Characterization of Natural Killer Cells after Allogeneic Stem Cell Transplantation in Humans,
Gabriele Hintzen
In humans NK cells are the first reconstituting lymphocyte population after allogeneic stem cell transplantation. They are capable to eliminate cells with altered expression of HLA-I due to infection or tumor transformation. NK cells are able to discriminate between self and non-self by recognizing HLA-I on target cells via corresponding re-ceptors. In different individuals the expression of these receptors is varying substan-tially with each NK cell expressing five to six different HLA-I-specific receptors on average but at least one.
During reconstitution after allogeneic stem cell transplantation no uniform pattern of expression level or –frequency for the different receptors could be detected. In oppo-site to the results in the murine system expression appears to be independent from the HLA environment.
Two distinct NK cell subpopulations differing in density of CD56 expression (CD56dim and CD56bright) are both considerably expanded after stem cell tranplantation with a particular increase of CD56bright cells. CD56bright cells exceed the CD56dim cells in re-gard to production of proinflammatory cytokines like IFNγ and TNFα attributing these cells a more regulatory role. Compared to CD56bright cells CD56dim cells exhibit more cytotoxic potential.
In early reconstitution most NK cells express CD26 which is normally borne only by CD56bright NK cells. Crosslinking of this molecule renders the cell to suppress pro-duction of IFNγ but not TNFα. In contrast, neither expression of activation markers nor cytotoxic function are affected by CD26 crosslinking.
In this study, we further characterized phenotypical and functional aspects of NK cells and their subpopulations after human allogeneic stem cell transplantation. In addition, we were able to exclude an substantial influence of the HLA-I environment on reconstitution of NK cells and expression pattern of their HLA-I specific receptors.
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ADCC Antikörper-abhängige zelluläre Zytotoxizität (antibody-dependent cell-mediated cytotoxicity)
ALL akute lymphatische Leukämie AML akute myeloische Leukämie
APC Allophycocyanin
BSA Rinderserumalbumin (bovine serum albumin) CD Cluster of Differentiation
CML chronische myeloische Leukämie
CMV Cytomegalovirus
DNTP Desoxyribonucleosintriphosphat DPP IV Dipeptidylpeptidase IV
EBV Epstein-Barr Virus
EDTA Ethylendiamintetraacetat E:T Effektor:Target
FACS Fluoreszenz-aktivierter Zellsortierer (fluorescence-activated cell sor-ter)
FcγR Fc-Rezeptor für IgG
FCS fetales Kälberserum (fetal calf serum) FITC Fluorescein-Isothiocyanat
GM-CSF Granulozyten-Makrophagen stimulierender Faktor (granulocyte macrophage colony stimulating factor)
GvHD Graft versus Host Disease GvL Graft versus leukemia
HLA humanes Leukozytenantigen (human leukocyte antigen) I.E. Internationale Einheiten
IFN Interferon
Ig Immunglobulin
IL Interleukin
ITAM immunoreceptor tyrosin-based activating motif ITIM immunoreceptor tyrosin-based inhibitory motif KARAP killer cell activating receptor-asscociated protein KIR killer cell immunoglobulin-like receptor
KMT Knochenmarktransplantation
KO Knock out
mAk monoklonaler Antikörper MDS myelodysplastisches Syndrom MFI mittlere Fluoreszenzintensität
MHC Haupthistokompatibilitätskompelx (major histocompatibility complex) NK-Zellen Natürliche Killerzellen
NKR NK-Zellrezeptoren ns nicht signifikant
PBMC periphere mononukleäre Zellen (peripheral blood mononuclear cells) PBS Phosphat-gepufferte Salzlösung (phosphate-buffered saline)
PBL periphere Blutlymphozyten
PCR Polymerase-Kettenreaktion (polymerase chain reaction)
PE Phycoerythrin
PMA Phorbol-Myristat-Azetat
rpm Umdrehungen pro Minute (rounds per minute) SCTX Stammzelltransplantation (stem cell transplantation) TAE Tris-Acetat-EDTA-Puffer
TCR T-Zellrezeptor (T cell receptor) TNF Tumor-Nekrose Faktor
TRAIL TNF-related apoptosis-inducing ligand WT Wildtyp
Originalpublikation
• Jacobs,R., Hintzen,G., Kemper,A., Beul,K., Behrens,G., Kempf,S., Sykora,K.W., and Schmidt,R.E., CD56bright cells differ in their KIR repertoire and function from CD56dim NK cells. Eur J Immunol 2001. 31: 3121-3126.
Abstracts
• Jacobs, R., Hintzen, G., Kemper, A., Schrauder, A., Sykora, K. W., Reiter, A., and Schmidt, R. E. Differential expression of killer inhibitory receptors on CD56dim and CD56bright NK cells. Immunobiology 200, 438. 1999.
• Hintzen, G., Jacobs, R., Behrens, G., Kemper, A., Biersack, H., and Schmidt, R.
E. Killer inhibitory receptors during immune reconstitution after allogeneic stem cell transplantation. Abstract DGFI-Frühjahrstagung, Köln 2000.
• Hintzen, G., Behrens, G., Kemper, A., Biersack, H., Schmidt, R. E., and Jacobs, R. Killer cell inhibitory receptors during immune reconstitution after human alloge-neic stem cell transplantation. Immunobiology 203, 239. 2000.
• Jacobs, R., Hintzen, G., Kemper, A., and Schmidt, R. E. CD56bright NK cells differ from CD56dim NK cells by diminished perforin expression and conjugate forma-tion. Immunobiology 203, 174. 2000.
• Hintzen, G., Wendt, K., Schmidt, R. E., and Jacobs, R. Cytokine production of human CD56bright NK cells is regulated via CD26. Immunobiology . 2001.
Hiermit möchte ich mich herzlich bei allen bedanken, die zum Gelingen dieser Arbeit beigetragen haben.
Professor Dr. R.E. Schmidt danke ich für die Möglichkeit, diese Arbeit in seiner Ab-teilung durchführen zu können und die ausgezeichnete wissenschaftliche Betreuung innerhalb des Ph.D.-Studiums und in allen Phasen der Dissertationszeit.
Dr. Roland Jacobs möchte ich herzlich danken, dass er die Betreuung der Arbeit übernommen hat, mir während der ganzen Zeit zur Seite gestanden hat und stets für alle meine Fragen offen war.
Esther Wilk danke ich für ihren vor allem fachlichen und auch sonstigen Beistand während des gemeinsamen Ph.D.-Studiums und ihre tatkräftige Unterstützung beim Verfassen der Arbeit.
Ich danke allen Mitgliedern der Abteilung Klinische Immunologie für die gute Zusammenarbeit, die nette Atmosphäre und die „corporate identity”.
Insbesondere danke ich Almut Kemper und Sabine Buyny, die mir in vielen techni-schen Dingen geholfen haben und für eine lustige Atmosphäre in Labor 1 gesorgt haben.
Ganz besonderer Dank gilt meiner Familie! Meinen Eltern danke ich für ihre immer-währende Unterstützung und Katrin und Marco dafür, dass sie an mich geglaubt ha-ben und immer für mich da waren.
Einen ganz lieben Dank an Tammo für die praktische Hilfe beim Erstellen der Arbeit, für die seelische Unterstützung und ständige Motivation.