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|Title:||Mechanisms of immune dysfunction in human lymphomas|
|Publisher:||Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)|
|Description:||Accumulating data suggest that tumor-induced immune dysfunction counteracts presumptively efficient tumor-specific immune responses, and thus contributes to disease progression. In the present work, focus was given on immune dysfunction and the underlying mechanisms in two human lymphomas, Hodgkin's disease (HD) and B cell chronic lymphocytic leukemia (B-CLL). Complex perturbations of the immune system are characteristic features of these diseases, affecting the cellular and humoral tumor immunity. Epstein-Barr virus (EBV) is present in the malignant Hodgkin Reed-Sternberg (HRS) cells in approximately 40% of patients with HD, defined as EBV+ HD. The EBV+ HRS cells express EBV-derived latent membrane proteins (LMP), which normally are immunogenic and thus should serve as potential tumor-rejection antigens for cytotoxic T lymphocytes (CTL). The demonstration of EBV-specific proliferative and cytotoxic responses in interleukin (IL)-2-propagated tumor associated lymphocytes (TAL) from EBV- HD tumors suggests that a generalized, constitutional defect of EBV-specific immunity is not a part of the inherent cellular immune deficiency observed in HD patients. On the contrary, TAL derived from EBV' HD tumors consistently lacked HLA class I-restricted EBV-specific cytotoxic activity. In one of the patients with an EBV+ HD tumor, EBV-specific CTL precursors were obtained from peripheral blood, with specificities comprising also LMP1. The results indicate, that a local suppression of EBV-specific CTL responses is present in EBV+ HD tumors. The mechanisms responsible for the immune escape of EBV-positive HRS cells are important to elucidate, as far as the development of immunotherapy-strategies for the disease is concerned. The TAL phenotype did not discriminate between EBV+ and EBV- HD tumors, nor did the cytokine mRNA expression in tumor tissue. Down-modulation of the CD3 and CD16-associated signal transduction molecule [zeta] is a common finding in TAL of various malignancies, and is associated with impaired lymphocyte function. HD TAL were shown to express equal or higher levels of this molecule compared to the autologous peripheral blood lymphocytes (PBL). Immunohistochemical studies revealed [zeta] to be expressed even in the TAL most adjacent to the HRS cells. Furthermore, tyrosine residues in [zeta) were found to be heavily phosphorylated in HD lymphocytes compared to normal donor PBL. Therefore, down-modulation of the signal transduction molecule [zeta) in HD TAL is unlikely to explain the local suppression of EBV-specific cytotoxicity described in EBV-positive HD. TNF-[alpha] is a central mediator of inflammation and cellular immune response and has been suggested to be involved in the biology of HD and B-CLL. In addition to local mechanisms, regulation of TNF-[alpha] gene transcription has also been shown to be under genetic control. A TNF-[alpha] promoter region polymorphism at the -308 position was investigated in patients with HD in complete remission and in B-CLL patients with active disease, and the results compared to the allele frequencies in a normal population. No differences were detected between the groups, and polymorphism of this locus is therefore not likely to be involved in B-CLL and non-aggressive HD. The results regarding B-CLL are in contrast to an earlier report. IL-10 has been suggested to act as an growth factor for B-CLL cells, as well as to induce apoptosis in vitro in these cells. Here, B-CLL cells were shown to express the IL-10 gene, assessed by means of reverse transcriptase-polymerase chain reaction and in situ hybridization. The expression of IL- 10 mRNA was found to be significantly associated with non-progressive disease. Therefore, given the differentiation-enhancing and proliferation-inhibiting properties of IL-10 on B-CLL cells in vitro, expression of the cytokine in the tumor cells may hypothetically contribute to a more indolent course of the disease.|
|Appears in Collections:||Dept of Microbiology, Tumor and Cell Biology|
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