Infusion of CD4+ donor lymphocytes induces the expansion of CD8+ donor T cells with cytolytic activity directed against recipient hematopoietic cells.
OBJECTIVE
Donor lymphocyte infusions (DLIs) provide effectivetherapy for patients with relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation. Previous studies have suggested that depletion of CD8+ T cells from the infused donor lymphocytes can reduce the incidence of graft-versus-host disease associated with DLI without reducing antileukemia activity. In this situation however, the immune effector cells responsible for tumor rejection have not been identified. The goal of this study was to characterize these effector populations.


METHODS
We studied three representative patients with relapsed chronic myeloid leukemia who achieved complete molecular remission after receiving CD8+ T-cell-depleted DLI from HLA-identical sibling donors. Effector T cells were characterized in patient samples after in vitro stimulation and functional assessment. T-cell clones relevant to the immune response were then isolated and further characterized.


RESULTS
Analysis of peripheral blood samples collected after DLI indicated the presence of a high frequency of circulating host-reactive cytolytic CD8+ T cells secreting IFN-gamma. These HLA class I-restricted CTLs were specific for recipient minor histocompatibility antigens (mHAs) because they did not recognize target cells of donor origin. One CTL clone was further expanded in vitro and shown to recognize a broadly expressed mHA presented by HLA-B5701. Using a molecular approach, we demonstrated that this clone was expanded in peripheral blood and marrow after DLI. It was not detected before DLI.


CONCLUSIONS
These results indicate that CD4+ DLI elicits a potent allogeneic response mediated by mHA-specific CD8+ T cells.
Center for Hematologic Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Emmanuel
E
Zorn
Kathy S
KS
Wang
Ephraim P
EP
Hochberg
Christine
C
Canning
Edwin P
EP
Alyea
Robert J
RJ
Soiffer
Jerome
J
Ritz
D000328:Adult; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D017252:CD3 Complex / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D016827:CD8 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D006410:Hematopoiesis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D017252:CD3 Complex; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma