Katharina Fleischhauer
e-mail: fleischhauer.katharina AT hsr.it
affiliation: San Raffaele Scientific Institute
research area(s): Genetics And Genomics, Immunity And Infection
Course:
Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
University/Istitution: Università Vita-Salute San Raffaele
Curriculum Vitae
2010 - Present Research Unit Head, Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
2002 - Present Director, HLA Tissue Typing Laboratory, Department of Immunohematology and Blood Transfusion, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
2005 Board in Allergology and Clinical Immunology, San Raffaele Vita-Salute University, Milan, Italy
2002 - 2010 Staff Project Leader, Immunogenetics, San Raffaele Telethon Institute for Gene Therapy, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1997 - 2002 Tenure Track Research Assistant, Tumor Immunology and Immunogenetics, Laboratory for Experimental Hematology, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1992 - 1997 Research Fellow, Tumor Immunology and Immunogenetics, Laboratory for Experimental Hematology, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1988 - 1992 Research Fellow, Immunogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, USA
1988 MD, University of Bonn, Germany
2010 - Present Research Unit Head, Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
2002 - Present Director, HLA Tissue Typing Laboratory, Department of Immunohematology and Blood Transfusion, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
2005 Board in Allergology and Clinical Immunology, San Raffaele Vita-Salute University, Milan, Italy
2002 - 2010 Staff Project Leader, Immunogenetics, San Raffaele Telethon Institute for Gene Therapy, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1997 - 2002 Tenure Track Research Assistant, Tumor Immunology and Immunogenetics, Laboratory for Experimental Hematology, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1992 - 1997 Research Fellow, Tumor Immunology and Immunogenetics, Laboratory for Experimental Hematology, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy
1988 - 1992 Research Fellow, Immunogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, USA
1988 MD, University of Bonn, Germany
Our research is aimed at elucidating the interplay between the immune system of host and donor after allogeneic hematopoietic stem cell transplantation for the cure of neoplastic and genetic hematologic diseases. Immunogenetic differences between the highly polymorphic human leukocyte antigen (HLA) molecules of patient and donor can be target of alloreactive responses from T and NK cells, which can on the one hand be exploited for eradication of residual neoplastic cells (beneficial graft versus leukemia effect), but are on the other hand responsible for graft versus host disease and rejection, the main clinical complications after stem cell transplantation. Using cellular and molecular systems, we are characterizing these responses both at the structural and at the functional level, with the aim of translating this knowledge into the refinement of clinical transplant protocols.
Selected Publications
Sizzano F, Zito L, Crivello P, Crocchiolo R, Vago L, Zino E, Fleischhauer K. Significantly higher frequencies of alloreactive CD4+ T cells responding to non-permissive than to permissive HLA-DPB1 T cell epitope disparities. Blood 2010: 116: 1991-1992 .
Marktel S*, Napolitano S*, Zino E*, Cappelli B, Chiesa R, Poli F, Crocchiolo R, Ronchi P, Rossini S, Ciceri F, Roncarolo MG, Fleischhauer K. Platelet transfusion refractoriness in highly immunized beta thalassemia children undergoing stem cell transplantation. Pediatr Transplant 2010: 14: 393-401. Epub 2010 Jan 7. *equal contribution.
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Lupo Stanghellini MT, Perrelli NF, Cosentino C, Torri F, Angius A, Forno B, Casucci M, Bernardi M, Peccatori J, Corti C, Bondanza A, Ferrari M, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009: 361: 478-488.
Crocchiolo R, Zino E, Vago L, Oneto R, Bruno B, Pollichieni S, Sacchi N, Sormani MP, Marcon J, Lamparelli T, Fanin R, Garbarino L, Miotti V, Bandini G, Bosi A, Ciceri F, Bacigalupo A, Fleischhauer K. Non-Permissive HLA-DPB1 Disparity is a Significant Independent Risk Factor for Mortality after Unrelated Hematopoietic Stem Cell Transplantation. Blood 2009: 114: 1437-1444. Epub 2009 Jun 10.
Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S, Lupo Stanghellini MT, Mazzi B, Perna SK, Bondanza A, Middleton D, Palini A, Bernardi M, Bacchetta R, Peccatori J, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Temporal, quantitative and functional characteristics of single-KIR positive alloreactive NK cell recovery account for impaired graft versus leukemia activity after haploidentical HSCT. Blood 2008: 112: 3488-3499. Epub 2008 Jul 21.
Mazzi B, Clerici TD, Zanussi M, Lupo Stanghellini MT, Vago L, Sironi E, Peccatori J, Bernardi M, Carrera P, Palini A, Rossini S, Bordigon C, Bonini C, Ferrari M, Ciceri F, Fleischhauer K. Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors. Leukemia 2008: 22: 2119-2222. Epub May 1.
Fleischhauer K, Locatelli F, Zecca M, Orofino MG, Giardini C, De Stefano P, Pession A, Iannone AM, Carcassi C, Zino E, La Nasa G. Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with non-permissive HLA-DPB1 disparity in host-versus-graft direction. Blood 2006: 107: 2984-2992. Epub 2005 Nov 29.
Sizzano F, Zito L, Crivello P, Crocchiolo R, Vago L, Zino E, Fleischhauer K. Significantly higher frequencies of alloreactive CD4+ T cells responding to non-permissive than to permissive HLA-DPB1 T cell epitope disparities. Blood 2010: 116: 1991-1992 .
Marktel S*, Napolitano S*, Zino E*, Cappelli B, Chiesa R, Poli F, Crocchiolo R, Ronchi P, Rossini S, Ciceri F, Roncarolo MG, Fleischhauer K. Platelet transfusion refractoriness in highly immunized beta thalassemia children undergoing stem cell transplantation. Pediatr Transplant 2010: 14: 393-401. Epub 2010 Jan 7. *equal contribution.
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Lupo Stanghellini MT, Perrelli NF, Cosentino C, Torri F, Angius A, Forno B, Casucci M, Bernardi M, Peccatori J, Corti C, Bondanza A, Ferrari M, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009: 361: 478-488.
Crocchiolo R, Zino E, Vago L, Oneto R, Bruno B, Pollichieni S, Sacchi N, Sormani MP, Marcon J, Lamparelli T, Fanin R, Garbarino L, Miotti V, Bandini G, Bosi A, Ciceri F, Bacigalupo A, Fleischhauer K. Non-Permissive HLA-DPB1 Disparity is a Significant Independent Risk Factor for Mortality after Unrelated Hematopoietic Stem Cell Transplantation. Blood 2009: 114: 1437-1444. Epub 2009 Jun 10.
Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S, Lupo Stanghellini MT, Mazzi B, Perna SK, Bondanza A, Middleton D, Palini A, Bernardi M, Bacchetta R, Peccatori J, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Temporal, quantitative and functional characteristics of single-KIR positive alloreactive NK cell recovery account for impaired graft versus leukemia activity after haploidentical HSCT. Blood 2008: 112: 3488-3499. Epub 2008 Jul 21.
Mazzi B, Clerici TD, Zanussi M, Lupo Stanghellini MT, Vago L, Sironi E, Peccatori J, Bernardi M, Carrera P, Palini A, Rossini S, Bordigon C, Bonini C, Ferrari M, Ciceri F, Fleischhauer K. Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors. Leukemia 2008: 22: 2119-2222. Epub May 1.
Fleischhauer K, Locatelli F, Zecca M, Orofino MG, Giardini C, De Stefano P, Pession A, Iannone AM, Carcassi C, Zino E, La Nasa G. Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with non-permissive HLA-DPB1 disparity in host-versus-graft direction. Blood 2006: 107: 2984-2992. Epub 2005 Nov 29.
Project Title:
Exploitation of human leukocyte antigen DP T cell epitopes for targeting cellular immunotherapy of leukemia
Hematopoietic stem cell transplantation (HSCT) from unrelated donors (UD) is the only possible cure for many patients with leukemia, however, relapse remains a major caveat. Human leukocyte antigen (HLA)-DP mismatches, present in 80% of UD-HSCT, are an attractive target for leukemia attack by donor T lymphocytes after UD-HSCT (1), and our group has shown that a subset of HLA-DP antigens carrying a shared T cell epitope (TCE) are particularly protective from leukemia relapse after transplantation (2,3). The reasons for this are currently unknown and could be related to presentation of immunogenic allopeptides, or molecular mimicry with other antigenic epitopes for instance from viral antigens. In this project, we intend to dissect the immune response to TCE+ and TCE- HLA-DP molecules by alloreactive T cells, in terms of cellular subsets involved in the response (memory versus effector T cells), peptide-specificity by testing of the cell type specificity of HLA-DP allorecognition, and T cell receptor usage. Post-transplant graft versus leukemia activity targeted to TCE+ or TCE- HLA-DP molecules will be modelled in vitro and in a preclinical model of immunodeficient mice in vivo. The possibility of leukemia immune escape via selective loss of mismatched HLA-DP, documented by us as a major mechanism of relapse after haploidentical HSCT (4), will be tested by quantitative PCR for HLA-DP in follow-up patients from patients after unrelated transplantation. The expected data will provide new insights into the mechanisms underlying cellular immunotherapy of leukemia by UD-HSCT, and open new windows of opportunity to the refinement of clinical protocols aimed at the prevention and treatment of leukemia relapse after transplantation.
1. Shaw BE et al. Blood 2007: 110: 4560-6
2. Crocchiolo R et al. Blood 2009: 114: 1437-44
3. Sizzano F et al. Blood 2010: 116: 1991-2
4. Vago L et al. N Engl J Med 2009: 361: 478-88
1. Shaw BE et al. Blood 2007: 110: 4560-6
2. Crocchiolo R et al. Blood 2009: 114: 1437-44
3. Sizzano F et al. Blood 2010: 116: 1991-2
4. Vago L et al. N Engl J Med 2009: 361: 478-88