What is TNF?

Tumor Necrosis Factor (TNF) is a protein (cytokine) which mediates tumor cell necrosis and destroys cancer cells. Found in two forms :

TNFalpha (cachetin)

TNFbeta (lymphotoxin)

The genes that encode both TNF forms are found in the MHC. Both forms of TNF bind to the same receptors and therefore have the same activities. TNFalpha is produced by macrophages and some other cells. TNFbeta is produced by T-cells. There is significant activity overlap with IL1. IL1 and TNF act alone or together to induce systemic inflammation (e.g., fever). LPS (an endotoxin) from bacteria stimulates production of TNFalpha. TNF is also chemotactic for neutrophils and monocytes, as well as increasing neutrophil activity. Is also thought to upregulate HIV replication, and may contribute to the pathogenesis of wasting (cachexia) due to the loss of fat from fat cells and increased metabolism of muscle cells.

TNF causes the symptoms associated with bacterial infections (septic shock, fever, muscle ache, lethargy, headache, nausea and inflammation). Remicade is an anti-TNF drug that first started out on rheumatoid arthritis patients.   It is given by intravenous injection under medical supervision and often prescribed in combination with methotrexate. Remicade is a monoclonal antibody to TNFa.

Enbrel inhibits the action of TNF, and is efficacious at slowing the progression of disease activity and joint damage in patients with early rheumatoid arthritis and emphasize the importance of early treatment.

Enbrel is a soluble receptor for TNF alfa and beta (lymphotoxin) while Remicade is an antibody to TNF alfa.

There was no significant toxicity with Enbrel, including no development of antibodies, and antibodies may be a problem with Remicade if not given with methotrexate. These products are genetically engineered, and predicting antibody problems is not straightforward, but Remicade is chimeral (human and mouse) while Enbrel is made by fusing two TNF receptors with part of the human immunoglobulin IgG1.

Remicade and Enbrel are from a class of biologic response modifiers that are genetically engineered to interfere with the autoimmune process that develops in patients with RA. Unlike many immunosuppressant drugs, Remicade and Enbrel have more focussed biologic targets and therefore do not propagate as significant immune system damage. Specifically, these drugs target immune factors such as tumor necrosis factor (TNF) and interleukins that are thought to be primary culprits in the degenerative cascade of RA.

The Immunosuppressant like Prednisone, Imuran, Cellcept and Methotrexate work on the whole immune system with each on targeting more or less of one area of it.

While they work on the inflammation and slowing the down the progression of the disease, these drugs also affect every other aspect of immune response, including leukocyte and lymphocyte proliferation, monocyte and basophil counts, and cellular communication.

Cyclospoine - seems to have several immunosuppressant effects, principally interferes with the action of helper T-lymphocytes.

Tacrolimus -  seems to work by interfering with the ability of interleukin-2 to communicate with the T-cell receptors, suppressing the activation and replication of the T-cells.

Rapamune -  This drug, like the others, must be used in combination with other drugs to suppress several actions of the immune system.

  Azathioprine - and a newer drug, Mycophenolate Mofetil (CellCept), have a similar end result, though the two have different ways of achieving it.  The outcome in both cases is the suppression of white blood cell proliferation (B-cells, T-cells, and macrophages).  

Methotrexate -  blocks an enzyme needed by the cell to live. This interferes with the growth of certain cells, such as skin cells in psoriasis that are growing rapidly. Since the growth of normal body cells may also be affected by methotrexate, other effects will also occur.

One drawback to Imuran is that, while it does suppress the white cells activated in an immune response, it also can suppress red cell and platelet production, which can be an unwanted side-effect.

CellCept works by limiting the division and development of white blood cells, but seems to have little effect on other bone-marrow products.

The major side effects are gastrointestinal discomfort, and the possibility of a lowered white count, usually reversible with reduced dosage.

A relatively new development in immunosuppression is the use of monoclonal antibodies to fight tissue rejection.  OKT3, ATGAM, Simulect and Zenapax all function by binding to receptor sites on the T-cells, thus preventing their activation.   They do not suppress the entire immune system.

A new drug, ISAtx247 manufactured by Isotechnika of Edmonton, Alberta, Canada entered Phase-1 clinical trials August 28, 2000. The drug is reportedly 3 time more potent than Cyclosporine and at the same time 5 times less toxic.