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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2632-2641.
Prepublished online as a Blood First Edition Paper on April 13, 2006; DOI 10.1182/blood-2005-09-3902.
 Previous Article | Next Article 
Submitted September 30, 2005
Accepted March 23, 2006
Molecular strategies for detection and quantitation of clonal cytotoxic T cell responses in aplastic anemia and myelodysplastic syndrome
Marcin W Wlodarski, Lukasz P Gondek, Zachary P Nearman, Magdalena Plasilova, Matt Kalaycio, and Jaroslaw P Maciejewski*
Experimental Hematology and Hematopoiesis Section, Cleveland Clinic Foundation, Cleveland, OH, USA; Insitute of Immunology, Charite Medical School, Berlin, Germany
Experimental Hematology and Hematopoiesis Section, Cleveland Clinic Foundation, Cleveland, OH, USA
Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
* Corresponding author; email: maciejj{at}ccf.org.
Immune mechanisms are involved in the pathophysiology of aplastic anemia (AA) and myelodysplastic syndrome (MDS). Immune inhibition can result from cytotoxic T cell (CTL) attack against normal hematopoiesis or reflect immune surveillance. We used clonally-unique TCR VB-CDR3 region as markers of pathogenic CTL responses and show that while marrow failure syndromes are characterized by polyclonal expansions, overexpanded clones exist in these diseases and can serve as investigative tools. To test the applicability of clonotypic assays, we developed rational molecular methods for the detection of immunodominant clonotypes in blood and in historical marrow biopsies of 35AA, 37 MDS and 21 PNH patients, in whom specific CDR3 sequences and clonal sizes were determined. CTL expansions were detected in 81% and 97% of AA and MDS patients, respectively. In total, 81 immunodominant signature clonotypes were identified. Based on the sequence of immunodominant CDR3 clonotypes we designed quantitative assays for monitoring corresponding clones, including clonotypic Taqman-PCR and clonotype specific sequencing. No correlation was found between clonality and disease severity but in patients treated with immunosuppression truly pathogenic clones were identified based on the decline that paralleled hematologic response. We conclude that immunodominant clonotypes associated with marrow failure may be used to monitor immunosuppressive therapy.
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