Mechanisms of immune dysfunction in human lymphomas
Author: Sjöberg, Jan
Date: 1999-12-17
Location: Föreläsningssal Medicin A6:04, Karolinska sjukhuset
Time: 9.30
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
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.
List of papers:
I. Dolcetti R, Frisan T, Sjöberg J, De Campos-Lima PO, Pisa P, De Re V, Gloghini A, Rizzo S, Masucci MG, Boiocchi M (1995). "Identification and characterization of an Epstein-Barr virus-specific T-cell response in the pathologic tissue of a patient with Hodgkins disease" Cancer Res 55(16): 3675-3681
Pubmed
II. Frisan T, Sjöberg J, Dolcetti R, Boiocchi M, De Re V, Carbone A, Brautbar C, Battat S, Biberfeld P, Eckman M, Öst Å, Christensson B, Björkolm M, Pisa P, Masucci MG (1995). "Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkins disease" Blood 86(4): 1493-1501
Pubmed
III. Sjöberg J, Andersson M, Garcia C, Palucka KA, Björkholm M, Porwit A, Pisa P (1970). "Suppression of Epstein-Barr virus-specific immunity in Hodgkins disease is not explained by down-regulation of the signal transduction molecule zeta in tumor associated lymphosytes" (Submitted)
IV. Wihlborg C, Sjöberg J, Intaglietta M, Axdorph U, Pisa EK, Pisa P. (1999). "Tumour necrosis factor-alpha cytokine promoter gene polymorphism in Hodgkins disease and chronic lymphocytic leukaemia" Br J Haematol 104(2): 346-349
Pubmed
V. Sjöberg J, Aguilar-Santelises M, Sjögren AM, Pisa EK, Ljungdahl Å, Björkholm M, Jondal M, Mellstedt H, Pisa P. (1996). "Interleukin-10 mRNA expression in B-cell chronic lymphocytic leukaemia inversely correlates with progression of disease" Br J Haematol 92(2): 393-400
Pubmed
I. Dolcetti R, Frisan T, Sjöberg J, De Campos-Lima PO, Pisa P, De Re V, Gloghini A, Rizzo S, Masucci MG, Boiocchi M (1995). "Identification and characterization of an Epstein-Barr virus-specific T-cell response in the pathologic tissue of a patient with Hodgkins disease" Cancer Res 55(16): 3675-3681
Pubmed
II. Frisan T, Sjöberg J, Dolcetti R, Boiocchi M, De Re V, Carbone A, Brautbar C, Battat S, Biberfeld P, Eckman M, Öst Å, Christensson B, Björkolm M, Pisa P, Masucci MG (1995). "Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkins disease" Blood 86(4): 1493-1501
Pubmed
III. Sjöberg J, Andersson M, Garcia C, Palucka KA, Björkholm M, Porwit A, Pisa P (1970). "Suppression of Epstein-Barr virus-specific immunity in Hodgkins disease is not explained by down-regulation of the signal transduction molecule zeta in tumor associated lymphosytes" (Submitted)
IV. Wihlborg C, Sjöberg J, Intaglietta M, Axdorph U, Pisa EK, Pisa P. (1999). "Tumour necrosis factor-alpha cytokine promoter gene polymorphism in Hodgkins disease and chronic lymphocytic leukaemia" Br J Haematol 104(2): 346-349
Pubmed
V. Sjöberg J, Aguilar-Santelises M, Sjögren AM, Pisa EK, Ljungdahl Å, Björkholm M, Jondal M, Mellstedt H, Pisa P. (1996). "Interleukin-10 mRNA expression in B-cell chronic lymphocytic leukaemia inversely correlates with progression of disease" Br J Haematol 92(2): 393-400
Pubmed
Issue date: 1999-11-26
Publication year: 1999
ISBN: 91-628-3682-X
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