The Immune Response and Transplants
To be effective the immune system must have the ability to discriminate between self and non-self cells in the body. Those identified as non-self, for example bacteria, viruses and antigens are attacked and destroyed by the immune system. The lack of an immune response against the body's own tissues is known as tolerance. When an organ transplant is introduced to the body, the immune system recognises it as foreign material and therefore attempts to attack and destroy it. It is this immune response that leads to transplants being rejected. When a transplant is carried out therefore, immunosuppressive drugs must also be administered to prevent the body attacking it, in an attempt to introduce tolerance of the transplanted organ.
The rejection of a transplant is primarily due to the immune response of the T lymphocytes, also called T cells, which attempt to attack and destroy any foreign material in the body. After being stimulated by the presence of an antigen the T cells reproduce by mitosis, producing a large number of cells which can attack the foreign material. Therefore most immunosuppressants work by interfering with their proliferation. To understand how rapamycin works we must therefore examine the events leading up to cell division in T cells.
The Cell Cycle
The main stages of the cell cycle are shown in the diagram below. Before entering the cell cycle at G1, cells are in the G0 or 'rest' phase, meaning they are not preparing to divide. G1 stands for 'Gap 1' when the cell is preparing for DNA replication in the S (synthesis) phase. Another gap follows (G2) then the actual cell division takes place in M.
Cells that stop dividing usually stop late in the G1 phase at what is called the R (restriction) point . This is the 'point of no return' after which the cell cycle will continue independently of external signals. It is at this point that it is thought rapamycin arrests the cell cyle, stopping progression into the S phase.
T cell Activation
Before entering G1, the beginning stage of cell division, the T cells must be stimulated by the presence of antigens. These associate with Antigen Presenting Cells (APC), then this complex interacts with a receptor on the T cell (TCR) leading to T cell activation.
The interactions with the receptor send a signal towards the nucleus of the T cell through a cascade of phosphorylation reactions. The signal causes the activation of nuclear transcription factors, which regulate the transcription of T cell activation genes, including that of lymphokine interleukin-2 (IL-2). Translation of the message leads to the secretion of IL-2, a stimulus which causes cell division by allowing cells to progress through the G1 phase of the cell cycle. Lastly, protein is synthesised in the S stage, before the T cell starts to proliferate (M-mitosis).
To introduce tolerance of the new organ the T cells must somehow be disabled, rapamycin achieves this by arresting the T-cells in the G1 phase.