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Identifizierung Und Charakterisierung Von T-Zell-Definierten Antigenen

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Identifizierung Und Charakterisierung Von T-Zell-Definierten Antigenen 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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