{"id":{"repo_id":"catania","oai_identifier":"oai:www.iris.unict.it:20.500.11769/586004"},"canonical_url":"https://search.dev.ndltd.org/etd/catania/oai:www.iris.unict.it:20.500.11769/586004","repository":{"repo_id":"catania","name":"Università degli Studi di Catania","base_url":"https://www.iris.unict.it/oai/request"},"display":{"title":"Histopathology of livers and native organs of recipients following genetically-engineered pig-to-baboon liver xenotransplantation","abstract":"In project 1, orthotopic liver transplantation was carried out in baboons using wild-type (WT,n=1) or genetically-engineered (GE) pigs (alpha1,3-galactosyltransferase gene-knockout, GTKO), n=1; GTKO pigs transgenic for human CD46, n=7). Biopsies of GE livers were obtained pre-transplantation, 2h after reperfusion and at necropsy (4 7 days after transplantation). The histopathology of livers and major native organs and lymph nodes were studied by direct light microscopy, immunohistology, and electron microscopy to determine morphological changes in the liver and native organs. In project 2, 12 baboons received carotid artery patch transplants from GE pigs (either GTKO/CD46/CIITA-DN; Group 1,n=8 or GTKO/CD46; Group 2,n=4). One baboon in Group 1 received no immunosuppressive therapy. Group 1A(n=2) received abatacept-based regimen. Groups 1B(n=3) received belatacept-based regimen and Group 1C(n=2) received a regimen based on costimulation blockade of both the CD28/B7 and CD40/CD154 pathways. Results: In project 1, after GE pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4 7 days due to repeated spontaneous bleeding as a result of profound thrombocytopenia which necessitated euthanasia. At 2h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role. In project 2, when GTKO/CD46/CIITA-DN grafts were transplanted (Group 1), but no immunosuppression was administered, an elicited anti-pig antibody response, a proliferative T cell response on MLR, and intense cell infiltration of the graft were documented. When CD28/B7 pathway blockade was administered (Group 1A), no proliferative response was seen in T cells on MLR, and the elicited antibody response was greatly attenuated. It was only when both pathways were blocked that no elicited antibody response was documented (Groups 1C and 2). In these cases, cell infiltration of the graft was minimal or absent. In recipients of CIITA-DN grafts with both CD28/B7 and CD40/CD154 costimulatory pathway blockades (Group 1C), there was no proliferative response on T cells post-transplantation, elicited antibody response was the lowest. Only blockade of both pathways (Group 1C) prevented T cell proliferative and elicited antibody responses and cell infiltration of the graft. In order to determine whether the CIITA-DN mutation was playing a role, this regimen was administered to four baboons receiving grafts from GTKO/CD46 pigs (Group 2). No proliferative or elicited antibody responses were documented and there was no significant cell infiltration of the graft. Conclusions: In project 1, after GTKO and GTKO/CD46 pig liver Tx in baboons, the rapid development of a profound thrombocytopenia was by far the major problem seen. The histopathologic features described can largely be explained on this basis. If platelet activation and aggregation/phagocytosis can be prevented, possibly by further genetic modification of the pigs or by novel therapeutic agents, bridging by a pig liver to allotransplantation may become a feasible clinical option. In project 2, blockade of both the CD40/CD154 and CD28/B7 pathways is required to prevent the baboon adaptive response to a pig artery patch graft. If the graft is taken from a CIITA-DN pig, then the adaptive response is reduced. The presence of a CIITA-DN graft reduced the baboon T cell-dependent anti-nonGal IgG response.","abstract_html":"In project 1, orthotopic liver transplantation was carried out in baboons using wild-type (WT,n=1) or genetically-engineered (GE) pigs (alpha1,3-galactosyltransferase gene-knockout, GTKO), n=1; GTKO pigs transgenic for human CD46, n=7). Biopsies of GE livers were obtained pre-transplantation, 2h after reperfusion and at necropsy (4 7 days after transplantation). The histopathology of livers and major native organs and lymph nodes were studied by direct light microscopy, immunohistology, and electron microscopy to determine morphological changes in the liver and native organs. In project 2, 12 baboons received carotid artery patch transplants from GE pigs (either GTKO/CD46/CIITA-DN; Group 1,n=8 or GTKO/CD46; Group 2,n=4). One baboon in Group 1 received no immunosuppressive therapy. Group 1A(n=2) received abatacept-based regimen. Groups 1B(n=3) received belatacept-based regimen and Group 1C(n=2) received a regimen based on costimulation blockade of both the CD28/B7 and CD40/CD154 pathways. Results: In project 1, after GE pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4 7 days due to repeated spontaneous bleeding as a result of profound thrombocytopenia which necessitated euthanasia. At 2h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role. In project 2, when GTKO/CD46/CIITA-DN grafts were transplanted (Group 1), but no immunosuppression was administered, an elicited anti-pig antibody response, a proliferative T cell response on MLR, and intense cell infiltration of the graft were documented. When CD28/B7 pathway blockade was administered (Group 1A), no proliferative response was seen in T cells on MLR, and the elicited antibody response was greatly attenuated. It was only when both pathways were blocked that no elicited antibody response was documented (Groups 1C and 2). In these cases, cell infiltration of the graft was minimal or absent. In recipients of CIITA-DN grafts with both CD28/B7 and CD40/CD154 costimulatory pathway blockades (Group 1C), there was no proliferative response on T cells post-transplantation, elicited antibody response was the lowest. Only blockade of both pathways (Group 1C) prevented T cell proliferative and elicited antibody responses and cell infiltration of the graft. In order to determine whether the CIITA-DN mutation was playing a role, this regimen was administered to four baboons receiving grafts from GTKO/CD46 pigs (Group 2). No proliferative or elicited antibody responses were documented and there was no significant cell infiltration of the graft. Conclusions: In project 1, after GTKO and GTKO/CD46 pig liver Tx in baboons, the rapid development of a profound thrombocytopenia was by far the major problem seen. The histopathologic features described can largely be explained on this basis. If platelet activation and aggregation/phagocytosis can be prevented, possibly by further genetic modification of the pigs or by novel therapeutic agents, bridging by a pig liver to allotransplantation may become a feasible clinical option. In project 2, blockade of both the CD40/CD154 and CD28/B7 pathways is required to prevent the baboon adaptive response to a pig artery patch graft. If the graft is taken from a CIITA-DN pig, then the adaptive response is reduced. The presence of a CIITA-DN graft reduced the baboon T cell-dependent anti-nonGal IgG response.","abstract_has_math":false,"creators":["EKSER, BURCIN"],"institution":"Università degli studi di Catania","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["VEROUX, Massimiliano","STEFANI, Stefania"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-12-03","date_published":"2013-12-03","updated_at":"2026-07-24T01:35:03Z","subjects":["liver, xenotransplantation, genetically-engineered, pigs, baboons, costimulation blockade, xenotrapianto, maiali, porcine, blocco di costimolazione"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.11769/586004","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Ekser, Burcin","VEROUX, Massimiliano","STEFANI, Stefania"]},{"key":"dc:creator","label":"Author","values":["EKSER, BURCIN"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-12-03"]},{"key":"dc:publisher","label":"Institution","values":["Università degli studi di Catania","place:Catania"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["liver, xenotransplantation, genetically-engineered, pigs, baboons, costimulation blockade, xenotrapianto, maiali, porcine, blocco di costimolazione"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/20.500.11769/586004"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["In project 1, orthotopic liver transplantation was carried out in baboons using wild-type (WT,n=1) or genetically-engineered (GE) pigs (alpha1,3-galactosyltransferase gene-knockout, GTKO), n=1; GTKO pigs transgenic for human CD46, n=7). Biopsies of GE livers were obtained pre-transplantation, 2h after reperfusion and at necropsy (4 7 days after transplantation). The histopathology of livers and major native organs and lymph nodes were studied by direct light microscopy, immunohistology, and electron microscopy to determine morphological changes in the liver and native organs. In project 2, 12 baboons received carotid artery patch transplants from GE pigs (either GTKO/CD46/CIITA-DN; Group 1,n=8 or GTKO/CD46; Group 2,n=4). One baboon in Group 1 received no immunosuppressive therapy. Group 1A(n=2) received abatacept-based regimen. Groups 1B(n=3) received belatacept-based regimen and Group 1C(n=2) received a regimen based on costimulation blockade of both the CD28/B7 and CD40/CD154 pathways. Results: In project 1, after GE pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4 7 days due to repeated spontaneous bleeding as a result of profound thrombocytopenia which necessitated euthanasia. At 2h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role. In project 2, when GTKO/CD46/CIITA-DN grafts were transplanted (Group 1), but no immunosuppression was administered, an elicited anti-pig antibody response, a proliferative T cell response on MLR, and intense cell infiltration of the graft were documented. When CD28/B7 pathway blockade was administered (Group 1A), no proliferative response was seen in T cells on MLR, and the elicited antibody response was greatly attenuated. It was only when both pathways were blocked that no elicited antibody response was documented (Groups 1C and 2). In these cases, cell infiltration of the graft was minimal or absent. In recipients of CIITA-DN grafts with both CD28/B7 and CD40/CD154 costimulatory pathway blockades (Group 1C), there was no proliferative response on T cells post-transplantation, elicited antibody response was the lowest. Only blockade of both pathways (Group 1C) prevented T cell proliferative and elicited antibody responses and cell infiltration of the graft. In order to determine whether the CIITA-DN mutation was playing a role, this regimen was administered to four baboons receiving grafts from GTKO/CD46 pigs (Group 2). No proliferative or elicited antibody responses were documented and there was no significant cell infiltration of the graft. Conclusions: In project 1, after GTKO and GTKO/CD46 pig liver Tx in baboons, the rapid development of a profound thrombocytopenia was by far the major problem seen. The histopathologic features described can largely be explained on this basis. If platelet activation and aggregation/phagocytosis can be prevented, possibly by further genetic modification of the pigs or by novel therapeutic agents, bridging by a pig liver to allotransplantation may become a feasible clinical option. In project 2, blockade of both the CD40/CD154 and CD28/B7 pathways is required to prevent the baboon adaptive response to a pig artery patch graft. If the graft is taken from a CIITA-DN pig, then the adaptive response is reduced. The presence of a CIITA-DN graft reduced the baboon T cell-dependent anti-nonGal IgG response.","Progetto 1, sono stati eseguiti 9 xenotrapianti di fegato: 1 da maiale non-modificato (WT), 1 da maiali con alpha1,3-galactosyltransferase gene-knockout (GTKO), 7 da maiali con GTKO/CD46. L'istopatologia di fegati e dei principali organi nativi e stata esaminata dalla microscopia diretta, immunoistologia e microscopia elettronica per determinare i cambiamenti morfologici nel fegato e negli organi nativi. Progetto 2, 12 babbuini hanno ricevuto trapianti di patch dell arteria da maiali geneticamente modificati (GTKO/CD46/CIITA-DN; Gruppo 1, n=8 o GTKO/CD46; Gruppo 2, n=4). Un babbuino nel Gruppo 1 non ha ricevuto terapia immunosoppressiva. Il Gruppo 1A (n=2) ha ricevuto la terapia con abatacept. Il Gruppo 1B (n=3) ha ricevuto la terapia con belatacept e il Gruppo 1C (n=2) ha ricevuto un regime basato sul blocco di costimolazione di 2 pathways CD28/B7 e CD40/CD154 con belatacept+anti-CD40mAb (2C10R4), come nel Gruppo 2. Risultati: Progetto 1, il rigetto iperacuto non e successo con il maiale geneticamente modificato. La sopravvivenza oltre 7 giorni è stata impedita da una profonda trombocitopenia, risultando nell emorragia spontanea. L istopatologia dopo 2h era normale, ma all autopsia, i fegati di maiale geneticamente modificato hanno mostrato la necrosi emorragica, l'aggregazione piastrinica, i trombi formati da piastrine-fibrina, una marginazione dei monociti-macrofagi soprattutto nei sinusoidi epatici ed ipertrofia delle cellule endoteliali vascolari, confermata da microscopia confocale ed elettronica. L'immunoistochimica ha evidenziato la minima deposizione di IgM e quasi mancanza di IgG, C3, C4d, C5b-9, e di infiltrato cellulare, suggerendo che né il rigetto cellulare né il rigetto umorale gioca un ruolo importante. Progetto 2, quando le arterie da maiali di GTKO/CD46/CIITA-DN sono state trapiantate (Gruppo 1), senza l immunosoppressione, una risposta anticorpale e proliferativa delle cellule T, e l'infiltrazione cellulare nell arteria e stata documentata. Quando il blocco di CD28/B7 pathway è stato somministrato (Gruppo 1A), nessuna risposta proliferativa si e osservata, ma la risposta umorale era presente. La risposta umorale era bloccato soltanto quando gli entrambi pathway sono state bloccate (Gruppi 1C e 2). In questi casi, l infiltrazione cellulare nell innesto arteriale era minima o mancante. Nei riceventi dell arteria di CIITA-DN con il blocco di entrambi pathway di CD28/B7 e CD40/CD154 (Gruppo 1C), non vi era alcuna risposta proliferativa delle cellule T, ne una risposta umorale. Per determinare se la mutazione CIITA-DN Il, Gruppo 2 (GTKO/CD46) ha ricevuto lo stesso regime immunosuppressivo. Come il Gruppo 1C nessuna risposta significativa immunitaria adattiva e stata vista. Tuttavia, quando i risultati del Gruppo 1A sono stati confrontati con quelli del gruppo storico (GTKO) con il blocco di CD28/B7 pathway, la risposta umorale è stata significativamente ridotta quando l arteria veniva dal maiale CIITA-DN. Conclusioni: Progetto 1, dopo il trapianto di fegato dai maiali GTKO e GTKO/CD46, lo sviluppo rapido di trombocitopenia profonda era il problema principale ed e stato suggerito come il fattore principale dell emorragia. Le caratteristiche istopatologiche descritte possono essere spiegato su questa base. Poiché le caratteristiche del rigetto erano minime o assenti, crediamo che, se l'attivazione e l'aggregazione o la fagocitosi delle piastrine potesse essere impedita, possibilmente con una ulteriore modifica genetica o con gli agenti terapeutici, l opzione del ponte all allotrapianto con il fegato di maiale potrebbe diventare una verita clinica. Progetto 2, ha dimostrato che il blocco di entrambi pathway CD40/CD154 e CD28/B7 è necessario per evitare la risposta immunitaria adattativa dello xenotrapianto. Il maiale CIITA-DN riduce la risposta proliferativa delle cellule T e la risposta umorale, percio la risposta immunitaria adattativa."]},{"key":"dc:title","label":"Title","values":["Histopathology of livers and native organs of recipients following genetically-engineered pig-to-baboon liver xenotransplantation"]}]}],"canonical_facts":{"dc:contributor":["Ekser, Burcin","VEROUX, Massimiliano","STEFANI, Stefania"],"dc:creator":["EKSER, BURCIN"],"dc:date":["2013-12-03"],"dc:description":["In project 1, orthotopic liver transplantation was carried out in baboons using wild-type (WT,n=1) or genetically-engineered (GE) pigs (alpha1,3-galactosyltransferase gene-knockout, GTKO), n=1; GTKO pigs transgenic for human CD46, n=7). Biopsies of GE livers were obtained pre-transplantation, 2h after reperfusion and at necropsy (4 7 days after transplantation). The histopathology of livers and major native organs and lymph nodes were studied by direct light microscopy, immunohistology, and electron microscopy to determine morphological changes in the liver and native organs. In project 2, 12 baboons received carotid artery patch transplants from GE pigs (either GTKO/CD46/CIITA-DN; Group 1,n=8 or GTKO/CD46; Group 2,n=4). One baboon in Group 1 received no immunosuppressive therapy. Group 1A(n=2) received abatacept-based regimen. Groups 1B(n=3) received belatacept-based regimen and Group 1C(n=2) received a regimen based on costimulation blockade of both the CD28/B7 and CD40/CD154 pathways. Results: In project 1, after GE pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4 7 days due to repeated spontaneous bleeding as a result of profound thrombocytopenia which necessitated euthanasia. At 2h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role. In project 2, when GTKO/CD46/CIITA-DN grafts were transplanted (Group 1), but no immunosuppression was administered, an elicited anti-pig antibody response, a proliferative T cell response on MLR, and intense cell infiltration of the graft were documented. When CD28/B7 pathway blockade was administered (Group 1A), no proliferative response was seen in T cells on MLR, and the elicited antibody response was greatly attenuated. It was only when both pathways were blocked that no elicited antibody response was documented (Groups 1C and 2). In these cases, cell infiltration of the graft was minimal or absent. In recipients of CIITA-DN grafts with both CD28/B7 and CD40/CD154 costimulatory pathway blockades (Group 1C), there was no proliferative response on T cells post-transplantation, elicited antibody response was the lowest. Only blockade of both pathways (Group 1C) prevented T cell proliferative and elicited antibody responses and cell infiltration of the graft. In order to determine whether the CIITA-DN mutation was playing a role, this regimen was administered to four baboons receiving grafts from GTKO/CD46 pigs (Group 2). No proliferative or elicited antibody responses were documented and there was no significant cell infiltration of the graft. Conclusions: In project 1, after GTKO and GTKO/CD46 pig liver Tx in baboons, the rapid development of a profound thrombocytopenia was by far the major problem seen. The histopathologic features described can largely be explained on this basis. If platelet activation and aggregation/phagocytosis can be prevented, possibly by further genetic modification of the pigs or by novel therapeutic agents, bridging by a pig liver to allotransplantation may become a feasible clinical option. In project 2, blockade of both the CD40/CD154 and CD28/B7 pathways is required to prevent the baboon adaptive response to a pig artery patch graft. If the graft is taken from a CIITA-DN pig, then the adaptive response is reduced. The presence of a CIITA-DN graft reduced the baboon T cell-dependent anti-nonGal IgG response.","Progetto 1, sono stati eseguiti 9 xenotrapianti di fegato: 1 da maiale non-modificato (WT), 1 da maiali con alpha1,3-galactosyltransferase gene-knockout (GTKO), 7 da maiali con GTKO/CD46. L'istopatologia di fegati e dei principali organi nativi e stata esaminata dalla microscopia diretta, immunoistologia e microscopia elettronica per determinare i cambiamenti morfologici nel fegato e negli organi nativi. Progetto 2, 12 babbuini hanno ricevuto trapianti di patch dell arteria da maiali geneticamente modificati (GTKO/CD46/CIITA-DN; Gruppo 1, n=8 o GTKO/CD46; Gruppo 2, n=4). Un babbuino nel Gruppo 1 non ha ricevuto terapia immunosoppressiva. Il Gruppo 1A (n=2) ha ricevuto la terapia con abatacept. Il Gruppo 1B (n=3) ha ricevuto la terapia con belatacept e il Gruppo 1C (n=2) ha ricevuto un regime basato sul blocco di costimolazione di 2 pathways CD28/B7 e CD40/CD154 con belatacept+anti-CD40mAb (2C10R4), come nel Gruppo 2. Risultati: Progetto 1, il rigetto iperacuto non e successo con il maiale geneticamente modificato. La sopravvivenza oltre 7 giorni è stata impedita da una profonda trombocitopenia, risultando nell emorragia spontanea. L istopatologia dopo 2h era normale, ma all autopsia, i fegati di maiale geneticamente modificato hanno mostrato la necrosi emorragica, l'aggregazione piastrinica, i trombi formati da piastrine-fibrina, una marginazione dei monociti-macrofagi soprattutto nei sinusoidi epatici ed ipertrofia delle cellule endoteliali vascolari, confermata da microscopia confocale ed elettronica. L'immunoistochimica ha evidenziato la minima deposizione di IgM e quasi mancanza di IgG, C3, C4d, C5b-9, e di infiltrato cellulare, suggerendo che né il rigetto cellulare né il rigetto umorale gioca un ruolo importante. Progetto 2, quando le arterie da maiali di GTKO/CD46/CIITA-DN sono state trapiantate (Gruppo 1), senza l immunosoppressione, una risposta anticorpale e proliferativa delle cellule T, e l'infiltrazione cellulare nell arteria e stata documentata. Quando il blocco di CD28/B7 pathway è stato somministrato (Gruppo 1A), nessuna risposta proliferativa si e osservata, ma la risposta umorale era presente. La risposta umorale era bloccato soltanto quando gli entrambi pathway sono state bloccate (Gruppi 1C e 2). In questi casi, l infiltrazione cellulare nell innesto arteriale era minima o mancante. Nei riceventi dell arteria di CIITA-DN con il blocco di entrambi pathway di CD28/B7 e CD40/CD154 (Gruppo 1C), non vi era alcuna risposta proliferativa delle cellule T, ne una risposta umorale. Per determinare se la mutazione CIITA-DN Il, Gruppo 2 (GTKO/CD46) ha ricevuto lo stesso regime immunosuppressivo. Come il Gruppo 1C nessuna risposta significativa immunitaria adattiva e stata vista. Tuttavia, quando i risultati del Gruppo 1A sono stati confrontati con quelli del gruppo storico (GTKO) con il blocco di CD28/B7 pathway, la risposta umorale è stata significativamente ridotta quando l arteria veniva dal maiale CIITA-DN. Conclusioni: Progetto 1, dopo il trapianto di fegato dai maiali GTKO e GTKO/CD46, lo sviluppo rapido di trombocitopenia profonda era il problema principale ed e stato suggerito come il fattore principale dell emorragia. Le caratteristiche istopatologiche descritte possono essere spiegato su questa base. Poiché le caratteristiche del rigetto erano minime o assenti, crediamo che, se l'attivazione e l'aggregazione o la fagocitosi delle piastrine potesse essere impedita, possibilmente con una ulteriore modifica genetica o con gli agenti terapeutici, l opzione del ponte all allotrapianto con il fegato di maiale potrebbe diventare una verita clinica. Progetto 2, ha dimostrato che il blocco di entrambi pathway CD40/CD154 e CD28/B7 è necessario per evitare la risposta immunitaria adattativa dello xenotrapianto. Il maiale CIITA-DN riduce la risposta proliferativa delle cellule T e la risposta umorale, percio la risposta immunitaria adattativa."],"dc:identifier":["https://hdl.handle.net/20.500.11769/586004"],"dc:language":["eng"],"dc:publisher":["Università degli studi di Catania","place:Catania"],"dc:rights":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"],"dc:subject":["liver, xenotransplantation, genetically-engineered, pigs, baboons, costimulation blockade, xenotrapianto, maiali, porcine, blocco di costimolazione"],"dc:title":["Histopathology of livers and native organs of recipients following genetically-engineered pig-to-baboon liver xenotransplantation"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-24T01:35:03Z"}