Genetic polymorphism and natural killer cell activity in multiple myeloma
Author: Zheng, Chengyun
Date: 2002-06-07
Location: Föreläsningssalen, Centrum för Molekylär Medicin, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
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Thesis (736.8Kb)
Abstract
Multiple Myeloma (MM) is a B cell malignancy characterised by an accumulation of clonal neoplastic plasma cells in bone marrow. Its aetiology remains unknown. Remarkable racial differences in the incidence of MM and occurrence of familial MM suggest that genetic factors may play a role in the development of MM. Susceptibility genes for MM, with the exception of MHC class I, have not yet been identified. Cytokines such as IL-10, IL-6, interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha are involved in normal B cell development and in MM tumour cell growth and/or survival.
In addition, IIL-10 appears to play an important role in the inhibition of T cell-mediated immune responses mainly through its effects on antigen presenting cells, which could contribute to T cell anergy. Furthermore, increases in the number of T cells producing IL-6 and abnormalities of T cells such as biased expression of T cell receptor variable beta chain in MM patients have been observed. However, potential genetic involvements of cytokine and co- stimulatory molecule genes in the development of MM have not been studied.
The overall aims of this study were to uncover susceptibility genes involved in immunoregulation of MM and to evaluate potential importance of NK cell cytotoxic activity in MM. The specific aims were to investigate a possible association between EL10, IL-6, IL-1beta, TNF-alpha and CTLA-4 genes and MM, and to analyse NK cell activity in patients with MM in an attempt to uncover a potential role for NK cells in tumour repression.
In the current study, our results showed that IL10.G and IL1O.R microsatellite polymorphisms in EL-10 promoter region were associated with MM. Moreover, allele 136 was related to a higher IL-10 production as analysed by an in vitro assay. The microsatellite polymorphism in the 3´-untranslated region of exon 4 in the CTLA-4 gene was associated with NIM and MGUS, and correlated in control samples to the level of CTLA-4 protein expression in CD4+ T cells. However, we did not find an association between the IIL-10 (-1082), IL-6 (-174), TNF-alpha (-308) or EL-10 TaqI polymorphism with MM. These results suggest that the loci in IIL-10 and CTLA-4 genes (or alternative genes in linkage disequilibrium) constitute risk factors for the development of MM.
NK cells from MM patients pre-cultured in the presence of rhIL-2 exhibited substantial cytolytic activity against autologous mature DCs that were pre-pulsed with patient's monoclonal immunoglobulin in vitro. Furthermore, patient NK cells showed higher cytotoxicity toward autologous DCs as compared to controls. In addition, the activated NK cells also lysed autologous plasma cells, indicating that the NK cell -mediated cytolysis may contribute to tumour regression in MM in vivo. On the other hand, the results suggest that NK cell-mediated killing of autologous DCs may influence the outcome of administration of tumour antigen pulsed DCs in clinical trials.
In brief, our results imply that the genetic factors associated with MM may influence cytokine production in vivo and control the T cell activation pattern leading to conditions that may favour growth of MM cells and inhibit generation of CTLs. It is likely that cytokine activated NK cells in MM patients are endowed with anti-tumour activities. These results would indicate that there are potential effects of both adoptive and innate immune activities on the development of MM.
In addition, IIL-10 appears to play an important role in the inhibition of T cell-mediated immune responses mainly through its effects on antigen presenting cells, which could contribute to T cell anergy. Furthermore, increases in the number of T cells producing IL-6 and abnormalities of T cells such as biased expression of T cell receptor variable beta chain in MM patients have been observed. However, potential genetic involvements of cytokine and co- stimulatory molecule genes in the development of MM have not been studied.
The overall aims of this study were to uncover susceptibility genes involved in immunoregulation of MM and to evaluate potential importance of NK cell cytotoxic activity in MM. The specific aims were to investigate a possible association between EL10, IL-6, IL-1beta, TNF-alpha and CTLA-4 genes and MM, and to analyse NK cell activity in patients with MM in an attempt to uncover a potential role for NK cells in tumour repression.
In the current study, our results showed that IL10.G and IL1O.R microsatellite polymorphisms in EL-10 promoter region were associated with MM. Moreover, allele 136 was related to a higher IL-10 production as analysed by an in vitro assay. The microsatellite polymorphism in the 3´-untranslated region of exon 4 in the CTLA-4 gene was associated with NIM and MGUS, and correlated in control samples to the level of CTLA-4 protein expression in CD4+ T cells. However, we did not find an association between the IIL-10 (-1082), IL-6 (-174), TNF-alpha (-308) or EL-10 TaqI polymorphism with MM. These results suggest that the loci in IIL-10 and CTLA-4 genes (or alternative genes in linkage disequilibrium) constitute risk factors for the development of MM.
NK cells from MM patients pre-cultured in the presence of rhIL-2 exhibited substantial cytolytic activity against autologous mature DCs that were pre-pulsed with patient's monoclonal immunoglobulin in vitro. Furthermore, patient NK cells showed higher cytotoxicity toward autologous DCs as compared to controls. In addition, the activated NK cells also lysed autologous plasma cells, indicating that the NK cell -mediated cytolysis may contribute to tumour regression in MM in vivo. On the other hand, the results suggest that NK cell-mediated killing of autologous DCs may influence the outcome of administration of tumour antigen pulsed DCs in clinical trials.
In brief, our results imply that the genetic factors associated with MM may influence cytokine production in vivo and control the T cell activation pattern leading to conditions that may favour growth of MM cells and inhibit generation of CTLs. It is likely that cytokine activated NK cells in MM patients are endowed with anti-tumour activities. These results would indicate that there are potential effects of both adoptive and innate immune activities on the development of MM.
List of papers:
I. Zheng C, Huang D, Liu L, Wu R, Bergenbrant Glas S, Osterborg A, Bjorkholm M, Holm G, Yi Q, Sundblad A (2001). Interleukin-10 gene promoter polymorphisms in multiple myeloma. Int J Cancer. 95(3): 184-8.
Pubmed
II. Zheng C, Huang D, Liu L, Bjorkholm M, Holm G, Yi Q, Sundblad A (2001). Cytotoxic T-lymphocyte antigen-4 microsatellite polymorphism is associated with multiple myeloma. Br J Haematol. 112(1): 216-8.
Pubmed
III. Zheng C, Huang DR, Bergenbrant S, Sundblad A, Osterborg A, Bjorkholm M, Holm G, Yi Q (2000). Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol. 109(1): 39-45.
Pubmed
IV. Zheng C, Andersson M, Ostad M, Celsing F, Holm G, Sundblad A (2002). Natural cytotoxicity to autologous antigen pulsed dendritic cells in multiple myeloma. Br J Haematol.
I. Zheng C, Huang D, Liu L, Wu R, Bergenbrant Glas S, Osterborg A, Bjorkholm M, Holm G, Yi Q, Sundblad A (2001). Interleukin-10 gene promoter polymorphisms in multiple myeloma. Int J Cancer. 95(3): 184-8.
Pubmed
II. Zheng C, Huang D, Liu L, Bjorkholm M, Holm G, Yi Q, Sundblad A (2001). Cytotoxic T-lymphocyte antigen-4 microsatellite polymorphism is associated with multiple myeloma. Br J Haematol. 112(1): 216-8.
Pubmed
III. Zheng C, Huang DR, Bergenbrant S, Sundblad A, Osterborg A, Bjorkholm M, Holm G, Yi Q (2000). Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol. 109(1): 39-45.
Pubmed
IV. Zheng C, Andersson M, Ostad M, Celsing F, Holm G, Sundblad A (2002). Natural cytotoxicity to autologous antigen pulsed dendritic cells in multiple myeloma. Br J Haematol.
Issue date: 2002-05-17
Rights:
Publication year: 2002
ISBN: 91-7349-222-1
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