, 11 tweets, 9 min read Read on Twitter
1/ Continuing the #immunosuppression #tweetorial series...@MedTweetorials

Today's player: #mTORi, mammalian/mechanistic target of rapamcyin inhibitors

Rapamcyin was @US_FDA approved for #kidneytransplant in 2003.

It was isolated from a soil sample from which island in 1975?
2/ Meet mTOR, a phosphatidylinositol 3-kinase (PI3)-related kinase (adds a phos). mTOR adds a phosphoryl group to serine/threonine residues.

It is a key component of the complexes mTORC1 and mTORC 2 - which regulate processes including cell growth, proliferation, and survival.
3/ mTOR inhibition blocks "Signal 3" of #TCell activation - reducing cytokine dependent cell proliferation and activation.

Take a look at all 3 signals below 👇🏽

4/ Rapamycin (sirolimus) and everolimus are macrolides & 1st generation mTORi.

Rapamycin was isolated in 1975 from a soil bacterium, S. hygrocopicus, on Easter Island (Rapa Nui). Anti-fungal properties were described before immunosuppressive activity.

5/ Like tacrolimus, rapamycin binds FK binding protein. Instead of inhibiting calcineurin, the main action of the rapamycin-FKBP complex is 🛑 of mTORC1 (with some effect on mTORC2)

For 🦕 fans, an important component of the mTORC1 complex is RAPTOR

6/ Worth mentioning now that mTOR signaling pathways are COMPLEX! Do you see mTORC1 & RAPTOR? 🦖🦕🦖 @CellSignal

7/ As dysregulation of #mTOR pathways has been shown in numerous malignancies, it is not surprising that post-transplant patients have a lower incidence of malignancy when treated with an mTORi - no matter if it is used with or without a #CNI.

8/ What about the kidneys?

#CNI nephrotoxicity may be enhanced mTORi-mediated inhibition of P-glycoprotein efflux of CNI ➡️ increased intracellular CNI concentrations.

mTORi have been also shown to induce or aggravate proteinuria 😭

9/ The lungs are not spared...another feared complications of mTORi use is interstitial lung disease #ILD


radiopaedia.org/cases/drug-ind… @Radiopaedia
10/ To keep this #tweetorial short & sweet, here's a graphic to summarize adverse effects of #mTORi

11/ In summary:

1. #mTOR signaling pathways are complex
2. Rapamycin (mTORi) binds to FKBP ➡️ inhibit mTORC1 🛑 #Tcell proliferation/activation
3. The good: Immunosuppression, anti-cancer
4. The bad: hyperTG, ILD, DM, HTN, proteinuria, CNI tox

Which player should be up next?
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