Terry Fisher | University of Central Florida (original) (raw)
Papers by Terry Fisher
Transplant Immunology, 1999
The induction of tolerance to organ allografts would eliminate acute and chronic rejection as wel... more The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecitic immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibllity barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by.flow cytometty of lymphocytes from reconstituted animals. A~ chimeras (ALC), Lewis/ACI F 1 (LACFI) , and Lewis (LEW) rats all received heterotopic ACI vasculatized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW--,LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVI-ID was quantified using the popliteal lymph node enlargement assay. All LACFI rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW--,LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-*LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF 1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Thl type proinilammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GHD. Preirradiating the donor bowel prior to SBTx can prevent GVI-ID.
Journal of Surgical Research, 1997
cific immunosuppression. The potential solution to Tolerance for organ allografts would eliminate... more cific immunosuppression. The potential solution to Tolerance for organ allografts would eliminate acute these problems would be the induction of donor specific and chronic rejection as well as the need for nonspetolerance. Additionally, this would allow for the succific immunosuppression. A potential hazard of tolercessful grafting of highly immunogenic organs such as ance is the susceptibility to graft vs host disease the small bowel where clinical success has been limited (GVHD) due to unresponsiveness to alloantigen. This because of infectious complications. Tolerance inducstudy sought to determine if our model of tolerance tion could be complicated by an unopposed reaction induction results in susceptibility to GVHD. Chimeras of the graft against the host when immune elements were created by transplantation of T-cell depleted ACI contained within the graft are of sufficient quantity. and Lewis bone marrow into lethally irradiated Lewis This phenomenon of graft vs host disease (GVHD) has rats. Chimerism was determined post-BMTx by flow been widely studied in experimental studies of bone cytometric analysis of recipient spleens for the presmarrow transplantation [1, 2] and has been reported ence of ACI cells. ACI/Lew chimeras (ALC), animals sporadically following liver, lung, and small bowel that reconstituted only with syngeneic (Lewis) martransplantation. In order for GVHD to occur, three crirow (so-called failed chimeras), and ACI/Lew F1 teria must be met: (a) immunologic mismatch between (LACF 1 ) hybrid rats were all given 200 1 10 6 ACI splengraft and host, (b) lack of host response against graft ocytes i.v. Animals were examined for evidence of for a period of time long enough for the graft to mount GVHD. GVHD was quantified using the popliteal a response against the host, and (c) sufficient lymphoid lymph node enlargement assay. All LACF 1 (n Å 6) rats tissue in graft to mount a significant response against developed severe lethal GVHD following ACI splenocyte injection. Similarly, ALC (n Å 6) developed fatal the host . In experimental small bowel transplanta-GVHD. Animals that reconstituted only with syngeneic tion, the phenomenon of GVHD in the parent to F1 Lewis marrow (failed chimeras) showed no signs of direction (Lew r Lewis/Brown-Norway F1) has been illness. GVHD was confirmed histologically and immudescribed . The susceptibility of the host to GVHD nohistochemically. Failed chimeras receiving ACI under conditions of experimentally induced tolerance splenocyte challenge showed no evidence of GVHD hishas not been investigated, but is a concern for the futologically. Popliteal lymph node enlargement indices ture application of strategies to induce tolerance, parreflected the presence of GVHD in the chimeras and hybrids but not in the failed chimeras. We conclude that tolerance induction by mixed chimerism results TABLE 1 in susceptibility to GVHD if enough donor lymphoid Summary of Results Following Splenocyte Injection tissue is given to the host at the time of organ transplant. Animals that are not mixed chimeras (failed GVHD GVHD Mean
Surgery, 1996
Background. Chronic rejection is the leading cause of late graft loss in kidney transplantation. ... more Background. Chronic rejection is the leading cause of late graft loss in kidney transplantation. We tested the ability of mixed hematopoietic chimerism to prevent chronic renal aUografl rejection in an established rat model and described possible mechanisms responsible for this tolerance. Methods. Mixed hematopoietic chimerism was established in lethally irradiated F-344 rats by reconstitution with Lewis bone marrow. Four groups (n = 5 each) received orthotopic kidney transplants: (1) allografl controls, (2) isograft controls, (3) experimental chimeras, and (4) specificity control. After 120 days kidney grafts were examined histologically, immunohistochemically, and for cytokine interferon-% interleukin-2 (IL-2), IL-4, and IL-IO gene transcripts by means of reverse transcriptase polymerase chain reaction techniques.
Transplantation, 1998
These experiments investigated the ability of the donor-specific unresponsiveness created by the ... more These experiments investigated the ability of the donor-specific unresponsiveness created by the intrathymic inoculation of donor alloantigen to effectively prevent chronic rejection in an established rat model of chronic renal allograft rejection. Three study groups were examined: (1) Allograft controls--F-344 rats received a Lewis renal allograft plus 10 days of low-dose cyclosporine (CsA); (2) isograft controls--F-344 rats received an F-344 renal isograft and low-dose CsA; (3) experimental group--F-344 rats received a T-cell depleted syngeneic bone marrow transplant and intrathymic injection of Lewis bone marrow. Twenty-one days after bone marrow transplant, these animals received a Lewis renal allograft. Allograft controls demonstrated severe parenchymal fibrosis; isograft controls and intrathymic (IT) animals failed to develop this lesion. Immunohistochemical analysis revealed increased CD4+ T cells infiltrating the cortex of the allograft controls. Cytokine interferon-gamma and interleukin-2 transcripts were strongly positive in allograft controls and were absent from isograft controls and IT allografts as determined by reverse transcriptase-polymerase chain reaction. Analysis of tolerant grafts by flow microfluorimetry and genomic DNA amplification could not detect chimerism to a level of < 0.1%. IT inoculation of donor alloantigen can confer long-term unresponsiveness and prevent the development of the characteristic lesions of chronic rejection.
Transplant Immunology, 1999
The induction of tolerance to organ allografts would eliminate acute and chronic rejection as wel... more The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecitic immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibllity barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by.flow cytometty of lymphocytes from reconstituted animals. A~ chimeras (ALC), Lewis/ACI F 1 (LACFI) , and Lewis (LEW) rats all received heterotopic ACI vasculatized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW--,LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVI-ID was quantified using the popliteal lymph node enlargement assay. All LACFI rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW--,LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-*LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF 1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Thl type proinilammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GHD. Preirradiating the donor bowel prior to SBTx can prevent GVI-ID.
Journal of Surgical Research, 1997
cific immunosuppression. The potential solution to Tolerance for organ allografts would eliminate... more cific immunosuppression. The potential solution to Tolerance for organ allografts would eliminate acute these problems would be the induction of donor specific and chronic rejection as well as the need for nonspetolerance. Additionally, this would allow for the succific immunosuppression. A potential hazard of tolercessful grafting of highly immunogenic organs such as ance is the susceptibility to graft vs host disease the small bowel where clinical success has been limited (GVHD) due to unresponsiveness to alloantigen. This because of infectious complications. Tolerance inducstudy sought to determine if our model of tolerance tion could be complicated by an unopposed reaction induction results in susceptibility to GVHD. Chimeras of the graft against the host when immune elements were created by transplantation of T-cell depleted ACI contained within the graft are of sufficient quantity. and Lewis bone marrow into lethally irradiated Lewis This phenomenon of graft vs host disease (GVHD) has rats. Chimerism was determined post-BMTx by flow been widely studied in experimental studies of bone cytometric analysis of recipient spleens for the presmarrow transplantation [1, 2] and has been reported ence of ACI cells. ACI/Lew chimeras (ALC), animals sporadically following liver, lung, and small bowel that reconstituted only with syngeneic (Lewis) martransplantation. In order for GVHD to occur, three crirow (so-called failed chimeras), and ACI/Lew F1 teria must be met: (a) immunologic mismatch between (LACF 1 ) hybrid rats were all given 200 1 10 6 ACI splengraft and host, (b) lack of host response against graft ocytes i.v. Animals were examined for evidence of for a period of time long enough for the graft to mount GVHD. GVHD was quantified using the popliteal a response against the host, and (c) sufficient lymphoid lymph node enlargement assay. All LACF 1 (n Å 6) rats tissue in graft to mount a significant response against developed severe lethal GVHD following ACI splenocyte injection. Similarly, ALC (n Å 6) developed fatal the host . In experimental small bowel transplanta-GVHD. Animals that reconstituted only with syngeneic tion, the phenomenon of GVHD in the parent to F1 Lewis marrow (failed chimeras) showed no signs of direction (Lew r Lewis/Brown-Norway F1) has been illness. GVHD was confirmed histologically and immudescribed . The susceptibility of the host to GVHD nohistochemically. Failed chimeras receiving ACI under conditions of experimentally induced tolerance splenocyte challenge showed no evidence of GVHD hishas not been investigated, but is a concern for the futologically. Popliteal lymph node enlargement indices ture application of strategies to induce tolerance, parreflected the presence of GVHD in the chimeras and hybrids but not in the failed chimeras. We conclude that tolerance induction by mixed chimerism results TABLE 1 in susceptibility to GVHD if enough donor lymphoid Summary of Results Following Splenocyte Injection tissue is given to the host at the time of organ transplant. Animals that are not mixed chimeras (failed GVHD GVHD Mean
Surgery, 1996
Background. Chronic rejection is the leading cause of late graft loss in kidney transplantation. ... more Background. Chronic rejection is the leading cause of late graft loss in kidney transplantation. We tested the ability of mixed hematopoietic chimerism to prevent chronic renal aUografl rejection in an established rat model and described possible mechanisms responsible for this tolerance. Methods. Mixed hematopoietic chimerism was established in lethally irradiated F-344 rats by reconstitution with Lewis bone marrow. Four groups (n = 5 each) received orthotopic kidney transplants: (1) allografl controls, (2) isograft controls, (3) experimental chimeras, and (4) specificity control. After 120 days kidney grafts were examined histologically, immunohistochemically, and for cytokine interferon-% interleukin-2 (IL-2), IL-4, and IL-IO gene transcripts by means of reverse transcriptase polymerase chain reaction techniques.
Transplantation, 1998
These experiments investigated the ability of the donor-specific unresponsiveness created by the ... more These experiments investigated the ability of the donor-specific unresponsiveness created by the intrathymic inoculation of donor alloantigen to effectively prevent chronic rejection in an established rat model of chronic renal allograft rejection. Three study groups were examined: (1) Allograft controls--F-344 rats received a Lewis renal allograft plus 10 days of low-dose cyclosporine (CsA); (2) isograft controls--F-344 rats received an F-344 renal isograft and low-dose CsA; (3) experimental group--F-344 rats received a T-cell depleted syngeneic bone marrow transplant and intrathymic injection of Lewis bone marrow. Twenty-one days after bone marrow transplant, these animals received a Lewis renal allograft. Allograft controls demonstrated severe parenchymal fibrosis; isograft controls and intrathymic (IT) animals failed to develop this lesion. Immunohistochemical analysis revealed increased CD4+ T cells infiltrating the cortex of the allograft controls. Cytokine interferon-gamma and interleukin-2 transcripts were strongly positive in allograft controls and were absent from isograft controls and IT allografts as determined by reverse transcriptase-polymerase chain reaction. Analysis of tolerant grafts by flow microfluorimetry and genomic DNA amplification could not detect chimerism to a level of < 0.1%. IT inoculation of donor alloantigen can confer long-term unresponsiveness and prevent the development of the characteristic lesions of chronic rejection.