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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0804310v1 183/9/5991    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Sugimoto, K. Articles by Naoe, T. PubMed PubMed Citation Articles by Sugimoto, K. Articles by Naoe, T.

CTL Clones Isolated from an HLA-Cw-Mismatched Bone Marrow Transplant Recipient with Acute Graft-Versus-Host Disease¹

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

HLA-Cw disparity in a donor increases the risk of acute graft-vs-host disease (GVHD) after bone marrow transplantation. Acute GVHD is mediated by donor CTLs. However, mismatched HLA-Cw-specific CTLs generated in posttransplant recipients who developed acute GVHD have not been characterized in detail. In this study, CTL clones isolated from a recipient at the onset of acute GVHD who was transplanted from an HLA-A, -B, and -DRB1-matched, HLA-Cw-mismatched (recipient, Cw*0303/Cw*0702; donor, Cw*0801/Cw*0702), unrelated donor were characterized. The seven isolated CTLs, including CD4⁺, CD8⁺, and CD4⁺CD8⁺ T lymphocytes, lysed recipient cells, HLA-Cw*0303-transfected 721.211 cells, and HLA-Cw*0303-transfected donor cells, but not untransfected 721.211 cells or donor cells. Thus, all CTLs recognized the mismatched Cw*0303 molecule as an alloantigen. The sequences of Cw*0303 and Cw*0801 differ by 16 aas. Stimulation of CTLs by COS cells transfected with Cw*0303 cDNA constructs demonstrated that Cw*0303 mutants in which individual amino acids constituting peptide-binding pockets were substituted with the corresponding Cw*0801 amino acids significantly decreased IFN- production by all CTLs, whereas Cw*0303 mutants bearing Cw*0801 amino acids outside the positions constituting peptide-binding pockets stimulated all CTLs to the same degree as the wild-type Cw*0303 construct. These data suggest that all CTLs recognized the Cw molecule in a peptide-dependent manner. ELISPOT revealed that Cw*0303-reactive T cells accounted for one-half of the total of alloreactive T cells in the blood during GVHD. Taken together, non-self Cw-specific CTL clones with a variety of phenotypes and peptide specificities can be generated in posttransplant recipients with acute GVHD.

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¹ This study was supported in part by Health and Labor Science Research Grant (Research on Allergic Disease and Immunology); Grant-in-Aid for Cancer Research 20–14 from the Ministry of Health, Labour and Welfare of Japan; and Grant-in-Aid for Scientific Research 20591149 from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Makoto Murata, Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan. E-mail address: mmurata{at}med.nagoya-u.ac.jp

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; ALL, acute lymphoblastic leukemia; B-LCL, EBV-transformed lymphoblastoid cell.