Hans-Jürgen Gruss

Hodgkin's disease: a tumor with disturbed immunological pathways

Abstract Hodgkins disease is a lympltoid neoplasia characterized by low frequeny of malignant Hodgkin and Reed-Sternberg (H-RS) cells in an abundant background of non-neoplastic cells. H-RS cells and their neighbors interact via a complex network of cellular activation/adhesion molecules and cytokines. Here, Hans-Jurgen Gruss and colleagues suggest that H-RS cells can be regarded as antigen-presenting cells able to interact with surrounding T cells, resulting in an intense, bid ineffective, immune response.

The mitogenic response to tumor necrosis factor alpha requires c-Jun/AP-1.

In the present study, we addressed the role of the c-jun proto-oncogene in the mitogenic response of human fibroblasts and primary acute myelogenous leukemia blasts to tumor necrosis factor alpha (TNF-alpha). Our data indicate that TNF-alpha treatment of these cells is associated with transcriptional activation of c-jun, resulting in accumulation of c-jun mRNA and protein expression. In order to elucidate the role of c-Jun/AP-1 in TNF-mediated growth stimulation, the antisense (AS) technique was used. Uptake studies of oligonucleotides were performed with fibroblasts, demonstrating that incorporation of oligomers was maximal at 4 h. Oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of fibroblasts with the AS oligonucleotide resulted in intracellular duplex formation followed by an efficient translation blockade of c-Jun/AP-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and also did not interfere with translation of c-Jun/AP-1, suggesting specific elimination of c-Jun/AP-1 by the AS oligomer. Fibroblasts cultured in the presence of the AS oligonucleotide but not those cultured in the presence of the S or NS oligonucleotide failed to respond proliferatively to TNF-alpha. These findings could be confirmed by experiments with primary acute myelogenous leukemia blasts, which also demonstrated that TNF-induced growth stimulation required c-Jun/AP-1 function. Taken together, our results indicate that activation of c-Jun/AP-1 plays a pivotal role in the signaling cascade initiated by TNF, which leads to a proliferative response of its target cells.

CD30 Ligand, a Member of the TNF Ligand Superfamily, with Growth and Activation Control for CD30+ Lymphoid and Lymphoma Cells*

Hodgkin disease (HD) is characterized by the presence of a small number (usually <1% of total tumor mass) of the typical Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils, and stromal cells. HRS cells produce various cytokines, growth factors, and express cytokine receptors and activation antigens, implying a predominant role for these molecules in the pathophysiology of Hodgkin disease. HD may therefore be regarded as a tumor of cytokine producing cells. The CD30 antigen has been characterized as a marker for cultured and primary Hodgkin and Reed-Sternberg cells, and was found to be overexpressed in Hodgkin disease and a subgroup of non-Hodgkin lymphomas including large cell anaplastic lymphomas and Burkitt lymphomas. The molecular cloning of the CD30 antigen revealed that CD30 is a member of the tumor necrosis factor/nerve growth factor receptor superfamily. The cloning of the cognate for CD30, currently termed CD30 ligand, confirmed that the CD30 antigen functions as a cytokine receptor. Recombinant CD30 ligand is a membrane-bound protein with pleiotropic biological activities for different CD30+ lymphoma types, but also for the immune system, mainly T cells. CD30L belongs to the emerging tumor necrosis factor ligand superfamily. The CD30-CD30 ligand interaction could have a critical pathophysiological role in malignant lymphomas, particularly Hodgkin disease, large cell anaplastic lymphomas and Burkitt lymphomas, and is also involved in activation and functioning of the T cell-dependent immune system.

RECENT PROGRESS ON THE ROLE OF AXL, A RECEPTOR TYROSINE KINASE, IN MALIGNANT TRANSFORMATION OF MYELOID LEUKEMIAS

Receptor tyrosine kinases (RTK) play an important role in the signal transduction of normal and malignant cells. There are different families of RTKs which are mainly characterized by differences in the ligang-binding extracellular domains. Axl (or UFO/Ark) is the first member of a new class of RTK with two fibronectin type III domains and two immunoglobulin-like domains present at the extracellular domain. The axl-gene has been isolated by means of gene transfection studies using DNA of patients with chronic myelogeneous leukemia. For a previous and the present study, we used a sensitive reverse-transcriptase polymerase chain reaction assay to detect axls mRNA in cells from normal and malignant hematopoietic tissue. Axls mRNA expression was mainly detected in myelo-monocytic cells, whereas much weaker transcription was seen in lymphatic cells and in lymphatic leukemias. In normal bone marrow, axl was heavily transcribed in marrow stromal cells. Further, we analysed Axl protein expression using monoclonal antibody M50 in peripheral stem cell harvests; in most harvests, no co-expression of CD34 and Axl was detected. However, in one patient with AML in complete remission, Axl was co-expressed on 80% of the CD34-positive population. These data show that axl is preferentially expressed in monocytes and stromal cells. Furthermore, a fraction of CD34-positive progenitor cells may express Axl. The exact mechanism for transformation of myeloid progenitor cells through Axl, however, remains to be determined.

CD30 Ligand: Cloning, Characterisation and Biological Activities

Hodgkin’s disease (HD) is characterised by the presence of a small number (< 1% of total tumour mass) of the typical, presumed malignant Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal, reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils, and stromal cells. The histopathological presentation and characteristic clinical features of HD correlate with an unbalanced production of multiple cytokines. H-RS cells produce various growth factors, cytokine receptors and activation antigens, implying a role for growth factors in the pathophysiology of HD. HD may therefore be characterised as a tumour of cytokine producing cells. The CD30 antigen has been described as a marker for cultured and primary H-RS cells, and found to be overexpressed in HD and some large cell anaplastic non-Hodgkin’s lymphoma cases. The molecular cloning of the CD30 antigen revealed that CD30 is a member of the tumour necrosis factor/nerve growth factor receptor superfamily. The cloning of the cognate for CD30, currently termed CD30 ligand, confirmed that the CD30 antigen functions as a cytokine receptor. Recombinant CD30 ligand is a type-II membrane-associated protein with pleiotropic biological activities for different CD30+ lymphoma types, but also normal immune system cells, predominantly T-cells. CD30L belongs to the emerging tumour necrosis factor ligand superfamily by virtue of homology to CD27L, CD40L, TNF and other members. These findings suggest that CD30-CD30L interactions could have a pathophysiological role in HD and large cell anaplastic lymphomas, and could also be involved in the activation and function of the immune system, particularly T-cell responses.