Costimulation molecule expression and subset distribution of blood dendritic cells in normal children and newly diagnosed pediatric leukemia and lymphoma patients.
ABSTRACT To characterize dendritic cell (DC) numbers, subset distribution, phenotype, and costimulation molecule expression in a normal pediatric population and in a lymphoblastic malignant pretherapy pediatric population. DC are potent antigen-presenting cells and are crucial for initiating specific immune responses.
We first analyzed peripheral blood samples of healthy pediatric controls (n=72). Once a range of normal parameters was established, we compared these to newly diagnosed pediatric leukemia and lymphoma patients prior to receiving therapy (n=69). Using flow cytometry, we examined blood DC cell-surface expression of CD80, CD86, CD40, CD18, CD50, CD83, CD123, CD58, CD54, and CD11c.
Expression of each of these molecules was significantly altered except for CD80, CD83, and CD58. When compared to healthy children, absolute blood DC were reduced in children with leukemia or lymphoblastic lymphoma (p<0.0001) and children with Hodgkin's disease (p=0.0028). Additionally, lymphocyte function in vitro, was impaired (p=0.0489) for children with lymphoblastic malignancies, while patients with Hodgkin's disease had normal proliferative function.
Our results show that peripheral blood DC from children with newly diagnosed leukemia or lymphoma are significantly altered in number, subset distribution, and costimulation molecule expression, and that lymphocyte function is impaired compared to healthy pediatric controls.
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ABSTRACT: The number of dendritic cells (DC) circulating in the peripheral blood of cancer patients were monitored at multiple time points during chemotherapy and granulocyte colony-stimulating factor (G-CSF) support. DC were identified via the lack of expression of standard lineage markers and high expression of HLA-DR (LN–/DR+). The expression of DC-associated markers, including CD83, CD11c, IL-3Rα (CDw123) and CD86, within this LN–/DR+ population was also monitored. Maximal mobilization occurred during recovery on d 12, with a mean 32-fold increase in LN–/DR+ numbers. The most striking increase was observed in the LN–/DR+/CD83+ cell population: 12 d after commencement of treatment, the proportion of these cells had increased by approximately 120-fold when compared with baseline. Peripheral blood mononuclear cell (PBMC) and CD34+ cell numbers also peaked 12 d into the treatment regimen in most patients. These data suggest that it should be possible to acquire substantial numbers of DC from leukapheresis products collected from cancer patients undergoing a standard treatment regimen of chemotherapy and G-CSF. This strategy may be a feasible, low-risk means of acquiring cells for DC-based vaccine studies.British Journal of Haematology 10/2002; 119(1):204 - 211. · 4.94 Impact Factor
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ABSTRACT: Both macrophages (MAC) and dendritic cells (DC) are members of the mononuclear phagocyte system (MPS) with monocytes (MO) as common precursor cells. Cells of the MPS are able to take up, process and present antigens to T lymphocytes, thereby inducing a primary or secondary immune response. Adhesion molecules are of crucial importance for the interaction of antigen-presenting cells with immune cells, especially T lymphocytes. By representational difference analysis, we identified CD49c (VLA-3), a member of the beta1-integrin family of adhesion receptors, as differentiation-associated antigen in MO-derived MAC. In contrast, MO-derived DC did not express CD49c mRNA. These data prompted us to compare the integrin expression pattern of MAC and DC. Both cell types showed a low expression of the alpha-chains of the beta1-integrins CD49a, CD49b, CD49d and CD49e, whereas a marked difference was observed for CD49c and CD49f. Expression of both integrins increased during MO to MAC differentiation, but was not detectable on DC. In parallel the beta1-chain (CD29) was clearly up-regulated during MO to MAC differentiation but was only weakly expressed on DC. On the other hand, the beta2-integrins CD11a, CD11b, CD11c and CD18 were all expressed on MAC and DC. Beside their role in cell-cell interaction and adhesion, beta2-integrins are also known as possible binding molecules for bacteria and lipopolysaccharide (LPS), especially for high LPS concentrations. Therefore we investigated the LPS response of MAC versus DC in terms of tumour necrosis factor-alpha (TNF-alpha) release. DC were less responsive to low doses of LPS, which can easily be explained by the very low CD14 expression on DC compared for MAC. In contrast, the TNF-alpha response was comparable to MAC when DC were stimulated with high LPS concentrations. Our results show a specific, differentiation-dependent pattern of beta1- and beta2-integrin expression on in vitro-generated MAC and DC. We suggest that the high expression of CD11/CD18 on DC could be involved in the LPS binding of DC. As LPS is not only an activation but also a differentiation stimulus for DC, the expression of CD11/CD18 on DC may be important for the successful maturation of DC and thereby the initiation of a primary immune response.Immunology 08/2000; 100(3):364-9. · 3.71 Impact Factor
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ABSTRACT: Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation. This down-regulation of SN immunity is likely the basis of its susceptibility to tumor metastases, suggesting a potential role of the immune system in the control of malignant tumors. Despite immune dysfunction in the SN, phase II trials of systemic post-operative immunotherapy with a polyvalent melanoma vaccine developed at the John Wayne Cancer Institute showed improved 5-year overall survival in patients with melanoma metastatic to regional nodes. However, most immunotherapy clinical trials have failed to demonstrate a significant clinical response, and analyses of immune responses to tumor-associated antigens that correlate clinical responses have not been established. Therefore, refinements in assay methodologies and improvements in vaccine designs are critical to the success of cancer immunotherapy. Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity. Dendritic cell-based immunotherapies have been vigorously attempted in the past decade. To improve the immunogenicity of cancer vaccines, we recently generated heterokaryons of DCs and tumor cells by electrofusion. The fusion hybrids retained their full antigen-presenting capacity and all natural tumor antigens. In pre-clinical animal experiments, a single injection of the DC-tumor fusion hybrids was sufficient to mediate the regression of tumors established in the lung, skin and brain. Most interestingly, successful therapy required the delivery of fusion hybrids directly into lymphoid organs such as lymph nodes. A clinical trial is now being carried out to test the immunogenicity and therapeutic effects of fusion hybrids for the treatment of metastatic melanoma.Cancer and metastasis reviews 07/2006; 25(2):233-42. · 7.79 Impact Factor