{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:2039"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:2039","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Stimulation of donor t-cells with leukemic blast-loaded dendritic cells for the generation of leukemia-specific immunity in the context of allogeneic stem cell transplantation","abstract":"Acute myeloid leukemia, a hematopoietic malignant monoclonal disease, is treated initially with chemotherapy and in some cases also by stem cell transplantation (SCT). The relapse rates are high, and long-term disease-free survival occurs in less than half of the AML patients. The curative potential of the allogeneic SCT can be explained by the pre-transplant chemo/radiotherapy in combination with an antitumor effect mediated by specific anti-leukemia donor lymphocytes cells, known as graft versus leukemia effect (GVL). This effect can be induced by the infusion of donor lymphocytes (DLI). Adoptive immunotherapy involving DLI, the current approach in relapsed allogeneic transplant patients, leads in this situation to a complete remission rate of 42%. Unfortunately, DLI is often complicated by graft versus host disease (GVHD), a potential lethal effect mediated also by donor T cells that target host tissues. Since different donor T-cell subsets may be responsible for the GVHD and GVL, it is desirable to generate more specific anti-leukemia cells, which would augment the beneficial GVL effect without causing GVHD. With this objective, we repetitively stimulated resting donor T cells (dTCs) by culturing them with autologous pre-activated dendritic cells (dDCs) loaded with irradiated patient leukemic blasts (p-LBs). The immune reactivity of the stimulated donor-TCs (dSTCs) to the pLBs and other haematopoietic derived patient cells, and a third party leukemic blast (3PLB) were measured by ELISPOT for IFN-g secreting cells and compared with the reaction of non-stimulated donor-TCs (dNSTCs). Three AML patients in relapse or progressive disease and their non-related matched donors were enrolled in the experiment. Although the absolute cell numbers in the cultures usually decreased to the end of the third stimulation, the percentage of dTCs (CD3+), especially the CD8+ subset and the expression of the activation markers CD25 and CD69 increased. dSTCs presented a stronger reaction to the different patient cells and 3P-LBs when compared with the dNSTCs. As dSTCs reacted not only with p-LB and 3P-LB, but also with other patient cells, we concluded that these cells were not strictly leukemia-specific. Since leukemic blasts and non-malignant haematopoietic cells share several antigens, especially the minor histocompatibility antigens, it would be desirable to test the same donor TCs against non-haematopoietic cells.","abstract_html":"Acute myeloid leukemia, a hematopoietic malignant monoclonal disease, is treated initially with chemotherapy and in some cases also by stem cell transplantation (SCT). The relapse rates are high, and long-term disease-free survival occurs in less than half of the AML patients. The curative potential of the allogeneic SCT can be explained by the pre-transplant chemo/radiotherapy in combination with an antitumor effect mediated by specific anti-leukemia donor lymphocytes cells, known as graft versus leukemia effect (GVL). This effect can be induced by the infusion of donor lymphocytes (DLI). Adoptive immunotherapy involving DLI, the current approach in relapsed allogeneic transplant patients, leads in this situation to a complete remission rate of 42%. Unfortunately, DLI is often complicated by graft versus host disease (GVHD), a potential lethal effect mediated also by donor T cells that target host tissues. Since different donor T-cell subsets may be responsible for the GVHD and GVL, it is desirable to generate more specific anti-leukemia cells, which would augment the beneficial GVL effect without causing GVHD. With this objective, we repetitively stimulated resting donor T cells (dTCs) by culturing them with autologous pre-activated dendritic cells (dDCs) loaded with irradiated patient leukemic blasts (p-LBs). The immune reactivity of the stimulated donor-TCs (dSTCs) to the pLBs and other haematopoietic derived patient cells, and a third party leukemic blast (3PLB) were measured by ELISPOT for IFN-g secreting cells and compared with the reaction of non-stimulated donor-TCs (dNSTCs). Three AML patients in relapse or progressive disease and their non-related matched donors were enrolled in the experiment. Although the absolute cell numbers in the cultures usually decreased to the end of the third stimulation, the percentage of dTCs (CD3+), especially the CD8+ subset and the expression of the activation markers CD25 and CD69 increased. dSTCs presented a stronger reaction to the different patient cells and 3P-LBs when compared with the dNSTCs. As dSTCs reacted not only with p-LB and 3P-LB, but also with other patient cells, we concluded that these cells were not strictly leukemia-specific. Since leukemic blasts and non-malignant haematopoietic cells share several antigens, especially the minor histocompatibility antigens, it would be desirable to test the same donor TCs against non-haematopoietic cells.","abstract_has_math":false,"creators":["Gil Alves Portugal, Tatiana"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Veelken, Hendrik"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:33Z","subjects":["stemcelltransplantation","Blast","Leukemia","dendritic cell","immunestimulation"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/2039","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Veelken, Hendrik"]},{"key":"dc:creator","label":"Author","values":["Gil Alves Portugal, Tatiana"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["stemcelltransplantation","Blast","Leukemia","dendritic cell","immunestimulation"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Acute myeloid leukemia, a hematopoietic malignant monoclonal disease, is treated initially with chemotherapy and in some cases also by stem cell transplantation (SCT). The relapse rates are high, and long-term disease-free survival occurs in less than half of the AML patients. The curative potential of the allogeneic SCT can be explained by the pre-transplant chemo/radiotherapy in combination with an antitumor effect mediated by specific anti-leukemia donor lymphocytes cells, known as graft versus leukemia effect (GVL). This effect can be induced by the infusion of donor lymphocytes (DLI). Adoptive immunotherapy involving DLI, the current approach in relapsed allogeneic transplant patients, leads in this situation to a complete remission rate of 42%. Unfortunately, DLI is often complicated by graft versus host disease (GVHD), a potential lethal effect mediated also by donor T cells that target host tissues. Since different donor T-cell subsets may be responsible for the GVHD and GVL, it is desirable to generate more specific anti-leukemia cells, which would augment the beneficial GVL effect without causing GVHD. With this objective, we repetitively stimulated resting donor T cells (dTCs) by culturing them with autologous pre-activated dendritic cells (dDCs) loaded with irradiated patient leukemic blasts (p-LBs). The immune reactivity of the stimulated donor-TCs (dSTCs) to the pLBs and other haematopoietic derived patient cells, and a third party leukemic blast (3PLB) were measured by ELISPOT for IFN-g secreting cells and compared with the reaction of non-stimulated donor-TCs (dNSTCs). Three AML patients in relapse or progressive disease and their non-related matched donors were enrolled in the experiment. Although the absolute cell numbers in the cultures usually decreased to the end of the third stimulation, the percentage of dTCs (CD3+), especially the CD8+ subset and the expression of the activation markers CD25 and CD69 increased. dSTCs presented a stronger reaction to the different patient cells and 3P-LBs when compared with the dNSTCs. As dSTCs reacted not only with p-LB and 3P-LB, but also with other patient cells, we concluded that these cells were not strictly leukemia-specific. Since leukemic blasts and non-malignant haematopoietic cells share several antigens, especially the minor histocompatibility antigens, it would be desirable to test the same donor TCs against non-haematopoietic cells.","Akute myeloide Leukämie (AML), eine hämatopoitische bösartige monoklonale Krankheit, wird zunächst mit Chemotherapie behandelt und in manchen Fällen auch mit Stammzellentransplantation (SCT). Die Quoten, einen Rückfall zu erleiden sind hoch, und ein langfristig krankheitsfreies Überleben tritt in weniger als der Hälfte der AML-Patienten auf. Das Heilungspotenzial der allogeneischen Stammzellentransplantation kann durch eine prä-transplantative Chemo-/Radiotherapie in Verbindung mit einem Antitumor-Effekt, der durch spezifische anti-leukämische Spender-Lymphozytenzellen vermittelt wird, die auch als graft versus leukemia Effekt (GVL) bekannt sind, begründet werden. Dieser Effekt kann durch die Infusion von Spenderlymphozyten (DLI) hervorgerufen werden. Adoptive Immuntherapie, die DLI beinhaltet, welches der gegenwärtige Ansatz für allogeneische Transplantationspatienten ist, die einen Rückfall erlitten haben, führt in dieser Situation zu einer vorübergehenden Besserungsrate von 42%. Unglücklicherweise wird DLI oft durch graft versus host disease (GVHD) kompliziert, einen unter Umständen fatalen Effekt, der auch durch Spender T Zellen hervorgerufen wird, die gegen das Empfängergewebe gerichtet sind. Da verschiedene Spender T Zellenuntergruppen für den GVHD und den GVL verantwortlich sein können, ist es wünschenswert spezifischere anti-leukämische Zellen zu generieren, welche den vorteilhaften GVL Effekt fördern würden ohne GVHD auszulösen. Mit dieser Zielsetzung haben wir wiederholt ruhende Spender T Zellen (cTCs) stimuliert, indem wir sie mit autolog voraktivierten dendritischen Zellen (dDCs) kultiviert haben, die mit irradiatiertem leukämischen Blast der Patienten geladen (p-LBs) waren. Die Immunreaktivität der stimulierten Spender T Zellen (dSTCs) gegenüber des leukämischer Blast des Patienten (pLBs) und anderen hämatopoitischen hergeleiteten Zellen des Patienten, sowie ein leukämischer Blast einer dritten Partei (3PLB) wurden mittels ELISPOT auf IFN-g ausschüttende Zellen untersucht und mit der Reaktion nicht stimulierter Spender T Zellen (dNSTCs) verglichen. Drei AML Patienten, die einen Rückfall erlitten hatten oder sich in fortgeschrittenem Krankheitsstadium befanden, sowie ihre nicht-verwandten passenden Spender wurden in diesem Experiment aufgenommen. Obwohl die absolute Anzahl an Zellen in den Kulturen zum Ende der dritten Stimulation in der Regel abnahm, nahm der Prozentsatz von dTCs (CD3+) zu, dabei nahmen insbesondere die CD8+ Untergruppe und der Ausdruck der Aktivitätsmarker CD25 und CD69 zu. DSTCs zeigten eine stärkere Reaktion gegenüber den verschiedenen Zellen des Patienten als dNSTCs. Da dSTCs nicht nur mit p-LB und 3P-LB reagieren, sondern auch mit anderen Zellen des Patienten, folgerten wir daraus, dass diese Zellen nicht ausschließlich leukämiespezifisch waren. Da sich leukämischer Blast und nicht-bösartige hämatopoitische Zellen diverse Antigene teilen, insbesondere die kleineren Histokompatibilitäts-Antigene, wäre es wünschenswert, die selben Spender T Zellen TCs gegen nicht hämatopoitische Zellen zu testen."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Stimulation of donor t-cells with leukemic blast-loaded dendritic cells for the generation of leukemia-specific immunity in the context of allogeneic stem cell transplantation","Stimulation von Spender T-Zellen mit leukämischem Blast geladenen dendritischen Zellen zur Generierung leukämiespezifischer Immunität im Kontext allogeneischer Stammzellentransplantation"]}]}],"canonical_facts":{"dc:contributor":["Veelken, Hendrik"],"dc:creator":["Gil Alves Portugal, Tatiana"],"dc:description.abstract":["Acute myeloid leukemia, a hematopoietic malignant monoclonal disease, is treated initially with chemotherapy and in some cases also by stem cell transplantation (SCT). The relapse rates are high, and long-term disease-free survival occurs in less than half of the AML patients. The curative potential of the allogeneic SCT can be explained by the pre-transplant chemo/radiotherapy in combination with an antitumor effect mediated by specific anti-leukemia donor lymphocytes cells, known as graft versus leukemia effect (GVL). This effect can be induced by the infusion of donor lymphocytes (DLI). Adoptive immunotherapy involving DLI, the current approach in relapsed allogeneic transplant patients, leads in this situation to a complete remission rate of 42%. Unfortunately, DLI is often complicated by graft versus host disease (GVHD), a potential lethal effect mediated also by donor T cells that target host tissues. Since different donor T-cell subsets may be responsible for the GVHD and GVL, it is desirable to generate more specific anti-leukemia cells, which would augment the beneficial GVL effect without causing GVHD. With this objective, we repetitively stimulated resting donor T cells (dTCs) by culturing them with autologous pre-activated dendritic cells (dDCs) loaded with irradiated patient leukemic blasts (p-LBs). The immune reactivity of the stimulated donor-TCs (dSTCs) to the pLBs and other haematopoietic derived patient cells, and a third party leukemic blast (3PLB) were measured by ELISPOT for IFN-g secreting cells and compared with the reaction of non-stimulated donor-TCs (dNSTCs). Three AML patients in relapse or progressive disease and their non-related matched donors were enrolled in the experiment. Although the absolute cell numbers in the cultures usually decreased to the end of the third stimulation, the percentage of dTCs (CD3+), especially the CD8+ subset and the expression of the activation markers CD25 and CD69 increased. dSTCs presented a stronger reaction to the different patient cells and 3P-LBs when compared with the dNSTCs. As dSTCs reacted not only with p-LB and 3P-LB, but also with other patient cells, we concluded that these cells were not strictly leukemia-specific. Since leukemic blasts and non-malignant haematopoietic cells share several antigens, especially the minor histocompatibility antigens, it would be desirable to test the same donor TCs against non-haematopoietic cells.","Akute myeloide Leukämie (AML), eine hämatopoitische bösartige monoklonale Krankheit, wird zunächst mit Chemotherapie behandelt und in manchen Fällen auch mit Stammzellentransplantation (SCT). Die Quoten, einen Rückfall zu erleiden sind hoch, und ein langfristig krankheitsfreies Überleben tritt in weniger als der Hälfte der AML-Patienten auf. Das Heilungspotenzial der allogeneischen Stammzellentransplantation kann durch eine prä-transplantative Chemo-/Radiotherapie in Verbindung mit einem Antitumor-Effekt, der durch spezifische anti-leukämische Spender-Lymphozytenzellen vermittelt wird, die auch als graft versus leukemia Effekt (GVL) bekannt sind, begründet werden. Dieser Effekt kann durch die Infusion von Spenderlymphozyten (DLI) hervorgerufen werden. Adoptive Immuntherapie, die DLI beinhaltet, welches der gegenwärtige Ansatz für allogeneische Transplantationspatienten ist, die einen Rückfall erlitten haben, führt in dieser Situation zu einer vorübergehenden Besserungsrate von 42%. Unglücklicherweise wird DLI oft durch graft versus host disease (GVHD) kompliziert, einen unter Umständen fatalen Effekt, der auch durch Spender T Zellen hervorgerufen wird, die gegen das Empfängergewebe gerichtet sind. Da verschiedene Spender T Zellenuntergruppen für den GVHD und den GVL verantwortlich sein können, ist es wünschenswert spezifischere anti-leukämische Zellen zu generieren, welche den vorteilhaften GVL Effekt fördern würden ohne GVHD auszulösen. Mit dieser Zielsetzung haben wir wiederholt ruhende Spender T Zellen (cTCs) stimuliert, indem wir sie mit autolog voraktivierten dendritischen Zellen (dDCs) kultiviert haben, die mit irradiatiertem leukämischen Blast der Patienten geladen (p-LBs) waren. Die Immunreaktivität der stimulierten Spender T Zellen (dSTCs) gegenüber des leukämischer Blast des Patienten (pLBs) und anderen hämatopoitischen hergeleiteten Zellen des Patienten, sowie ein leukämischer Blast einer dritten Partei (3PLB) wurden mittels ELISPOT auf IFN-g ausschüttende Zellen untersucht und mit der Reaktion nicht stimulierter Spender T Zellen (dNSTCs) verglichen. Drei AML Patienten, die einen Rückfall erlitten hatten oder sich in fortgeschrittenem Krankheitsstadium befanden, sowie ihre nicht-verwandten passenden Spender wurden in diesem Experiment aufgenommen. Obwohl die absolute Anzahl an Zellen in den Kulturen zum Ende der dritten Stimulation in der Regel abnahm, nahm der Prozentsatz von dTCs (CD3+) zu, dabei nahmen insbesondere die CD8+ Untergruppe und der Ausdruck der Aktivitätsmarker CD25 und CD69 zu. DSTCs zeigten eine stärkere Reaktion gegenüber den verschiedenen Zellen des Patienten als dNSTCs. Da dSTCs nicht nur mit p-LB und 3P-LB reagieren, sondern auch mit anderen Zellen des Patienten, folgerten wir daraus, dass diese Zellen nicht ausschließlich leukämiespezifisch waren. Da sich leukämischer Blast und nicht-bösartige hämatopoitische Zellen diverse Antigene teilen, insbesondere die kleineren Histokompatibilitäts-Antigene, wäre es wünschenswert, die selben Spender T Zellen TCs gegen nicht hämatopoitische Zellen zu testen."],"dc:format.medium":["application/pdf"],"dc:subject":["stemcelltransplantation","Blast","Leukemia","dendritic cell","immunestimulation"],"dc:title":["Stimulation of donor t-cells with leukemic blast-loaded dendritic cells for the generation of leukemia-specific immunity in the context of allogeneic stem cell transplantation","Stimulation von Spender T-Zellen mit leukämischem Blast geladenen dendritischen Zellen zur Generierung leukämiespezifischer Immunität im Kontext allogeneischer Stammzellentransplantation"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:33Z"}