From the Guidelines
Sirolimus is the drug that acts downstream of the Interleukin-2 (IL-2) receptor to inhibit mTOR protein kinase activity and block T-cell proliferation in response to IL-2. This immunosuppressive medication works by binding to the FK-binding protein (FKBP), forming a complex that then inhibits the mTOR pathway, as described in the study by 1. When IL-2 binds to its receptor on T-cells, it normally triggers a signaling cascade that activates mTOR, which promotes cell cycle progression and proliferation. By inhibiting mTOR, sirolimus prevents T-cells from moving from the G1 to S phase of the cell cycle, effectively blocking clonal expansion of activated T-lymphocytes. Some key points about sirolimus include:
- It has regulatory approval for prophylaxis of organ rejection in patients aged 13 years receiving renal transplants, as noted in the study by 1
- It is used for immune modulation for clinical transplantation of solid organs, graft-vs-host disease, autoimmune diseases, autoimmune lymphoproliferative syndrome, and asthma
- Its antiproliferative and antiangiogenic effects are potentially useful in the treatment of cancer and attenuation of radiation-induced effects
- The antiproliferative effects of sirolimus have also led to its successful use in cardiac stents to prevent restenosis, as mentioned in the study by 1. Sirolimus is commonly used in transplant medicine to prevent organ rejection, typically at doses of 2-5 mg daily with therapeutic drug monitoring to maintain blood levels between 4-12 ng/mL. Unlike calcineurin inhibitors (tacrolimus, cyclosporine) which block IL-2 production, sirolimus specifically targets the downstream effects of IL-2, making it mechanistically distinct in the immunosuppression pathway, as supported by the evidence from 1.
From the FDA Drug Label
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC) Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity.
The drug that acts downstream of the Interleukin-2 receptor to inhibit mTOR protein kinase activity, and ultimately to block the proliferation of T-cells in response to IL-2 is Everolimus 2.
- Key points:
- Everolimus inhibits mTOR, a serine-threonine kinase.
- mTOR is downstream of the PI3K/AKT pathway.
- Inhibition of mTOR by everolimus reduces cell proliferation.
- Everolimus binds to FKBP-12, forming an inhibitory complex with mTORC1.
- Main action: Inhibition of mTOR kinase activity, reducing T-cell proliferation in response to IL-2.
From the Research
Drug Mechanism
The drug that acts downstream of the Interleukin-2 (IL-2) receptor to inhibit mechanistic target of rapamycin (mTOR) protein kinase activity and block T-cell proliferation in response to IL-2 is:
- Sirolimus, as it inhibits mTOR activity and modulates IL-2 receptor-driven signal transducer and activator of transcription-5 (STAT-5) signaling, thereby fine-tuning T-cell programming for enhanced antiviral response 3
- Everolimus, which is an mTOR inhibitor that can inhibit cell growth, proliferation, and angiogenesis, and has been shown to have immunosuppressive effects 4, 5
mTOR Inhibition
mTOR inhibition is a key mechanism for immunosuppression, and drugs such as sirolimus and everolimus have been shown to be effective in inhibiting mTOR activity and suppressing T-cell proliferation 3, 4, 5
IL-2 Receptor Signaling
The IL-2 receptor signaling pathway is crucial for T-cell development and function, and disruption of this pathway can result in severe T cell-mediated autoimmunity 6, 7
- The IL-2 receptor signaling pathway can act through the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway, the Janus kinase (JAK)/Signal transducers and Activators of Transcription (STAT) pathway, and the mitogen-activated protein kinase (MAPK) pathway 7