← Back to Nov 2013


Epigenetics and Transplantation


links image

Howard Eisen, MD
ISHLT BSTR Council Communications Liaison
Drexel University College of Medicine and Hahnemann University Hospital
Philadelphia, PA, USA
Howard.Eisen@DrexelMed.edu



Recently, while actively engaged in my hobby—writing patient notes in our electronic medical record—I was confronted with a sudden, unexpected outage of the system. Not knowing when the system would restart, I began to ponder complexity, in this case complexity in entering patient data and in how we conduct medical care. As it was clear that the outage was not going to end anytime soon and since the last patient in whose record I was entering information had recently been diagnosed with breast cancer, I thought about the complexity of the genetics of this disease and how the understanding of genesis of malignancies has become far more intricate.

Certainly, the understanding of genetics has become far more complex in recent years. If you are like me, your first introduction to genetics in school was the mid-19th century experiments of Gregor Mendel on pea plants in Bohemia. Mendel identified seven traits that were independently inherited including seed shape, pod shape, flower color and so on. From this work, involving over 29,000 pea plants (apparently without the help of graduate or medical students or fellows or residents), the concepts of alleles and inherited recessive and dominant traits were first proposed and understood. In the mid-20th century, Avery's identification of DNA as the heritable material (a discovery that did not apparently merit the Nobel Prize) and Watson and Crick's deciphering of the structure of DNA provided a molecular understanding of genetic inheritance (1,2). The idea that all inheritance came from the nucleotide sequence of DNA would remain the cornerstone of genetic inheritance for the next few decades. However, even in the 1970s, it appeared that the prevalent conception of genetics as it applied to human diseases such as cancer was lacking in details. While the term "epigenetics" was first coined in 1942 to mean the differentiation of cells from the initial embryonic ones, the present definition is "the study of mitotically or meiotically heritable changes that cannot be explained by changes in DNA nucleotide sequences" and must therefore imply stable changes in chromosome structure but not DNA sequences (3,4). Numerous mechanisms can account for this including DNA methylation, an important regulator of gene expression, and modification of the chromatin proteins such as histones associated with DNA; the latter play a role in gene expression and may be activated or silenced (5,6). Processes that can cause epigenetic changes include gene silencing, imprinting, X chromosome inactivation, reprogramming and the effects of carcinogens and teratogens (7,8). The latter work through damage of DNA with subsequent repair (DNA damage occurs a surprising 10,000 times per day per human cell which kept me up for most of the night after I realized this). It is these repair sites that are subject to epigenetic changes such as methylation or gene silencing.

Where epigenetic changes such as DNA methylation, seem to have the most obvious impact in clinical medicine is in oncology. Familial mutations account for a very small number of malignancies whereas epigenetic changes resulting in diminished expression of DNA repair genes are quite frequent. These epigenetic changes have become potential targets of new cancer therapies with an inhibitor of histone deacetylase (HDAC), vorinostat, being introduced to blunt HDAC's facilitation of squamous cell cancer progression.

Is any of this relevant to organ transplantation? Transplantation is more complex in some ways than oncology because we are dealing with two genomes (the donor organ and the recipient) and the epigenetic changes that occur to each of these. There are several ways that these seem to be manifested in transplantation. Modern immunosuppression has been very successful in controlling acute cellular rejection but more chronic insults such as cardiac allograft vasculopathy (CAV) have been more resistant. Additionally, immunosuppression can be weaned or doses reduced over time. Why is that possible if the donor-recipient combination remains the same?

Ischemia/reperfusion is known to produce epigenetic changes in MHC antigen expression levels in donor organs through activation of Hypoxia-inducible factor which modifies histones and in turn increases MHC expression (9). This would make the transplanted organ more of a target to the recipient immune system. Epigenetic biomarkers might therefore allow a way to quantify the immunogenicity of transplanted organs and thus determine the rate of immunosuppression weaning and other adjustments in post-transplant management. Epigenetic markers may also provide a way of assessing over time the immunogenicity of the transplant organ and guide post-transplant therapy.

Epigenetics also play a role in the allo-immune response to the transplanted heart. HDACs mentioned above are involved in regulatory Tcell (Treg) activity. HDAC inhibitors have been shown to inhibit T cell reactivity and may promote tolerance, highly desirable in transplantation (10). An important gene in the regulation of Tregs, Foxp3, is also susceptible to changes in its expression modulated by epigenetic regulation. Foxp3 levels can be altered by methylation (11). HDAC also plays a role in Foxp3 expression and Treg generation and stability (11). As with the cardiac allograft, epigenetic biomarkers may be useful in assessing immune reactivity to the allograft, this time on the recipient side, and may help guide adjustment of immunosuppression as well as identifying patients at risk for acute cellular rejection, antibody-mediated rejection or CAV. Even more intriguing is the thought that drugs that modulate epigenetically regulated genes might be useful as immunosuppressive therapy and may accomplish this through the generation of Tregs. For example, HDAC inhibitors increase the number and activity of Tregs in mice (11,12) and primates (11,13). This offers the possibility of new therapies with fewer side effects than standard immunosuppression and with far more specific effects including the prevention of chronic adverse sequelae like CAV. These epigenetic therapeutic agents might be used in conjunction with much lower dose of traditional immunosuppressive agents, reducing their adverse side effects like infection and malignancy. With the development of epigenetic regulators as therapeutic agents for malignancies, some of these agents may also prove useful in solid organ transplantation. But the use of oncologic agents in organ transplantation is actually an old story: remember azathioprine? What we may well see in the future is an updating and a logical extension of an old tradition of cross-fertilization between the clinical arenas of oncology and organ transplantation.

Disclosure Statement: The author has no conflicts of interest to disclose. He is now able to rest more easily despite knowing about the large numbers of DNA errors that occur in each of his cells every day.


References:

  1. Reichard, Peter ."Osvald T. Avery and the Nobel Prize in medicine". J. Biol. Chem. 2002. 277: 13355-62.
  2. James D. Watson, The Double Helix: A Personal Account of the Discovery of the Structure of DNA (1968), Atheneum, 1980. (Author's note: interesting for its insights into the politics of science and the role of the British pub in the scientific discovery process.)
  3. Riggs AD, Russo VEA, Martienssen RA (1996). Epigenetic mechanisms of gene regulation. Plainview, N.Y: Cold Spring Harbor Laboratory Press.
  4. Berger SL, Kouzarides T, Shiekhattar R, et al. An operational definition of epigenetics" Genes Dev. 2009;23: 781-3.
  5. Slotkin RK, Martienssen R. "Transposable elements and the epigenetic regulation of the genome". Nature Reviews Genetics 2007;8: 272-85.
  6. Nottke A, Colaiácovo MP, Shi Y. "Developmental roles of the histone lysine demethylases". Development 2009;136: 879-89.
  7. Ilnytskyy Y, Kovalchuk O. "Non-targeted radiation effects-an epigenetic connection". Mutat. Res. 2011; 714: 113-25.
  8. Friedl AA, Mazurek B, Seiler DM. "Radiation-induced alterations in histone modification patterns and their potential impact on short-term radiation effects". Front Oncol 2012.;2: 117.
  9. Wei L, Lu J, Feng L, et al. HIF-1alpha accumulation upregulates MICA and MICB expression on human cardiomyocytes and enhances NK cell cytotoxicity during hypoxia-reoxygenation. Life Sci 2010 87:111-119.
  10. Moon C, Kim SH, Park KS, et al. Use of epigenetic modification to induce FOXP3 expression in naive T cells. Transplant Proc 2009; 41:1848-1854.
  11. Lal G, Bromber JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009; 114: 3727-3735.
  12. Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13:1299-1307.
  13. Johnson J, Pahuja A, Graham M, et al. Effects of histone deacetylase inhibitor SAHA on effector and FOXP3+ regulatory T cells in rhesus macaques. Transplant Proc. 2008;40:459-461.



Share via:

links image    links image    links image    links image