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Identifizierung Und Charakterisierung Von T-Zell-Definierten Antigenen

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Identifizierung und Charakterisierung von Zielantigenen alloreaktiver zytotoxischer T-Zellen mittels cDNA-Bank-Expressionsklonierung in akuten myeloischen Leukämien Dissertation zur Erlangung des Grades Doktor der Naturwissenschaften am Fachbereich Biologie der Johannes Gutenberg-Universität Mainz Sabine Domning Mainz, 2012 Fachbereich Biologie der Johannes Gutenberg-Universität Mainz Dekan: 1.Berichterstatter: 2.Berichterstatter: Tag der mündlichen Prüfung: ZUSAMMENFASSUNG Zusammenfassung Allogene hämatopoetische Stammzelltransplantationen (HSZTs) werden insbesondere zur Behandlung von Patienten mit Hochrisiko-Leukämien durchgeführt. Dabei bewirken T- Zellreaktionen gegen Minorhistokompatibilitätsantigene (mHAgs) sowohl den therapeutisch erwünschten graft-versus-leukemia (GvL)-Effekt als auch die schädigende graft-versus-host (GvH)- Erkrankung. Für die Identifizierung neuer mHAgs mittels des T-Zell-basierten cDNA- Expressionsscreenings waren leukämiereaktive T-Zellpopulationen durch Stimulation naïver CD8+- T-Lymphozyten gesunder HLA-Klasse I-identischer Buffy Coat-Spender mit Leukämiezellen von Patienten mit akuter myeloischer Leukämie (AML) generiert worden (Albrecht et al., Cancer Immunol. Immunother. 60:235, 2011). Im Rahmen der vorliegenden Arbeit wurde mit diesen im AML-Modell des Patienten MZ529 das mHAg CYBA-72Y identifiziert. Es resultiert aus einem bekannten Einzelnukleotidpolymorphismus (rs4673: CYBA-242T/C) des Gens CYBA (kodierend für Cytochrom b-245 α-Polypeptid; syn.: p22phox), der zu einem Austausch von Tyrosin (Y) zu Histidin (H) an Aminosäureposition 72 führt. Das mHAg wurde von T-Lymphozyten sowohl in Assoziation mit HLA-B*15:01 als auch mit HLA-B*15:07 erkannt. Eine allogene T-Zellantwort gegen CYBA-72Y wurde in einem weiteren AML-Modell (MZ987) beobachtet, die ebenso wie in dem AML-Modell MZ529 polyklonal war. Insgesamt konnte bei drei von fünf getesteten HLA-B*15:01-positiven Buffy Coat-Spendern, die homozygot für CYBA-72H (H/H) waren, eine CYBA-72Y-spezifische T- Zellantwort generiert werden. Das von den T-Lymphozyten übereinstimmend in niedrigster Konzentration erkannte Peptid umfasste die Aminosäuren 69 - 77, wobei das homologe Peptid aus CYBA-72H auch in hohen Konzentrationen keine Reaktivität auslöste. Eine reziproke Immunogenität des mHAg ist bislang nicht belegt. T-Lymphozyten gegen CYBA-72Y erkannten Leukämiezellen bei acht von zwölf HLA-B*15:01-positiven Patienten (FAB-Subtypen: M1, M2, M4, M5). Da das Gen CYBA für eine Komponente des mikrobiziden Oxidasesystems von phagozytierenden Zellen kodiert, ist es überwiegend in Zellen des hämatopoetischen Systems exprimiert. Von Leukozytensubtypen, aufgereinigt aus HLA-B*15:01-positiven Buffy Coat-Spendern mit CYBA-242T-Allel, wurden Monozyten und daraus abgeleitete dendritische Zellen durch CYBA- 72Y-reaktive T-Lymphozyten sehr stark, untransformierte B-Zellen in weit geringerem Maße und Granulozyten sowie T-Lymphozyten nicht erkannt. Das für CYBA-72Y kodierende Allel CYBA-242T wurde bei 56% aller getesteten gesunden Spender und Malignompatienten (n=481) nachgewiesen. Unter Berücksichtigung der Häufigkeit des präsentierenden HLA-Allels ist davon auszugehen, dass etwa 4,5% der Kaukasier das mHAg CYBA-72Y zusammen mit HLA-B*15:01 tragen. Nach bisherigen Beobachtungen führt ein immunogener CYBA-72Y-Mismatch bei allogenen HSZTs nicht notwendigerweise zu einer schweren GvH-Erkrankung. Das hier beschriebene mHAg CYBA-72Y erscheint potenziell geeignet, im Rahmen einer allogenen HSZT die präferenzielle Elimination der Empfänger-Hämatopoese unter Einschluss von myeloischen Leukämiezellen zu bewirken. Jedoch sind weiterführende Untersuchungen erforderlich, um die therapeutische Relevanz des Antigens zu belegen. i SUMMARY Summary In particular patients with high-risk leukemias (AMLs) are treated with allogeneic hematopoietic stem cell transplantation (HSCT). As a result, donor-derived T-cell responses against minor histocompatibility antigens (mHAgs) can cause the desirable graft-versus-leukemia (GvL) effect, but also the graft-versus-host disease (GvHD) associated with significant morbidity. For the identification of new mHAgs via cDNA expression screening leukemia-reactive T-cell populations had been generated by stimulating naïve CD8+ T lymphocytes from healthy HLA class I-matched buffy coat donors with leukemia cells from patients with acute myeloid leukemia (AML) (Albrecht et al., Cancer Immunol. Immunother. 60:235, 2011). Using such allogeneic leukemia- reactive T cells CYBA-72Y was identified within this thesis as a new mHAg expressed on AML cells of patient MZ529. This mHAg depends on a known single nucleotide polymorphism (rs4673: CYBA-242T/C) of the gene CYBA (encoding cytochrome b-245 α-polypeptide; syn.: p22phox) resulting in a tyrosine(Y)-to-histidine(H) exchange on amino acid position 72. CYBA-72Y was recognized by T lymphocytes in association with HLA-B*15:01 as well as HLA-B*15:07. An independent allogeneic T-cell response against CYBA-72Y was observed in the model system of AML patient MZ987. In both models these responses were polyclonal. In total, CYBA-72Y-reactive T lymphocytes were generated in three of five HLA-B*15:01 positive buffy coat donors, all of whom were homozygous for CYBA-72H (H/H). These T lymphocytes consistently recognized a nonameric peptide comprising amino acids 69 - 77 in lowest concentration. The homologous peptide derived from CYBA-72H did not induce reactivity even at very high concentrations. So far, no reciprocal immunogenicity has been found. CYBA-72Y-reactive T lymphocytes recognized leukemic blasts from eight out of twelve HLA-B*15:01 positive AML patients (FAB subtypes were M1, M2, M4, M5). CYBA encodes a component of the microbicidal oxidase system of phagocytic cells. Therefore, CYBA expression is preferentially confined to cells of hematopoietic origin. Among leukocyte subtypes derived from HLA-B*15:01 positive buffy coat donors carrying a CYBA-242T allele CYBA- 72Y-specific T lymphocytes strongly recognized monocytes and monocyte-derived dendritic cells, weakly recognized untransformed B cells, but reacted neither with granulocytes nor with T cells. Genotyping revealed that 56% of tested healthy donors and patients with malignant diseases (n=481) carried at least one CYBA-242T allele. Taking into account the frequency of the presenting HLA allele, approximately 4,5% of Caucasians carry CYBA-72Y together with HLA-B*15:01. According to observations made so far, immunogenic CYBA-72Y mismatches do not necessarily induce severe GvHD after allogeneic HSCT. The mHAg CYBA-72Y has the potential to induce after allogeneic HSCT a preferential elimination of recipient hematopoietic cells including myeloid leukemia cells. But further investigations are required to prove the antigen´s therapeutic relevance. ii INHALTSVERZEICHNIS Inhaltsverzeichnis Zusammenfassung ...................................................................................................................... i Summary ......................................................................................................................................ii Inhaltsverzeichnis ........................................................................................................................ I Abbildungsverzeichnis ............................................................................................................... V Tabellenverzeichnis .................................................................................................................. VII Abkürzungsverzeichnis ........................................................................................................... VIII 1 Einleitung ..................................................................................................................................1 1.1 Maligne Erkrankungen..............................................................................................................1 1.1.1 Bedeutung und Entwicklung von Malignomen ........................................................................1 1.1.2 Klassifizierung und Bedeutung leukämischer Erkrankungen ..................................................2 1.1.3 Akute myeloische Leukämie (AML) ........................................................................................3 1.1.3.1 Bedeutung und Entstehung ................................................................................................3 1.1.3.2 Klassifizierung und Prognostik ............................................................................................4 1.1.3.3 Therapiemöglichkeiten........................................................................................................5 1.2 Grundlagen der Antigenerkennung durch T-Lymphozyten ........................................................7 1.2.1 Antigenprozessierung und -präsentation über Haupthistokompatibilitätskomplexe (MHCs).....7 1.2.2 Antigenspezifische Aktivierung von T-Lymphozyten über T-Zellrezeptoren (TZRs) .................9 1.2.3 Eigenschaften von T-Lymphozyten mit unterschiedlichen Funktionen .................................. 10 1.3 Interaktionen des Immunsystems mit malignen Zellen ............................................................ 11 1.3.1 Immunosurveillance und Immunescape ............................................................................... 11 1.3.2 Zielantigene von T-Lymphozyten ......................................................................................... 12 1.3.2.1 Leukämieassoziierte Antigene (LAAs)..............................................................................
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    Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST -CNRS Volume 17 - Number 9 September 2013 The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST -CNRS Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences. Editorial correspondance Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected] Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Vanessa Le Berre, Anne Malo, Carol Moreau, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).
  • Integration of Text Mining with Systems Biology Provides New Insight Into the Pathogenesis of Diabetic Neuropathy

    Integration of Text Mining with Systems Biology Provides New Insight Into the Pathogenesis of Diabetic Neuropathy

    INTEGRATION OF TEXT MINING WITH SYSTEMS BIOLOGY PROVIDES NEW INSIGHT INTO THE PATHOGENESIS OF DIABETIC NEUROPATHY by Junguk Hur A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in The University of Michigan 2010 Doctoral Committee: Professor Eva L. Feldman, Co-Chair Professor Hosagrahar V. Jagadish, Co-Chair Professor Matthias Kretzler Research Assistant Professor Maureen Sartor Professor David J. States, University of Texas Junguk Hur © 2010 All Rights Reserved DEDICATION To my family ii ACKNOWLEDGMENTS Over the past few years, I have been tremendously fortunate to have the company and mentorship of the most wonderful and smartest scientists I know. My advisor, Prof. Eva Feldman, guided me through my graduate studies with constant support, encouragement, enthusiasm and infinite patience. I would like to thank her for being a mom in my academic life and raising me to become a better scientist. I would also like to thank my co-advisors Prof. H. V. Jagadish and Prof. David States. They provided sound advice and inspiration that have been instrumental in my Ph.D. study. I am also very grateful to Prof. Matthias Kretzler and Prof. Maureen Sartor for being an active part of my committee as well as for their continuous encouragement and guidance of my work. I would also like to thank Prof. Daniel Burns, Prof. Margit Burmeister, Prof. Gil Omenn and Prof. Brain Athey from the Bioinformatics Program, who have been very generous with their support and advice about academic life. I am also very grateful to Sherry, Julia and Judy, who helped me through the various administrative processes with cheerful and encouraging dispositions.