Biological Mechanism

Rapamycin is believed to block the immune response by causing programmed cell death, or apoptosis in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle. In the diagram below FKBP-12 is blue and FRAP is the red protein, with rapamycin between them.

Fig. 1

This rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1. Rapamycin therefore stops the cell at the G1-S transition. In this way the proliferation of T-cells is stopped and apoptosis is induced instead.8

When T cells are activated it is found that a small population of regulatory T cells are also produced, with the power to control the rejection causing T cells. Usually these regulatory cells have little effect on the more powerful rejection-causing cells, however, the apoptotic death of many of the rejection-causing T cells enables the regulatory cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells but doesn't block apoptosis, the programmed suicide of cells that occurs after they have reproduced a certain number of times. Therefore by inducing apoptosis in rejection-causing T cells, rapamycin is able to reduce the tendency to reject the transplant, while allowing the body to develop a tolerance for it. 9, 10

Other commonly used immunosuppressants, cyclosporin and FK-506 have a different mode of action, working by blocking the Ca2+ dependent signalling pathway to the nucleus of the T cell by binding to calcineurin. Calcineurin is the key molecule in the T-cell receptor signalling pathway which activates resting T-cells to enter the cell cycle. The T cell is therefore halted at the G0-G1 transition, where G0 is the state of a resting cell, before it is stimulated to proliferate. However, the side effects associated with these drugs are thought to be caused by the inhibition of calcineurin activity in non-immune cells. Rapamycin would not cause these side effects but only selectively block proliferation of T cells.

Rapamycin only affects activated cells so leaves the rest of the immune system to fight infection. This is because rapamycin stops the proliferation of cells which have already been activated to enter the cell cycle, at the G1-S transition rather than at G0-G1.



Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. A p53 mutation is the most common mutation leading to cancer, as this will prevent abnormal cells from dying by apoptosis, instead they will continue to divide, reproducing the error. Rapamycin could cease the division of cancer cells in a similar manner to the way in which it stops cell division in T-cells, and also cause apoptosis. It could therefore have applications in the treatment of cancer.

Studies have shown rapamycin to inhibit growth and cause cell death by apoptosis in B lymphoma cells. Neither FK506 nor cyclosporin affected the normal growth of these cells, however FK506 appeared to reverse the growth inhibition caused by rapamycin. Cyclosporin did not have this effect, probably due to the fact that rapamycin and FK506 compete for FKBP binding sites.


Fig. 1 from:


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