Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD.
Administration of cyclosporine A (CsA) after autologous stem cell transplantation elicits an autoimmune syndrome with pathology similar to graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with the appearance of autoreactive T cells directed at major histocompatibility class (MHC) class II antigens. In the rat model of autologous GVHD, clonal analysis reveals that the effector T cells are highly conserved and recognize a peptide from the invariant chain peptide presented by MHC class II. Although human autologous GVHD effector T cells share a similar phenotypic specificity, clonality of the response in humans has not been determined. To examine the human effector T-cell response, the T-cell repertoire of peripheral blood lymphocytes was assessed by complementarity-determining region 3 (CDR3) size distribution analysis and T-cell clonotype analysis in 26 patients treated with CsA after transplantation. Autologous GVHD developed in 3 of 4 patients with human leukocyte antigen (HLA)-DRB1*0701, and clonal expansions of beta-chain variable region (BV)16(+) T cells were shared. Clonal expansions within BV15(+) and BV22(+) T cells were also detected in 4 of 6 patients with HLA-DRB1*1501 and in 3 of 4 patients with HLA-DRB1*0401, respectively. Sequencing of BV16 cDNA for which the CDR3 size pattern exhibited apparent clone predominance revealed an identical CDR3 peptide sequence in 2 different patients, one with HLA-DRB1*0701 and the other with HLA-DRB1*1502. These findings indicate that the discrete antigen-driven expansion of T cells is involved in autologous GVHD. (Blood. 2001;98:868-876)
Miura
Y
Y
Oncology Center, Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Bldg., 1650 Orleans St., Baltimore, MD 21231, USA. ymiura@mail.jhmi.edu
Thoburn
C J
CJ
Bright
E C
EC
Sommer
M
M
Lefell
S
S
Ueda
M
M
Nakao
S
S
Hess
A D
AD
D000328:Adult; D001483:Base Sequence; D001943:Breast Neoplasms / Q000150:complications / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D022801:Complementarity Determining Regions / Q000737:chemistry; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006680:HLA Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000097:blood; D059811:HLA-DRB1 Chains; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014182:Transplantation, Autologous
D022801:Complementarity Determining Regions; D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine