Until now IL-21 was thought to be produced only by T cells, another group of immune cells. Blocking IL-21 production could lead to the development of new therapy strategies for Hodgkin lymphoma in the future, according to the researchers in Professor Bernd Dörken's laboratory, who collaborated with researchers at the University Tor Vergata, Rome (Italy).
It was not until 1994, some 160 years after Hodgkin's lymphoma (HL) was first described by the British physician Thomas Hodgkin (1832), that - using molecular biological methods - scientists discovered that the disease originates from the white blood cells, the B cells. They noticed, however, that the malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) exhibit a phenotype and characteristics that are considerably altered. Although HRS cells are derived from B cells, they have lost the expression of most of the B cell genes due to reprogramming.
The research hypothesis of the just-published paper was that the tumour cells, due to the loss of many B-cell specific genes, need alternative signalling pathways to maintain their malignant growth. As Dr. Mathas explained, "Reprogramming can provide the cells of Hodgkin lymphoma with this survival advantage." Hence, the researchers were searching for factors that normally do not originate from B cells. They found what they were looking for in the gene for the cytokine IL-21.
Different Functions of IL-21
It has only been a few years since IL-21 was discovered in T cells. The function of IL-21, however, varies greatly depending on the kind of cell. In some cell types IL-21 stimulates the body's protection program, which researchers call programmed cell death or apoptosis. Each cell contains this apoptosis program so that it will self-destruct when it is altered or defective. This prevents the defective cell from damaging the entire organism.
Thus, IL-21 stimulates the T cells of the immune system and, for instance, drives cells of the chronic-lymphatic leukaemia of the B-cell type (B-CLL) to apoptosis. By contrast, in T-cell leukaemia's, IL-21 does just the opposite and stimulates malignant growth. For the first time, the researchers from Berlin and Rome were able to show that IL-21 is produced by lymphatic cells originally derived from B cells. IL-21 activates a specific signalling pathway (STAT3), thus up-regulating the expression of a group of specific genes in HRS cells which support the unchecked growth and survival of HRS cells.
IL-21 also activates a chemoattractant for cells which suppress the immune system
On top of that, according to further findings of the researchers, IL-21 activates a protein (MIP-3 alpha) in the HRS cells that attracts a group of T cells to the tumour which suppress the immune system. In the healthy organism, these regulatory T cells keep the immune system in check and prevent excessive immune responses.
In proximity to the HRS cells there are a large number of these regulatory T cells. Attracted by MIP-3-alpha, they can suppress an effective immune defence of the body against the HRS cells. The production of such chemoattractants could, according to the researchers, also be a cause for why Hodgkin lymphoma contains so few tumour cells. They comprise merely 0.1 to one percent of the tissue.
Animal experiments have shown that in immunological diseases like rheumatoid arthritis and lupus erythematosus, a disease accompanied by symptoms such as skin changes and inflammation of blood vessels and joints, these symptoms can be significantly improved if IL-21 is inhibited. "If we could block IL-21 or also MIP-3 alpha in human tumour cells," Dr. Mathas added, "this might be a new therapeutic approach for Hodgkin lymphoma." The present cure rate for the disease - also in its advanced stages - is 80 to 90 percent, particular when chemotherapy is used. However, these therapy regimens might have severe side effects including the risk of therapy-induced secondary malignancies.
