Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation

Table 1 Classification of biological and pharmacological immunosuppressive agents[1,3]

Biologic immunosuppressive agents	Function
Lymphocyte-depleting agents
Monoclonal anti-CD20 (rituximab)	Depletion of B-cells
Monoclonal anti-CD52 (alemtuzumab)	Depletion of T-cells, monocytes, macrophages and natural killer cells
Monoclonal anti-CD3 (OKT3)	Interference with signal 1 in T-cells
Anti-thymocyte globulin	Interference with signals 1, 2 and 3 in T-cells
Non-lymphocyte-depleting agents
Anti-IL-2 receptor (basiliximab, daclilumumab)	Inhibition of T-cell proliferation and signal 3
Belatacept	Inhibition of signal 2 in T-cells (competition with CD28 for CD80/CD86 binding) inhibiting T-cell co-stimulation
Daclizumab	Inhibition of signal 2 in T-cells (binds to CD25, the alpha subunit of the IL-2 receptor) preventing IL-2-induced T-cell activation
Pharmacological drugs	Function
Corticosteroids	Inhibition of cytokine transcription by APCs
Azathioprine	Inhibition of nucleotide synthesis, blocking lymphocyte proliferation
Mycophenolic acid	Inhibition of nucleotide synthesis, blocking lymphocyte proliferation
Calcineurin inhibitors (cyclosporine A, tacrolimus)	Inhibition of signal 2 transduction in T-cells [inhibits calcineurin via cyclophilin (cyclosporine A) or via FKBP12 (tacrolimus)], blocking IL-2 transcription
FK778 (manitimus)	Inhibits dihydro-orotate dehydrogenase, interrupting de novo pyrimidine synthesis, thereby acting on both B-cells and T-cells beyond the early S phase of the cell cycle, differentially from calcineurin inhibitors
mTOR inhibitors (rapamycin, everolimus)	Inhibition of signal 3 transduction in T-cells (inhibits mTOR), preventing IL-2-induced T-cell proliferation

APC: Antigen-presenting cell; IL-2: Interleukin-2; mTOR: Mammalian target of rapamycin.