Cytotoxic and proliferative T-cell clones with antidonor reactivity from a patient transplanted for severe combined immunodeficiency disease.
Patients who have become split lymphoid chimeras (T cells of donor origin, B cells and monocytes of host origin) following transplantation of HLA-haploidentical marrow for the treatment of severe combined immunodeficiency disease provide a unique model for the study of tolerance. One such patient, UPN 345, was transplanted with maternal marrow and was found to have antidonor proliferative reactivity without detectable donor-directed cytotoxicity when tested at 18, 23, and 66 mos following bone marrow transplantation. In bulk culture, the proliferation to donor cells could be blocked by monoclonal antibodies to HLA-DR and -DQ. Nine clones with antidonor reactivity were established by limiting dilution techniques from a mixed lymphocyte culture between engrafted T cells and irradiated donor E rosette-negative cells. All of the clones were of maternal donor origin, and all were CD3+CD4+CD8-. The clones were tested for proliferative and cytotoxic activity toward donor, host, and paternal B-lymphoblastoid cell lines (B-LCL). Six clones proliferated strongly to maternal B-LCL but not to host B-LCL. Six clones were found to exclusively lyse maternal B-LCL. Four of the clones had both antidonor cytotoxic and antidonor proliferative reactivity. Monoclonal antibody blocking studies were performed on five of the six clones with cytotoxic activity. The antidonor cytotoxicity was not inhibited by monoclonal antibodies to class I determinants; however, three clones were inhibited in the presence of monoclonal antibody to DR, one clone was inhibited by anti-DQ monoclonal antibody, and one clone was inhibited by anti-DP monoclonal antibody. The cytotoxicity of all five clones was inhibited by monoclonal antibody to CD4. These data indicate that antidonor reactivity may also include a cytotoxic component which is not apparent in bulk cultures and which, based on our limiting dilution studies, is probably controlled by regulatory cells. Both the antidonor cytotoxicity and the antidonor proliferation appear to be directed primarily toward donor HLA class II antigens that are not shared with the patient.
Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
C A
CA
Keever
N
N
Flomenberg
M V
MV
Gazzola
K
K
Pekle
S Y
SY
Yang
T N
TN
Small
N H
NH
Collins
R J
RJ
O'Reilly
D000328:Adult; D000911:Antibodies, Monoclonal; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D006681:HLA-D Antigens / Q000276:immunology; D006789:Host vs Graft Reaction / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000628:therapy; D007231:Infant, Newborn; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D006681:HLA-D Antigens