Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) β-chain variable (Vβ) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVβ skewing was present in 40% of RCC patients. TCRVβ skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVβ skewing was not clearly related with treatment response. However, TCRVβ skewing did correlate with a disturbed CD4(+)/CD8(+) T-cell ratio, a reduction in naive CD8(+) T cells, an expansion of effector CD8(+) T cells and an increase in activated CD8(+) T cells (defined as HLA-DR(+), CD57(+) or CD56(+)). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC.

] Department of Immunology Erasmus MC Erasmus University Medical Center Rotterdam The Netherlands [2] Department of Pediatric Infectious Disease and Immunology Sophia Children's Hospital Erasmus University Medical Center Rotterdam The Netherlands

] Department of Pediatric Oncology Hematology Sophia Children's Hospital Erasmus University Medical Center Rotterdam The Netherlands [2] Department of Immunology Erasmus MC Erasmus University Medical Center Rotterdam The Netherlands

Department of Clinical Genetics Erasmus MC Erasmus University Medical Center Rotterdam The Netherlands

Department of Hematology University Children's Hospital Zurich Switzerland

Department of Immunology Erasmus MC Erasmus University Medical Center Rotterdam The Netherlands

Department of Pathology Clinical Centre South West Böblingen Clinics Böblingen Germany

Department of Pediatric Hematology Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology Oncology Ghent University Hospital Ghent Belgium

Department of Pediatric Hematology Oncology IRCCS Ospedale Bambino Gesù Rome University of Pavia Pavia Italy

Department of Pediatric Oncology Hematology Sophia Children's Hospital Erasmus University Medical Center Rotterdam The Netherlands

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark

Department of Pediatrics St Anna Children's Hospital and Children's Cancer Research Institute Medical University of Vienna Vienna Austria

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine University of Freiburg Freiburg Germany

Institute of Cell and Molecular Pathology Hannover Medical School Hannover Germany

Pediatric Hematology Fondazione IRCCS Policlinico San Matteo Pavia Italy

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