Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens.
We studied the degree and the pattern of skewing of the variable region of beta-chain (VB) T-cell receptor (TCR) repertoire in aplastic anemia (AA) at initial presentation and after immunosuppression using a high-resolution analysis of the TCR VB complementarity-determining region 3 (CDR3). Age-matched healthy individuals and multitransfused patients with non-immune-mediated hematologic diseases were used as controls. In newly diagnosed AA, the average frequency of CDR3 size distribution deviation indicative of oligoclonal T-cell proliferation was increased (44% +/- 33% vs 9% +/- 9%; P =.0001); AA patients with human leukocyte antigen (HLA)-DR2 and those with expanded paroxysmal nocturnal hemoglobinuria clones showed more skewed VB repertoires. Nonrandom oligoclonal patterns were found for VB6, VB14-16, VB21, VB23, and VB24 subfamilies in more than 50%, and for VB15, VB21, and VB24 in more than 70% of AA patients with HLA-DR2. Patients received immunosuppression with antithymocyte globulin (ATG)/cyclosporine (CsA) or cyclophosphamide (CTX) with CsA in combination, and their VB repertoire was reanalyzed after treatment. Whereas no significant change in the degree of VB skewing in patients who had received ATG was seen, patients treated with CTX showed a much higher extent of oligoclonality within all VB families, consistent with a profound and long-lasting contraction of the T-cell repertoire. VB analysis did not correlate with the lymphocyte count prior to lymphocytotoxic therapy; however, after therapy the degree of VB skewing was highly reflective of the decrease in lymphocyte numbers, suggesting iatrogenic gaps in the VB repertoire rather than the emergence of clonal dominance. Our data indicate that multiple specific clones mediate the immune process in AA.
Kook
Hoon
H
Hematology Branch of the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Risitano
Antonio M
AM
Zeng
Weihua
W
Wlodarski
Marcin
M
Lottemann
Craig
C
Nakamura
Ryotaro
R
Barrett
John
J
Young
Neal S
NS
Maciejewski
Jaroslaw P
JP
D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002648:Child; D022801:Complementarity Determining Regions / Q000235:genetics; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*
D000961:Antilymphocyte Serum; D022801:Complementarity Determining Regions; D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016572:Cyclosporine; D003520:Cyclophosphamide