T cells and immunosuppression after organ transplantation - Post II

As promised in the last post, in this post I shall further delve into the pharmacodynamics of immunosuppressants that interact with cellular immunophilins and are used as primary immunosuppressants in clinic. Broadly there are two drug types in this category, first is the calcineurin inhibitors and second is the mTOR (mammalian target of rapamycin) inhibitors. In context of T cells these inhibitors hinder the proliferation signal as well as proliferation of T cells. Here we can think of immunosuppression as basically inhibiting proliferation of immune system cells so as to inhibit an immune response.

Calcineurin is a phosphoprotein serine/threonine phosphatase. In T cells this is involved in calcium dependent immunogenic pathway which is activated when APC interacts with a T cell receptor, resulting in an increase of calcium in T cell cytoplasm. Protein calmodulin binds calcium, then binds calcineurin which activates calcineurin. Activated calcineurin (http://cgap.nci.nih.gov/Pathways/BioCarta/h_calcineurinPathway) then dephosphorylates NFATs (Nuclear factor for activated T cells) which are now able to get inside the nucleus and induce different transcription factors that help in expression of IL-2 genes. Recall IL-2 is a short range lymphokine that effects the behavior of same or another cell. Here it can be T cells as well B cells. Once secreted IL-2 signal activates Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling in the target cell by interacting with IL-2 receptor on target cell surface. The PI 3-kinase/Akt patwhway activates mTOR, a very important serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription (http://www.biocarta.com/pathfiles/h_mtorPathway.asp). As you can already imagine inhibiting either calcineurin or mTOR can have very negative effect on cell growth. With calcineurin specifically on various types of T-cell's cell growth, differentiation and multiplication. mTOR has an overall effect on cell growth of all cell types in humans, that's why mTOR inhibitors have another prominent use of being anti-cancer drugs besides being immuosuppressants.

The calcineurin inhibitors were found earlier compared to mTOR inhibitors and other drugs and still remain the primary immunosuppressants post transplantation. However they have low therapeutic index and in long term use they are highly toxic to the body, specially to the kidney. In these type of long term toxic drug therapy cases, the strategy is to have a synergistic drug partner that can enhance drug effect (possibly by suppressing the target biochemical pathway via a different effector) and at the same time reduce the drug dose which is causing the toxicity. This way lesser drug toxicity with different side effect spectrum is achieved. This is where mTOR inhibitors come in picture after sirolimus was discovered. The calcineurin and mTOR inhibitors such as cyclosporine A and sirolimus/everolimus respectively don't bind these targets by themselvs. They first need binding parter which can then enable them to bind to calcineurin and mTOR. Calcineurin inhibitors cyclosporine A and tacrolimus bind immunophilins cyclophilin A and FKBP 12 (FK506 (tacrolimus) Binding Protein) respectively. Sirolimus/everolimus also bind to FKBP12 but due to combined structural difference they form complex with mTOR and thus inhibit its activity. Here is a representation of this (click to enlarge).

It was found out after several clinical trials that sirolimus enhances nephrotoxicity by an unexplained mechanism but some studies have found out that sirolimus actually increases blood and tissue concentration of calcineurin inhibitors there by increasing the overall toxicity. Brain has notably high levels of Calcineurine, and no surprise cyclosporine A has a serious side effect of neurotoxicity in long term treatment. Although tacrolimus has a different binding parter the toxicity profile is quite similar to that of cyclosporine. Side effects of mTOR inhibitors are those associated with depleted cell growth and divison such as thrombocytopenia. the focus of concern about toxicity related to these drugs is more on possible drug interaction or any other synergistic negative effects which remain unexplained. Why these drugs negatively effect kidney the most, is not yet known, but a possible involvement of mitochondrial dysfucntion due to calcium imbalance is being considered by several groups.

Thanks for reading this post !! until the next one ......