T cells and immunosuppression after organ transplantation

In the 7630 course transplantation unit, it has been mentioned that graft rejection is majorly a T cell unintentional wrongdoing and immunosuppression regimen should be able to take care of that. What comes to be a little surprising is dating from mid 50's uptill now, though we have learned the mechanism of how rejection happens but we still don't have a surefire way of saying right away what kind of success we will have with a given transplantation. Reason to that is the transplantation success more relies on post procedure patient monitoring and the right cocktail of immunosuppressive drugs (least toxic but effective) tailored for an individual with multiple given physical conditions. Post-transplantation, for some time the focus is on the transplanted organ, its health and how its coping with the host body, but later on the long term overall patient survival becomes the critical point. Why? because with organ transplantation, its not only the transplanted organ, but the all of host's body at stake. The major reason to this is the inherent toxicity that long term immunosuppressive drug regimen ultimately manifests. I believe the holy grail in organ-transplantation is to find better biomarkers which give the patient's state of the system picture accurately, timely, preferably non-invasively and the immunosuppression, such that its localized, does what its supposed to and nothing else. Of course if in future we are able to make organs in-vitro that are made with patient's own cells, then we don't have to worry about immunosuppression (ref: tissue/organ skeleton re-population by stem cells and "chromosome 6" by Robin cook). But for now, ideal long term immunosuppression may be the biggest challenge in transplantation and that's where T-cells come in picture.

Standard immunosuppression therapy has two phases, the more aggressive, "stand down or I WILL shoot" approach during the initial post-transplantation period. It is to prevent acute rejection episode with cocktail of multiple drugs targeting multiple aspects of host immune system. Then later on, as the patient and the graft stabilize a bit, a subdued but still effective dosing of choice immunosuppressants specifically targeting T-cells, is administered such that toxicity is minimal. Before describing more on T-cells, immunosuppression mechanism and resultant toxicity, a short description of different immunosuppressive drug classes is in order. These are mainly glucocorticoids, anti inflammatory drugs, antimetabolites, antibodies and lymphocyte cell-proliferation inhibitors via interaction with immunophilins. Glucocorticoids are administered generally in the first phase and suppress cell mediated immunity (pro-inflammatory genes of interleukins and TNF ). Anti inflammatory properties of a drug suppress the attraction of immune system components to a site of inflammation / injury. This means less epithelial adhesion, emigration, chemotaxis, phagocytosis, metabolic acceleration and release of inflammatory mediators. Antimetabolites and cytostatics are targeted to suppress cell division specifically that of T and B cells. For example purine and pyramidine analogs stunt the DNA replication process thereby inhibiting cell division. Polyclonal and monoclonal antibodies are directed towards T and B lymphocytes, some cause lysis of these cells by complement and others cause opsonization, some target receptors such as IL-2 and CD-3 to prevent interaction and activation. As you can imagine these drugs can be given in combinations minding the patient specific and sound just wonderful for the treatment. However none of these drugs are without serious adverse impacts if not given correctly. The same goes for immunosuppressants which kick in the first phase of the therapy and stay on for the long term suppression. I am indicating towards drugs that interact with immunophilins to inhibit T cell proliferation. This is the drug class that is T cell specific and has major implications in long term immunosuppression drug regimen and drug toxicity due to lengthy exposure.

I shall further delve into the last drug class, their partial pharmacodynamics, T-cell behavior under these drugs and as an example nephrotoxicity vs chronic rejection in my next post. I hope you found this post useful.

Thanks !

- Rahul