ABSTRACT
Dendritic cells (DCs) are professional antigen-presenting cells playing a pivotal role in the induction of humoral and cellular immune responses, and chronic myeloid leukemia-derived DCs (CML-DCs) are possible candidates for inducing anti-leukemic immunity. This review describes phenotypic and functional features of DCs derived from CML patients as compared with DCs from healthy volunteers. In short, distinct deficiencies have been reported for CML-DCs, such as reduced migration, endocytosis, phagocytosis, antigen processing, DC maturation and cytokine production. DC abnormalities of CML patients can be abrogated by proper in vitro stimulation of leukemic DCs. This underscores the importance of proper generation and maturation of CML-DCs when considering clinical vaccination protocols.
Subject(s)
Dendritic Cells/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Antineoplastic Agents/therapeutic use , Benzamides , Cancer Vaccines/therapeutic use , Cytokines/biosynthesis , Dendritic Cells/drug effects , Fusion Proteins, bcr-abl/immunology , Humans , Imatinib Mesylate , Immunophenotyping , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Lymphocyte Activation , Myeloid Cells/immunology , Piperazines/therapeutic use , Pyrimidines/therapeutic use , T-Lymphocytes/immunologyABSTRACT
Chronic myeloid leukaemia (CML) dendritic cells (DC) are possible candidates for inducing antileukaemic immunity. This study aimed to investigate the frequency, phenotype and function of blood-derived leukaemic DC in comparison with DC from healthy donors using flow cytometric assays and mixed leucocyte reaction (MLR). Immature leukaemic DC displayed a reduced endocytotic capacity as compared with healthy controls. Moreover, in vitro maturation of leukaemic DC was found to be deficient. Expression of CD80, CD83, CD86, and major histocompatibility complex class I and class II antigens were reduced on lipopolysaccharide (LPS)-matured leukaemic DC but were enhanced by a mixture of interleukin 1beta (IL-1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2). Upon stimulation with bacterial LPS, intracellular TNF-alpha and IL-8 production was diminished in maturing DC from CML patients. This distinct cytokine deficiency was overcome when leukaemic DC were stimulated with cytokines/PGE2. MLR showed fully functional leukaemic DC after TNF-alpha-induced maturation, but a reduced proliferative alloresponse of leukaemic peripheral blood mononuclear cells. Further, intracellular production of cytokines in CML-derived T cells was markedly reduced. These data indicated that, in CML, the maturation response of leukaemic monocyte-derived DC to a natural stimulus like LPS is abnormal and may be caused by an aberrant TNF-alpha response in these cells. Thus, TNF-alpha alone or in combination with pro-inflammatory and T-cell stimulatory cytokines should be considered as an adjuvant for DC-based immunotherapy in CML.
Subject(s)
Dendritic Cells/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cells, Cultured , Endocytosis , Female , Flow Cytometry , Humans , Immunophenotyping , Interleukin-2/metabolism , Interleukin-4/metabolism , Leukocyte Count , Lipopolysaccharides/pharmacology , Lymphocyte Culture Test, Mixed , Male , Middle Aged , Statistics, Nonparametric , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Stem cell transplantation from unrelated donors is associated with an increased risk of graft failure and graft-versus-host disease (GVHD). Addition of pretransplant antithymocyte globulin (ATG), although reducing the risk of graft rejection and GVHD, bears the risk of overimmunosuppression, resulting in an increased relapse rate and transplant-related mortality. Therefore, we evaluated in 21 consecutive patients receiving unrelated stem cell grafts from either HLA-matched (38%) or -mismatched (62%) donors whether low-dose rabbit ATG added to cyclosporin A and methotrexate at a total dose of 3.5 mg/kg for HLA-identical and 5.0 mg/kg for HLA-mismatched transplants given in two divided doses on days -2 and -1 provides sufficient immunosuppression for prevention of GVHD and graft rejection but is associated with an acceptable risk of relapse and transplant-related mortality. Stable leukocyte engraftment was achieved in all patients (100%). Overall survival after a median follow-up of 26 (median, range 14-42) months was 56 +/- 26% (95% confidence interval, CI) and the overall relapse rate at 3 years was 24 +/- 21%. Three-year survival for standard-risk patients, i.e., chronic myeloid leukemia (CML) in first chronic phase or acute leukemia in first complete remission, was 87% +/- 13% versus 40% +/- 31% for patients with more advanced disease. The incidence of acute GVHD II-IV degrees was 55 +/- 22%; that of severe acute GVHD III-IV degrees was 21 +/- 19%. Chronic GVHD was observed in 5/17 (29%) patients surviving more than 100 days post stem cell transplantation. Transplant-related mortality was 16 +/- 15% (95% CI) at day + 100 and 25 +/- 19% (95% CI) at 1 year after the transplant. The data presented show that pretransplant in vivo T cell depletion with low-dose rabbit ATG results in a low transplant-related mortality due to a low incidence of severe acute and chronic GVHD and a low relapse rate. To find out the optimal rabbit ATG dose in the unrelated stem cell transplantation setting, further dose-finding studies comparing high- and low-dose regimens are necessary.
