Identification of novel regulators in T-cell differentiation of aplastic anemia patients.
BACKGROUND
Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR.


RESULTS
Among more than 22,200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response.


CONCLUSIONS
Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.
Franzke
Anke
A
Department of Hematology, Hemostasis and Oncology, Hannover Medical School, Hannover, Germany. franzke.anke@mh-hannover.de
Geffers
Robert
R
Hunger
J Katrin
JK
Pförtner
Susanne
S
Piao
Wenji
W
Ivanyi
Philipp
P
Grosse
Jens
J
Probst-Kepper
Michael
M
Ganser
Arnold
A
Buer
Jan
J
D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood / Q000235:genetics* / Q000628:therapy; D000961:Antilymphocyte Serum / Q000097:blood / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D016000:Cluster Analysis; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D000961:Antilymphocyte Serum; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D016572:Cyclosporine