A Short History of Immunosuppressants And The Woman Who Invented Them
I’ve been thinking about the field of experimental transplantation research lately. There has been great research in this area recently, including work in Circulation Research on using nanoparticles to target potent immunosuppressants to key areas to suppress rejection (Bahmani, Uehara et al. 2018). There was also an interesting paper that used an aortic arch transplant model to study regression of atherosclerosis published in ATVB (Li, Luehmann et al. 2018). I began thinking about transplantation and the issue of acute rejection. There is also the problem of longer-term chronic vasculopathy and remodeling, but how did the field get over the first hurdle of acute rejection? It’s so fundamental to all organ transplantation that takes place in the clinic today. I decided to look into how we got to where we are today.
I found out that one of the earliest immunosuppressive agents was 6-mercaptopurine (6-MP). 6-MP was developed by a chemist named Gertrude Elion. I was delighted to find out that a woman developed this drug, especially as it was recently Women in Science Day on February 11th. Elion was born in New York City and earned a Bachelor’s degree at Hunter College and a Master’s degree in chemistry at NYU. She submitted 15 applications for graduate fellowships which were all turned down, leading her to enroll in secretarial school. She moved through several other jobs before working in as an assistant at what is now GlaxoSmithKline (GSK). While working there, she began earning her doctorate at night but stopped due to the difficulty of the commute. It was at GSK that Elion developed 6-MP, but she was only getting started.
6-MP was first used in the late 1950’s as chemotherapy to suppress antibody formation in pediatric cancer which improved survival from 3-4 months up to 12 months. 6-MP was next used in rabbits that were injected with bovine serum albumin to stimulate a powerful antigen response, but 6-MP prevented it (Schwartz, Stack et al. 1958). Next, a British surgeon, Roy Calne wanted to test whether 6-MP’s immune suppression could be used to prevent rejection after a transplant. He treated a dog with 6-MP and then transplanted a kidney from another dog. Ordinarily, the recipient dog’s immune system would attack the new kidney as if it were an invader. The kidney in the 6-MP treated dog survived 44 days compared to only 10-days for dogs that weren’t given 6-MP (Calne 1960). This drug seemed promising, but it had a high risk of toxicity, and this is where the story gets interesting.
Roy Calne wanted to find a drug that was as effective as 6-MP but less toxic, so he asked Gertrude Elion. Elion suggested another compound that she had recently synthesized, which was azathioprine (AZA) (Elion, Callahan et al. 1960). Clinicians will be familiar with this drug, but as a PhD scientist, I had never heard of it before now (and I did my PhD in pharmacology, but don’t hold it against me). AZA is a pro-drug that that is activated by glutathione in red blood cells to produce the active metabolite 6-MP in plasma. AZA was not only superior to 6-MP for preventing alloimmune transplant rejection, it was far less toxic. In 1962, only 2 years after the kidney transplant study with dogs, AZA was being used in human kidney transplants together with prednisone (Murray, Merrill et al. 1963). From this point onward, kidney transplants using Gertrude Elion’s AZA compound skyrocketed.
In 1988, Gertrude Elion was awarded the Nobel Prize in Physiology or Medicine, just the 5th woman to receive the award at the time. The development of AZA and more importantly, its use as an immunosuppressive agent allowed for the transplantation of many other organs, including livers, lungs, and hearts (Elion 1989). Other immunosuppressants have been developed which are in use for heart transplantation today but AZA is still being used for kidney transplants and chronic inflammatory diseases like rheumatoid arthritis and Crohn’s disease. Elion’s AZA is also listed as an essential medicine by the World Health Organization.
Gertrude Elion was an amazing scientist that had an enormous impact on health across the world. In addition to the synthesis and development of AZA, she is credited with the synthesis of allopurinol to treat gout and ancyclovir to treat herpes simplex virus. Both of these drugs are classified as essential medicines by the WHO. Her knowledge of both chemical synthesis and the biochemical basis of disease set her apart as a truly remarkable scientist who overcame many obstacles that women in science still face. Gertrude Elion should serve as a role model for anyone interested in science.
“Gertrude B. Elion.” https://en.wikipedia.org/wiki/Gertrude_B._Elion
“Gertrude B. Elion Biographical.” https://www.nobelprize.org/prizes/medicine/1988/elion/biographical/
Bahmani, B., M. Uehara, L. Jiang, F. Ordikhani, N. Banouni, T. Ichimura, Z. Solhjou, G. J. Furtmuller, G. Brandacher, D. Alvarez, U. H. von Andrian, K. Uchimura, Q. Xu, I. Vohra, O. A. Yilmam, Y. Haik, J. Azzi, V. Kasinath, J. S. Bromberg, M. M. McGrath and R. Abdi (2018). “Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival.” J Clin Invest 128(11): 4770-4786.
Calne, R. Y. (1960). “The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine.” Lancet 1(7121): 417-418.
Elion, G. B. (1989). “The purine path to chemotherapy.” Science 244(4900): 41-47.
Elion, G. B., S. W. Callahan, G. H. Hitchings and R. W. Rundles (1960). “The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (B.W. 57-323) in man.” Cancer Chemother Rep 8: 47-52.
Li, W., H. P. Luehmann, H. M. Hsiao, S. Tanaka, R. Higashikubo, J. M. Gauthier, D. Sultan, K. J. Lavine, S. L. Brody, A. E. Gelman, R. J. Gropler, Y. Liu and D. Kreisel (2018). “Visualization of Monocytic Cells in Regressing Atherosclerotic Plaques by Intravital 2-Photon and Positron Emission Tomography-Based Imaging-Brief Report.” Arterioscler Thromb Vasc Biol 38(5): 1030-1036.
Murray, J. E., J. P. Merrill, J. H. Harrison, R. E. Wilson and G. J. Dammin (1963). “Prolonged survival of human-kidney homografts by immunosuppressive drug therapy.” N Engl J Med 268: 1315-1323.
Schwartz, R., J. Stack and W. Dameshek (1958). “Effect of 6-mercaptopurine on antibody production.” Proc Soc Exp Biol Med 99(1): 164-167.