Tucaresol is a drug that appears to have immune-boosting effects. Before the body can mount an immune response to a foreign organism, the organism first has to be 'shown' to CD4 T-cells. This is achieved by a foreign protein (or antigen) from the organism being captured by an antigen-presenting cell such as a macrophage. Subsequently, a second signal, called the co-stimulatory or accessory signal, is needed before the CD4 T-cell can start to coordinate the immune response against that antigen.

An important part of the co-stimulatory signal involves the formation of chemical links between the surface of the antigen-presenting cell and 'amines' on the CD4 T-cell's surface. This link is known as a Schiff base.

Tucaresol can also bind to the CD4 T-cell amines and form a Schiff base. It thus provides an artificial co-stimulatory signal, theoretically strengthening and enhancing the immune system's response to viruses and bacteria.

It was originally tested as a treatment for sickle-cell anaemia because by forming Schiff bases with haemoglobin it helped to stabilise the blood cells. However, the drug also pronounced effects on the immune system, making it hyperreactive and causing side-effects of immune activation. As these immune-boosting effects are not sought in sickle-cell anaemia, its development for this disease was discontinued.

Now tucaresol is being developed for treating immune-based diseases including hepatitis B, metastatic melanoma and HIV. Test tube studies have found that tucaresol stimulates the production of the cytokines interleukin-2 and interferon gamma. Cytokines are natural substances used by cells to communicate with other cells. Interleukin-2 encourages the growth of CD4 T-cells, and interferon gamma helps the body to fight infections. Both of these substances are often found at abnormally low levels in people with HIV. Tucaresol also boosts cytotoxic CD8 T-cells, infection-fighting immune cells. Some studies have linked high levels of CD8 T-cells to a reduced risk of disease progression in people with HIV.

Tucaresol is made by GlaxoSmithKline, and has also been known by the codename 589C80.

Current use

An initial phase II study in people with HIV was stopped early when the first two participants developed side-effects of high fever, tender lymph nodes, rash, muscle aches and tiredness. These are thought to be related to the high dose that was used.

However, a small phase I / II study has shown that giving tucaresol to HIV-positive patients can stimulate production of HIV-specific cytotoxic T-cells, and enhance the production of new CD4 T-cells (Gori 2004).

Key research

Gori (2004) treated 21 HIV-positive patients with tucaresol in a pulse dose escalation protocol (25 to 100mg daily). 6 patients were on HAART with CD4 cell counts between 300 and 500 cells/mm³ and VLs <80 copies/ml, 6 were HAART-naive with CD4 cell counts <500 cells/mm³ and VLs >10,000 copies/ml, 3 were HAART-naive with CD4 cell counts >500 cells/mm³ and VLs <10,000 copies/ml and 6 were on HAART with CD4 cell counts <300 cells/mm³ and VLs <80 copies/ml. Tucaresol-related serious side-effects were seen in 2 of 21 patients on HAART. It did not affect VL but caused increases in CD4 percentage (mainly naive CD4 cells, p < 0.01) and CD8 T-cell numbers.

Reference

Gori A et al. Immunomodulation induced by tucaresol in HIV infection: results of a 16 week pilot Phase I/II trial. Antivir Ther 9: 603-614, 2004.