Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

We investigated whether minor histocompatibility (mH) antigen-specific cytotoxic T lymphocytes (CTL) can discriminate between leukemic hematopoietic progenitor cells (leukemic-HPC) from AML or CML patients, the HPC from their remission bone marrow (remission-HPC), and normal HPC from their HLA-identical sibling bone marrow donor (donor-HPC). Specific lysis by CD8+ CTL clones was observed not only of the leukemic-HPC but also of the donor-HPC in 3/4 patient/donor combinations expressing mH antigen HA-1, 3/5 combinations expressing mH antigen HA-2, 2/3 combinations expressing mH antigen HA-3, and 2/2 combinations expressing mH antigen HY-A1. In four patient/donor combinations the recognition of the donor-HPC was clearly less than of the leukemic-HPC, indicating differential susceptibility to lysis by these mH CTL clones. In addition, differential recognition of leukemic-HPC and remission-HPC within seven patients was analyzed. In one patient expressing the HA-2 antigen on the leukemic cells the recognition of the remission-HPC was clearly less than of the leukemic-HPC. One CD4+ CTL clone showed specific lysis of the leukemic-HPC from an AML patient and a CML patient as well as of normal remission-HPC and donor-HPC. These results illustrate that in general CD8+ and CD4+ mH antigen specific CTL clones do not differentially recognize leukemic-HPC and normal-HPC. However, differences in susceptibility to lysis of malignant versus normal cells may contribute to a differential GVL effect.

Generation of donor-derived antileukemic cytotoxic T-lymphocyte responses for treatment of relapsed leukemia after allogeneic HLA-identical bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has been associated with an antileukemic effect, the graft-versus-leukemia (GVL) reactivity. Since T-cell depletion of the bone marrow graft performed to reduce the incidence and severity of graft-versus-host disease (GVHD) after BMT has been associated with an increase risk of relapse, the GVL reactivity has been attributed to the T lymphocytes from the graft. Previously, we demonstrated that leukemia-reactive cytotoxic T-lymphocyte (CTL) lines and clones could be generated from the peripheral blood of HLA-genotypically identical siblings of patients with leukemia by stimulation of the donor cells with irradiated leukemic cells from the patients. HLA class I as well as class II restricted CTL clones could be generated that recognized the leukemic cells. Some clones recognized the leukemic cells from the patient, but not the interleukin (IL)-2-stimulated lymphocytes from the same individual. To explore the possibility of clinically using donor-derived CTL lines directed against the leukemic cells from patients who relapsed after allogeneic BMT, a pilot study was performed using eight donor-recipient combinations. In seven of eight combinations donor-derived CTL lines could be generated that showed specific lysis of the leukemic cells from the patient. In five of these cases, the CTL lines showed reactivity with the leukemic cells, but not with the IL-2-stimulated lymphocytes from the same individual. In two cases, the CTL lines were cytotoxic for the IL-2-stimulated lymphoblasts as well as the leukemic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of the leucocyte integrin LFA-1 (CD11a/CD18) and its ligand ICAM-1 (CD54) in lymphoid malignancies is related to lineage derivation and stage of differentiation but not to tumor grade.

The leucocyte adhesion molecule LFA-1 (CD11a/CD18) and its counter structure ICAM-1 (CD54) play a pivotal role in cell-cell interactions in the immune system and hence their expression on malignant cells might play an important role in determining the biological behavior of lymphoid malignancies. This study examined the LFA-1 (CD11a/CD18) and ICAM-1 (CD54) expression profiles of a large series of non-Hodgkin's lymphomas (NHL, n = 220) and lymphoid leukemias (LL, n = 48), which, by their differentiation-antigen phenotype represented essentially all stages of lymphoid development from stem cell to mature activated T- and B-lymphocyte. It was found that NHL and LL differentially express LFA-1 and ICAM-1 molecules according to their lineage derivation, stage of differentiation, and growth pattern. Specifically: (a) T-cell neoplasms nearly always express LFA-1 whereas B-cell tumors are often LFA-1 low/negative; (b) ICAM-1 expression is largely confined to tumors with a mature or activated T- or B-cell phenotype; (c) neoplasms with a leukemic dissemination pattern are either ICAM-1 low or negative. Importantly, neither LFA-1 nor ICAM-1 expression was related to tumor grade.