBMC ) into mice with severe combined immunodeficiency (SCID) or into lethally irradiated BALB/c mice radioprotected with SCID bone marrow, leads to marked engraftment of human T and B cells. In such Chimeras, human serum antibody responses can be stimulated readily by vaccination with recall antigens, but the detection of antigen-specific functional T or B cells has been extremely diYcult. In the present study, we were able to detect by Elispot analysis high frequencies of immunoglobulin G (IgG)-secreting B cells and mitogen-responsive interferon-c (IFN-c) or interleukin-4 (IL-4)secreting T cells in peritoneum and spleen of human/BALB/c chimeric mice during the first 3 weeks after PBMC transfer. Moreover, specific memory responses were elicited by vaccination with tetanus toxoid (TT ) or hepatitis B virus (HBV ) surface (HBs) antigen of chimeric mice transplanted with PBMC derived from TT- or HBV-immune donors. Substantially higher TT-specific B-cell frequencies were found during the first 3 weeks after vaccination in mice challenged with the specific antigen compared to the levels found in control animals. High numbers of TT-specific IFN-c-secreting T cells persisted in the peritoneum of vaccinated, but not of unvaccinated, animals during the entire observation period, but only low numbers of specific IL-4-secreting T cells were found in vaccinated mice. Similar results were achieved following vaccination with HBs antigen of chimeric mice, transplanted with PBMC of HBV immunized donors. Thus, TT or HBsAg-specific antibody responses in our model correlate closely with the existence of specific IFN-c-secreting T helper 1/0 cells. Furthermore, these results show that adoptive transfer of human PBMC into lethally irradiated mice provides an eYcient approach to generate specific B-cell fusion partners for the production of human monoclonal antibodies and specific T-cell lines for adoptive cell therapy of malignant or infectious diseases.
-
Intranasal administration of peptide vaccine protects human/mouse Radiation Chimera from influenza infection
International immunology, 1999Co-Authors: Tamar Ben-yedidia, Yair Reisner, Hadar Marcus, Ruth ArnonAbstract:Influenza virus is characterized by frequent and unpredictable changes of the surface glycoproteins which enable the virus to escape the immune system. Approved vaccines which consist of the whole virus or the surface glycoproteins fail to induce broad specificity protection. We have previously reported that a peptide-based experimental recombinant vaccine which includes conserved epitopes of B and T lymphocytes was efficient in mice, leading to cross-strain, long-term protection. In the present study, this approach was adapted for the design of a human vaccine, based on epitopes recognized by the prevalent HLAs. These epitopes were expressed in Salmonella flagellin and tested for their efficacy in human/mouse Radiation Chimera in which human peripheral blood mononuclear cells (PBMC) are functionally engrafted. The vaccinated mice demonstrated clearance of the virus after challenge and resistance to lethal infection. The production of virus-specific human antibodies was also higher in this group. Control groups of either non-vaccinated, or vaccinated mice which had not been engrafted with the human PBMC, did not exhibit the protective immune response. FACS analysis showed that most human cells in the transplanted mice are CD8(+) and CD4(+). Hence, it may be concluded: (i) that the protection involves cellular mechanisms, but is most probably accomplished without direct lysis of influenza-infected pulmonary cells by cytotoxic T lymphocytes, but rather via a cytokine-mediated mechanism, (ii) that the human/mouse Radiation Chimera model may be of some value in the investigation of new vaccines, as an additional tool prior to clinical trials, and (iii) that the synthetic recombinant vaccine can induce a response in the human immune system and confers protection against influenza infection. Further investigation is needed to establish the efficacy of such a peptide vaccine in human subjects.
Allon Canaan - One of the best experts on this subject based on the ideXlab platform.
-
Autologous t cells control b-chronic lymphocytic leukemia tumor progression in human →mouse Radiation Chimera
Cancer research, 1999Co-Authors: Avichai Shimoni, Benjamin Dekel, Hadar Marcus, Allon Canaan, Rachel Shkarchi, Fabian D. Arditti, Lev Shvidel, Mordechai Shtalrid, Wulf Bucher, David ErgasAbstract:B-chronic lymphocytic leukemia (B-CLL) is characterized by the clonal accumulation of CD5+ B cells. It has been suggested that CLL cells may be regulated by inhibitory and growth-promoting signals exerted by autologous T cells. We have recently described a model for human B-CLL in which peripheral blood mononuclear cells (PBMCs) are transplanted into the peritoneal cavity of lethally irradiated mice radioprotected with bone marrow from mice with severe combined immunedeficiency. In this model, adoptive transfer of low-stage PBMCs leads to marked engraftment of T cells or combined T and CLL cell engraftment, whereas infusion of high-stage PBMCs leads to dominance of CLL cells with a miniscule level of T-cell engraftment. This mutual exclusive pattern of engraftment indicated that T cells might control the expansion of tumor cells in the peritoneum of recipient BALB/c mice. In the present study, we further investigated this question and we demonstrate that in vivo T-cell depletion, using OKT3 antibody, markedly enhances the engraftment of B-CLL cells from patients with early-stage disease. In mice receiving PBMCs from 11 donors with advanced-stage disease, the results were more heterogeneous. In five patients the results were similar to those observed in early stage, whereas in two cases no CLL cell engraftment was found in the absence of T cells. The addition of purified T cells to PBMCs led to a substantial decrease of CLL engraftment in three advanced-stage cases. These results strengthen the working hypothesis that autologous T cells can actively suppress the expansion of the pathological cells in human→mouse Radiation Chimera. This effect is prominent in early-stage disease, whereas in advanced stage suppresive and/or stimulatory effects may occur in different patients. The interaction of T cells with tumor cells and the potential of autologous T cell/immune-therapy in CLL can be further explored in this model.
-
human balb Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
-
Human/BALB Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
-
Engraftment of human kidney tissue in rat Radiation Chimera: I. A new model of human kidney allograft rejection.
Transplantation, 1997Co-Authors: Benjamin Dekel, Hadar Marcus, Elias Shezen, Allon Canaan, Tatyana Burakova, Sylvie Polack, Justen H. Passwell, Yair ReisnerAbstract:Background. We have recently shown that lethally irradiated normal strains of mice and rats, reconstituted with bone marrow from severe combined immune deficiency (SCID) mice, can be engrafted with human peripheral blood mononuclear cells (PBMC). Methods. The feasibility of transplanting human renal tissue under the kidney capsule of the SCID/Lewis and SCID/nude Radiation Chimera and the effects of intraperitoneal infusion of allogeneic human PBMC on the human renal implants were investigated by histology, electron microscopy, immunohistochemis-try, and fluorescence-activated cell sorter analysis. Results. Sequential evaluation of the human renal implants from 10 days to 2 months after transplantation showed that human parenchymal elements survive in the implants up to 2 months after transplantation. The overall architecture of the transplanted kidney tissue and the normal structure of individual cells in the glomeruli and tubuli were preserved. Infusion of allogeneic human PBMC after kidney implantation resulted in patchy cellular infiltrates, composed mainly of activated human T cells, and led to prompt rejection of the human renal tissue, whereas no signs of inflammation were observed in human renal implants of chimeric rats that did not receive human PBMC. Treatment with OKT3 antibody, anti-human CD25 antibody, or CTLA4Ig fusion protein in vivo ameliorated the rejection process. Conclusions. Human adult kidney fragments transplanted into SCID-like rats transiently retain competent parenchymal structures. When these grafts are combined with allogeneic human PBMC, acute cellular rejection develops. We suggest that this chimeric model might be useful for the investigation of the effects of experimental manipulation on the kinetics of the inflammatory response during human renal allograft rejection.
-
Engrafted human T and B lymphocytes form mixed follicles in lymphoid organs of human/mouse and human/rat Radiation Chimera.
Transplantation, 1997Co-Authors: Tanya Burakova, Benjamin Dekel, Hadar Marcus, Elias Shezen, Magda David, Allon Canaan, Ido Lubin, Harry Segal, Reisner YairAbstract:Background We recently described a new approach that enables the generation of human/mouse Chimera by adoptive transfer of human peripheral blood mononuclear cells into lethally irradiated normal strains of mice or rats, radioprotected with bone marrow from donors with severe combined immune deficiency. In such human/mouse Chimera, a marked humoral response to recall antigens, as well as a significant primary response to keyhole limpet hemocyanin, has been generated. Methods In the present study, the organ distribution of the engrafted human cells in the human/mouse and human/rat Chimera was investigated by immunohistochemistry. Results Our results show that the T cells seem to be distributed throughout the reticular endothelial system, almost behaving like particles without any homing specificity. The B cells, however, can barely be found in internal organs, such as the liver or the pancreas, and are concentrated in the secondary lymphoid system (e.g., spleen, lymph node, and nonencapsulated lymphoid tissue). The B cells, together with the engrafted human T cells, form mixed lymphoid follicles. Conclusions The different homing patterns exhibited by the T and B lymphocytes indicate that the homing receptors on human B cells might be cross-reactive with their mouse counterparts, in contrast to the human T cells, which seem to be unable to interact with the mouse homing receptors. The presence of human B and T lymphocytes in close proximity to each other in the lymphoid tissues is in accordance with the ability of human/BALB Radiation Chimera to mount significant primary human antibody responses.
Alain Berrebi - One of the best experts on this subject based on the ideXlab platform.
-
human colon adenocarcinoma in the scid cb6 Radiation Chimera is susceptible to adoptive transfer of allogeneic human peripheral blood mononuclear cells
Journal of Hematotherapy & Stem Cell Research, 2002Co-Authors: Fabian D. Arditti, Benjamin Dekel, Alain Berrebi, Hadar Marcus, Ron Greenberg, Arnon Nagler, Y Skornick, Yair ReisnerAbstract:The aim of this study was to develop a murine model of human colon carcinoma (hCC) and to ascertain the potential of cellular immunotherapy in this model. Fragments of hCC obtained at surgery from 6 patients were transplanted under the kidney capsule of lethally irradiated CB6 mice radioprotected with severe combined immunodeficient (SCID) mice bone marrow. Tumor xenografts conserved their malignant behavior in the new environment, invading the mouse kidney parenchyma and expanding into the peritoneal cavity and adjacent tissues. Their growth was typically exponential, and they expanded to dimensions that allowed their subsequent fragmentation and passage to further preconditioned mice. Human carcinoembryonic antigen (hCEA) was detected on the implanted tumor and at occasionally spontaneous lung metastases. Most significantly, high levels of this tumor marker were detected in the sera of tumor-bearing mice, providing a useful tool, which allowed long-term experiments, monitoring of tumor progression, and ...
-
human balb Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
-
Human/BALB Radiation Chimera engrafted with splenocytes from patients with idiopathic thrombocytopenic purpura produce human platelet antibodies
Immunology, 1998Co-Authors: Benjamin Dekel, Alain Berrebi, Hadar Marcus, Allon Canaan, B. Shenkman, A. Shimoni, Y. Shechter, David Varon, Yair ReisnerAbstract:We have previously shown that lethally irradiated normal strains of mice, radioprotected with severe combined immunodeficient (SCID) bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). The human/mouse Radiation Chimera can mount marked humoral and cellular responses to recall antigens, as well as primary responses. In the present study, we adoptively transferred splenocytes from patients with chronic immune thrombocytopenic purpura (ITP) into lethally irradiated BALB/c mice, radioprotected with SCID bone marrow. High titres of total human immunoglobulin appeared as early as 2 weeks post-transplant and declined after 6 weeks, while human anti-human platelet antibodies were detected 2-8 weeks after the transfer of splenocytes. The immunoglobulin G (IgG) fraction contained antibodies against glycoprotein (GP) IIb/IIIa (CD41) or GPIb/IX (CD42). The human platelet antibodies showed a low level of cross-reactivity with mouse platelets, and thrombocytopenia in the animals was not observed. Splenocytes from individual ITP patients differed in their capacity to produce either human platelet antibodies or total human immunoglobulin. Furthermore, antibodies produced in the murine system were not always identical to the original antibodies present in the serum of the patients. The study of the serological aspects of autoantibodies against human platelets in an animal model might be useful for the investigation of potential therapeutics in ITP.
-
Human/mouse Radiation Chimera generated from PBMC of B chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti-human red cell antibodies
Leukemia, 1997Co-Authors: H. Marcus, Avichai Shimoni, David Ergas, A Canaan, Benjamin Dekel, D Ben-david, M David, E Sigler, Yair Reisner, Alain BerrebiAbstract:Human/mouse Radiation Chimera generated from PBMC of B chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti-human red cell antibodies
-
human mouse Radiation Chimera generated from pbmc of b chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti human red cell antibodies
Leukemia, 1997Co-Authors: H. Marcus, Avichai Shimoni, David Ergas, A Canaan, Benjamin Dekel, M David, E Sigler, Yair Reisner, D Bendavid, Alain BerrebiAbstract:Human/mouse Radiation Chimera generated from PBMC of B chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti-human red cell antibodies