What drug 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?

From the Guidelines

Sirolimus is the drug that acts downstream of the Interleukin-2 receptor to inhibit mTOR protein kinase activity and block T-cell proliferation in response to IL-2. This is based on the evidence from the study published in Chest in 2012 1, which highlights the mechanism of action of sirolimus. The drug binds to FK-binding protein, and this complex binds to mammalian target of rapamycin (mTOR), inhibiting IL-2-mediated transduction pathways that promote T-cell proliferation.

Key Points

• Sirolimus has regulatory approval for prophylaxis of organ rejection in patients aged 13 years receiving renal transplants 1.
• The antiproliferative effects of sirolimus have led to its successful use in cardiac stents to prevent restenosis, and potentially in the treatment of cancer and attenuation of radiation-induced effects 1.
• Sirolimus may also be useful in the treatment of diseases linked to the mTOR pathway, such as tuberous sclerosis, lymphangioleiomyomatosis (LAM), and diabetes mellitus 1.

Mechanism of Action

The mechanism of action of sirolimus involves binding to FK-binding protein, forming a complex that inhibits the mTOR pathway. When IL-2 binds to its receptor on T cells, it normally triggers a signaling cascade that activates mTOR, which then promotes T-cell proliferation and immune function. By inhibiting mTOR, sirolimus prevents this proliferation, effectively suppressing the immune response.

Clinical Use

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, sirolimus specifically targets the downstream effects of IL-2, making it particularly useful in combination immunosuppressive regimens or in patients who cannot tolerate calcineurin inhibitors due to nephrotoxicity.

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

mTOR Inhibitors and Their Role in T-Cell Proliferation

• mTOR inhibitors, such as sirolimus and everolimus, act downstream of the Interleukin-2 (IL-2) receptor to inhibit mechanistic target of rapamycin (mTOR) protein kinase activity, ultimately blocking the proliferation of T-cells in response to IL-2 3.
• These inhibitors prevent T lymphocyte activation and B cell differentiation by blocking the cytokine signal transduction, arresting cells in the G1 to S phase 3.
• Sirolimus, in particular, has been shown to improve CMV-specific T-cell function via modulation of the environmental milieu, allowing for fine-tuning of T-cell programming for enhanced antiviral response 4.

Mechanism of Action

• mTOR inhibitors, such as rapamycin and everolimus, bind to FKBP12, which then inhibits the mTOR pathway, preventing cell growth and proliferation 5.
• The binding of mTOR inhibitors to FKBP12 also antagonizes tacrolimus-based calcineurin inhibition, which can affect the immunosuppressive action of these drugs 6.
• The inhibition of mTOR activity by these drugs can also affect the differentiation of naive T cells to the memory phenotype and allow the production of interleukin-2 7.

Specific Drugs

• Sirolimus (rapamycin) is an FDA-approved drug for the treatment of post-renal transplantation and lymphangioleiomyomatosis (LAM) 3.
• Everolimus is an FDA-approved drug for the treatment of postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer, progressive neuroendocrine tumors of pancreatic origin, and advanced renal cell carcinoma, among other conditions 3.
• Temsirolimus is an FDA-approved drug for the treatment of advanced renal cell carcinoma 3.