The immune system is designed to aid in protection against
potential infection and disease from invasion of foreign bodies. One example of
how this defense mechanism becomes problematic, however, is when the ‘foreign’
tissue is a necessity for one’s survival – as in the case of organ
transplantation.
Organ
transplants, especially kidney transplantations, impact many lives each year. According
to the Kidney Alliance of Kentucky, “there are over 750 people in Kentucky
waiting for a life saving kidney transplant.”1 The University of
Kentucky Transplant Center set a record for the most transplants performed by
any Kentucky medical center in a single year with 208 total transplants in 2017
– of those, 101 were kidney transplants, 43 were heart transplants, 41 were
liver transplants, and 23 were lung transplants2. The basis
for transplant ‘success’ is the ability to use drugs that suppress the immune
system (called immunosuppressants) in a manner in which the immune system does
not recognize and/or target the foreign organ to allow for successful donated organ
function.
Immunosuppressants
are a highly specialized class of drugs that are essential in the organ
transplant process. They not only function as a hinderance to organ rejection
but are also used to treat graft versus host disease and reduce damage to
tissues in autoimmune and other inflammatory diseases3.
There are several classes of immunosuppressants in this particular drug family,
including corticosteroids, calcineurin inhibitors, mTOR (mammalian target
of rapamycin) inhibitors, IMDH (inosine monophosphate
dehydrogenase) inhibitors, biologics, and monoclonal antibodies4.
Some examples of the most common
classes of immunosuppressants involved in organ transplantation are calcineurin
inhibitors and IMDH inhibitors. Calcineurin acts to catalyze reactions
associated with T cell activation in the immune response; inhibitors of
calcineurin bind to immunophilin proteins to block its effect and prevent NFAT (nuclear
factor of activated T-cells) activation4.
The result is a reduction in production of cytokine IL-2 and proliferating T
cells6. In contrast, IMDH inhibitors perform by blocking the
inosine monophosphate dehydrogenase pathway, an important enzyme involved in
cell interactions and DNA replication4. This results in a reduction
of infiltrating immune cells during potential transplant rejection7.
Prograf (tacrolimus) and Mycophenolate mofetil (MMF) are
two commonly prescribed combination immunosuppressant drugs to prevent organ
rejection for transplant patients; they fall under the calcineurin inhibitor
and IMDH inhibitor classes respectively8. There are several
other immunosuppressant drugs being used in similar clinical settings that fall
under different subcategories according to other pathways used to target the
immune system.
 |
 |
|
Immunosuppressive Drugs. (n.d.). Retrieved from
https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs
|
Like any drug, there are side
effects/precautions when taking immunosuppressants. By weakening the immune
system, patients are more susceptible to infection and illness while taking
immunosuppressants. Those taking these types of drugs may also be subject to
delayed wound healing for similar reasons. Doctors often prescribe antibiotics
in addition to these medications to help prevent such problems and advise
patients to limit their interactions/possibilities of introducing bacteria into
their compromised environment3. These risks can be especially troublesome
because transplant recipients must often take these drugs for the rest of their
lives to ensure the viability and protection of the donated organ.
While
the immune system is normally a beneficial protective mechanism, it can be
detrimental to the successful integration of a transplanted organ. It is quite interesting
to explore the mechanisms that scientists, chemists, pharmacologists, and other
teams have utilized to suppress this system in order to help save the lives of
many people through organ transplantation.
References:
1. How To Help: Be a Living Kidney Donor. (n.d.). Retrieved
from https://www.khaky.org/how-to-help/living-kidney-donor.html
2. UK Transplant Center Sets New State Record for Total
Transplants in 2017. (2018, January 08). Retrieved from https://uknow.uky.edu/uk-healthcare/uk-transplant-center-sets-new-state-record-total-transplants-2017
3. Immunosuppressants in Organ Transplantation. (2014, March
13). Retrieved from https://www.myvmc.com/treatments/immunosuppressants-in-organ-transplantation/
4. Immunosuppressants. (n.d.). Retrieved from https://www.amboss.com/us/knowledge/Immunosuppressants
5. Immunosuppressive Drugs. (n.d.). Retrieved from https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs
6. P. (2006, August 01). Immunosuppressants - mechanisms of
action and monitoring | Australian Prescriber. Retrieved from https://www.nps.org.au/australian-prescriber/articles/immunosuppressants-mechanisms-of-action-and-monitoring
7. Blaheta, R. A., Leckel, K., Wittig, B., Zenker, D.,
Oppermann, E., Harder, S., . . . Markus, B. H. (1998, December). Inhibition of
endothelial receptor expression and of T-cell ligand activity by mycophenolate
mofetil. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10342739
8. Giorgi, A., & Gregory, P. (2016, December 7). About
Immunosuppressant Drugs. Retrieved from
https://www.healthline.com/health/immunosuppressant-drugs#drug-list
By Caitlin Seward, Master of
Medical Sciences Student, University of Kentucky
I find the idea of organ transplants to be fascinating and so important in the medical community. After taking an immunology course last semester, I was able to gain much better insight into the importance of our immune systems as a whole. However, in organ transplant cases it's crucial to regulate the immune response so that our bodies do not reject the donor organ. My own stepdad donated one of his kidneys to his brother a few years ago and I remember watching them go through that process together. It's interesting that almost everyone who has had a transplant must take immunosuppressive drugs every single day. The only exception is if the kidney comes from an identical twin (National Kidney Foundation, 2017).
ReplyDeleteResearchers at Brigham and Women's Hospital have recently discovered that extracellular vesicles released by glioblastomas include a protein known as programmed death ligand-1 (PD-L1) that normally helps to regulate T-cell activity (Daley, 2018). This protein is also present on the surface of tumor cells, which allows it to hide from circulating immune cells (Daley, 2018). Therefore, the protein has become a target for checkpoint inhibitors (Daley, 2018). This has been a major advancement in the field of immunology because immune checkpoints were discovered to operate not only through cell surface signaling, but also via extracellular vesicles (Daley, 2018).
These researchers analyzed blood samples from patients with glioblastomas and compared them against healthy individuals (Daley, 2018). The researchers discovered that 14 out of the 21 patients with glioblastomas did have circulating extracellular vesicles containing PD-L1 DNA, which corresponded with larger tumors (Daley, 2018). The researchers are hopeful this discovery may lead to an easier way to detect glioblastomas in blood samples (Daley, 2018).
It's an interesting paradox that the immune system is necessary for our protection and survival, but sometimes we need to suppress it in order to maintain normal function. This is why many people suffer from allergies and autoimmune diseases. What are the mechanisms behind autoimmune diseases? Are those patients also treated with immunosuppressant's?
References:
Daley J. PD-LI in Extracellular Vesicles May Help Glioblastoma Evade Immunotherapies. The Scientist. https://www.the-scientist.com/the-nutshell/pd-l1-in-extracellular-vesicles-may-help-glioblastoma-evade-immunotherapies-29982. Published March 8, 2018. Accessed October 18, 2018.
Immunosuppressants. National Kidney Foundation. https://www.kidney.org/atoz/content/immuno. Published 2017. Accessed October 18, 2018.
It is so amazing to see the power behind immunosuppressants when it comes to transplantations. However, I find it interesting that scientists have yet to find a way to avoid the adverse effects of these immunosuppressant drugs. A study conducted by Scotta et al., 2016 focused on a cell therapy in connection with naturally occurring regulatory T cells (Tregs) for the initiation of transplantation acceptance. Clinical trials were already introducing transplanted patients with a combination of Tregs and immunosuppressant drugs (Scotta et al., 2016). The unknown however, was whether the existence of immunosuppressant drugs negatively affected the function of Tregs, as well as its stability (Scotta et al., 2016). Scotta, et al., 2016 experimented the effects in vitro and in vivo of three immunosuppressant drugs, tacrolimus, mycophenolate, and methylprednisolone on human Tregs. Results indicated that there was a decrease in Treg feasibility and proliferation (Scotta et al., 2016). Tacrolimus had the biggest effect by also affecting the cytokine structure and the expression of certain chemokine receptors (Scotta et al., 2016). In the months that followed the transplantation, studies have shown that the patients that were taking immunosuppressant drugs with calcineurin inhibitors, see a decrease in Tregs (Scotta et al., 2016). Tregs are said to improve autoimmune diseases, graft-vs.-host disease (GvHD), and prevent solid organ transplant rejection (Scotta et al., 2016). Based on the study, regulatory T cells seem to be quite essential, so it makes me wonder whether there are current experiments being done to preserve them?
ReplyDeleteReference:
Scotta, C., Fanelli, G., Hoong, S. J., Romano, M., Lamperti, E. N., Sukthankar, M., . . . Lombardi, G. (2015). Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells. Haematologica,101(1), 91-100. doi:10.3324/haematol.2015.128934
Immunosuppression remains the mainstay of treatments for many autoimmune diseases and to prevent organ rejections from transplants. Glucocorticoids and thiopurines are still widely used, however, they also lead to undesired consequences such as immunodeficiency to opportunistic infections or non-immune toxicity to liver and/or kidneys. The newer generation of immunosuppressants such as calcineurin inhibitors, mTOR inhibitors and IMDH inhibitors minimize the risk of the undesired affects while delivering targeted suppression of the immune system. Another class of immunosuppressants that is garnering increased attention is biologics i.e. antibodies. Basiliximab and Daclizumab, among others, are widely prescribed monoclonal antibodies (mAbs) used against acute rejection after renal transplants. These mAbs bind to CD25 receptor on the surface T cells and prevents interleukin-2 (IL-2) induced T- cell activation. Basiliximab has been shown to be effective in preventing graft versus host disease (GVHD). Daclizumabis used to treat autoimmune diseases, particularly multiple sclerosis. Daclizumabis has also been reported to cause Treg depletion in patients with Hodgkins lymphoma. Our fight against autoimmune related diseases looks more promising than ever as we continue to discover and develop novel targets using our own immune system against itself.
ReplyDeleteReferences:
Immunosuppressants - mechanisms of action and monitoring.
https://www.nps.org.au/australian-prescriber/articles/immunosuppressants-mechanisms-of-action-and-monitoring#antiproliferative-drugs
Anti-CD25 monoclonal antibody (basiliximab) for prevention of graft-versus-host disease after haploidentical bone marrow transplantation for hematological malignancies.
https://www.ncbi.nlm.nih.gov/pubmed/15968293
90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620907/
After reading about how immunosuppressants were used so heavily in all patients with organ transplants, it sparked my interest in the topic and led me to look into how the long term use of immunosuppressants for organ transplants related to the risk of cancer. The study I found takes a look at 175,000 organ transplant recipients, and looks at how many of them developed cancer over a period of 20 years after the transplant. It was found that these transplant recipients do indeed have a higher risk from the immunosuppression. (Engels, 2011) The incidence of all types of cancer in transplant recipients was over a 2-fold increase when compared to the general population. (Engels, 2011)
ReplyDeleteAnother finding from this cohort study was that Non-Hodgkin lymphoma, lung, kidney, and liver cancer comprised 43% of cancers in transplant recipients, as opposed to 21% of the general population. (Engels, 2011)
I agree with Beverly, more research needs to be done in order to prevent adverse conditions from the weakened immune system, such as cancer. Immunosuppressants are vital for the survival of hundreds of thousands of patients, we have to find a way to selectively suppress the immune system, so that our immune response is still able to find and kill cancer cells before they become deadly.
Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of Cancer Risk Among US Solid Organ Transplant Recipients. JAMA. 2011;306(17):1891–1901. doi:10.1001/jama.2011.1592
I have actually had some personal experience with the Transplant Center here at UK. A little over three years ago, I was diagnosed with a rare condition that caused a blood clot to develop in my hepatic vein. While in the hospital, the doctors at the Transplant Center handled my case and I continue to follow up with them to this day. While I was fortunate enough to not need a liver transplant, I will always be grateful for the amazing doctors at the Transplant Center. I routinely visit for check-ups, and it seems to me they do a wonderful job of advising the patients who have had transplants and discussing their medications with them. I'm hoping that as a pharmacy student, I might be able to shadow with them and learn a little more about how they use drugs to modulate the immune system.
ReplyDeleteI found an interesting article that discusses the possibility of organ transplantation without immunosuppressants. Clinical trials have examined the potential of infusing bone marrow cells from the donor into the recipient to create a chimeric immune system containing both donor and recipient cells. While this effect was short lived, researchers at the University of Louisville are examining ways to make this last long term. The preliminary results from their study showed that after a year, 5 of 8 patients had achieved long-lasting chimerism and showed no signs of rejecting the organ. These promising results show that maybe one day we will be able to eliminate the need for immune suppressing drugs altogether.
Reference:
Organ Transplants Without Life-Long Drugs. (2016, March 30). Retrieved from https://www.nih.gov/news-events/nih-research-matters/organ-transplants-without-life-long-drugs
Interesting Cassie. Even if 37% of the patients start to reject an organ, worst case is they have to take immunosuppressants, right? Glad you're all better!
ReplyDeleteWhile organ transplant can save lives & give people new hope, there's a lot of issues that need to be addressed. The use of immunosuppressants is the most important one. To me it's the ultimate trade of. While people might die immediately without organ transplant, management through whole life after transplant seems to be a better choice.
ReplyDeleteThere are a lot of diseases where people just do disease management with few drugs but can live easily for a much longer time. For example, high blood pressure, diabetes etc. If people can manage that for a long time, I would assume that managing a post transplant health wouldn't be that difficult for anyone.
After reading, I became interested in immunosuppressants as therapy for autoimmune diseases. The most common autoimmune diseases that use immunosuppressants are psoriasis, lupus, and rheumatoid arthritis. Sometimes a combination of drugs may be used, it all depends on the patient and may result in some trial and error to determine which drugs produce the least amount of side effects. Regular blood tests are necessary to monitor the drug's effect and determine if a change in dose is needed. Side effects vary by drug, but of course all immunosuppressants come with a high risk of infection (Giorgi, 2016).
ReplyDeleteImmunosuppressants prescribed for autoimmune diseases are much less common than for transplant patients, but they have been shown to significantly reduce inflammation and other symptoms. However, they are not a reliable cure and unfortunately, patients are at risk of developing a second autoimmune disease. Other approaches to treatment are currently in clinical trials (Chandrashekara, 2012).
Chandrashekara, S. (2012). The treatment strategies of autoimmune disease may need a different approach from conventional protocol: A review. Indian Journal of Pharmacology, 44(6), 665-671. https://dx.doi.org/10.4103%2F0253-7613.103235
Giorgi, A. (2016, December 7). About Immunosuppressant Drugs. Retrieved from https://www.healthline.com/health/immunosuppressant-drugs
One thing that Katie mentioned that piqued my interest was that if the organ comes from an identical twin, the patient will not have to take immunosuppressants. This made me wonder if this was always the case. There was a retrospective study done in 2015 examining the outcomes of kidney transplants between five groups of identical twins. I found this study very interesting because kidney transplants are particularly difficult to successfully complete due to its complex mechanics and vasculature. The study found that all five patients had excellent outcomes without the usage of immunosuppressants. I wonder if we can somehow figure out the exact biological mechanisms by which the twin's organs evade the immune system. Obviously, twins can still have very different bodies and different immune responses. This is definitely a topic that upon further research might make transplantation easier.
ReplyDeleteReference:
Sánchez-Escuredo, A., Barajas, A., Revuelta, I., Blasco, M., Cofan, F., Esforzado, N., . . . Diekmann, F. (2015). Trasplante renal de donante vivo entre gemelos monocigotos sin inmunosupresión de mantenimiento. Nefrología, 35(4), 358-362.
With the need for organ transplants growing daily, I think it is important note the advancements in stem cell research as scientists are trying to grow viable organs in a lab from host stem cells. This was recently achieved, in a sense, when a team of scientists were able to harvest fetal progenitor cells in the lungs of mice to help regenerate damaged tissues (Krentsis et. al, 2018). The scientists were able to repair parts of a damaged lung in an adult mouse by implanting the progenitor cells, provided that that the environment of the mouse was at a certain standard (Krentsis et. al, 2018). While there are still ethical implications for using fetal stem cells, the scientists continue to look for ways to produce the same effect using adult stem cells. I think this is one of the greatest advancements in modern technology because it can help to speed up the process of transplantation for those who are of high priority. It is also a less invasive procedure to implant a small colony of cells to produce the effect of regeneration. Hopefully we will see this to completion in our lifetime!
ReplyDeleteReference:
Krentsis, I. M., Rosen, C., Shezen, E.,...,Resiner, Y. (2018). Lung Injury Repair by Transplantation of Adult Lung Cells Following Preconditioning of Recipient Mice. Stem Cells Translational Medicine, 7(1): 68-77
I've always been a huge fan of the movie "Steel Magnolias" and every time immunosuppressants or organ transplants are brought up, I always think of the film. If you have ever seen the film you know that the leading character and diabetic, Shelby, dies from a failed kidney transplant due to infection from immunosuppressants. Immunosuppressants have worked so many miracles for so many people but we still need to address the cases where they did not. We are so quick to talk about the successes of transplant, because the odds are GOOD but... we rarely talk about the failures, which are also important for educational purposes. When immunosuppressants do not comply, the body begins to attack the kidney and either cause the patient to retreat back to dialysis, or if undetected, can become fatal. Although the success rates of immunosuppression treatments are phenomenal, we should also look for more strategies in treating those who are not as lucky.
ReplyDeletehttps://www.kidney.org/transplantation/transaction/TC/summer09/TCsm09_TransplantFails
https://www.uptodate.com/contents/withdrawal-of-immunosuppression-after-renal-transplant-failurehttps://www.uptodate.com/contents/withdrawal-of-immunosuppression-after-renal-transplant-failure
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