Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome.
Clinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell-dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8+ T-cell expansions of one or more T-cell receptor (TCR) Vbeta subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded Vbeta subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoietic culture. The negative effects of Vbeta-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS.
Sloand
Elaine M
EM
Hematology Branch, National Heart, Lung, and Blood Institute, Bldg 10, Rm 7C108, National Institutes of Health, Bethesda, MD 20892, USA. sloande@nih.gov
Mainwaring
Lori
L
Fuhrer
Monika
M
Ramkissoon
Shakti
S
Risitano
Antonio M
AM
Keyvanafar
Keyvan
K
Lu
Jun
J
Basu
Atanu
A
Barrett
A John
AJ
Young
Neal S
NS
D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D015551:Autoimmunity; D001854:Bone Marrow Cells; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D002898:Chromosomes, Human, Pair 8; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome; D014314:Trisomy; D014407:Tumor Cells, Cultured
D000961:Antilymphocyte Serum; D016693:Receptors, Antigen, T-Cell, alpha-beta