Last month, physicians at the University of Maryland Medical Center made headlines after performing what is regarded as the most extensive face transplant in history. In 1997, a firearm accident left Richard Norris without a nose, lips, and part of his tongue. For the next fifteen years, he kept his face hidden. But three days after his trailblazing surgery last March, he looked in the mirror and saw the new face that he could show to the world without fear [1].

The biology behind transplantation plays a huge part in how they’re done and what can happen afterwards. Whether it’s a boundary-breaking face transplant or a more common kidney transplant, the biology behind transplantation influences how donors and recipients are matched up, the care a patient will need after the surgery, and ultimately, the outcome of the transplant, even years down the road.

Getting rejected: “Really, it’s not you, it’s my immune system”

One of the biggest risks associated with organ transplantation is that the recipient’s body may reject the transplant. The recipient’s immune system attacks the donated organ or tissue (also called a “graft”) because it believes the graft to be foreign. If left unchecked, rejection eventually damages the graft to the point that it stops functioning or dies. This can require another transplant and can be life-threatening if the rejected graft is a vital organ, like the heart.

The biology of rejection is based on the way your immune system tells the difference between your own cells and foreign ones. To do this, the immune system looks at the molecules that stick out from the surfaces of cells. The molecules that the immune system can recognize are called “antigens.” To identify antigens as your own or foreign, the immune system uses proteins called “major histocompatibility complex” (MHC) molecules. MHC molecules, also called “human leukocyte antigens” (HLAs) in humans, are found on almost all the cells in our bodies, where they act as a pedestal to present little chunks of protein to our immune system (Figure 1). These small chunks of protein, also called “peptides,” normally come from our own cells, but if pathogens (disease-causing organisms) are present, MHC molecules will present their peptides, too.

Figure 1. Proteins inside the cell are chopped up into peptides that are placed on MHC molecules and presented on the surface of the cell. (Image credit: Wikimedia Commons user Scray)

A class of immune cells called T-cells or T-lymphocytes examines the peptides that are displayed on MHC molecules. If they find a foreign peptide, they carry out a variety of actions such as killing infected cells or directing appropriate immune responses against the threat (Figure 2).

Figure 2. A T-cell encounters a foreign antigen presented on a MHC complex, and can respond in several ways. (Image credit: NIH, modified by Wikimedia Commons user Hazmat2)

There are two types of MHC molecules, class I and class II. Proteins inside a cell are cut into peptides that are displayed on MHC class I molecules. Almost all cells have MHC class I molecules, but only antigen-presenting cells (APCs) have MHC class II molecules. APCs engulf proteins from outside the cell and present their peptides on MHC class II molecules. Having these two MHC classes allows T-cells to scan the body for different kinds of pathogens, and both classes can take part in immune responses that can cause a transplant to be rejected.

“Allorecognition”: when the immune system won’t look past our differences

Transplanted organs or tissues often contain many antigens that differ from the recipients’. “Allorecognition” is the ability of an organism to distinguish between its own antigens and those of a genetically different member of the same species. Transplant rejection is caused by allorecognition of a donor’s antigens by a recipient’s immune system. Interestingly, the antigens responsible for most strong rejection reactions are actually MHC molecules themselves. Their name, “major histocompatibility complex”, refers to the substantial role they play in determining donor/recipient compatibility. MHC molecules trigger allorecognition through two pathways: direct and indirect (Figure 3).

Figure 3. In both the direct and indirect pathways of allorecognition, the high variability between different individual’s MHC molecules is responsible for recognition of donor antigens as foreign by the recipient’s immune system. In the direct pathway (left), donor MHC molecules are examined by recipient T-cells, and the intact donor MHC is recognized as foreign. In the indirect pathway (right), peptide fragments of donor MHC molecules presented on host MHC class II molecules are identified as foreign.

So how do we perform successful transplants?

In order to minimize the severity of transplant rejection, potential donors and recipients are usually tested for compatibility through “tissue typing.” This tests how closely the MHC molecules of prospective donors and recipients match up. While MHC molecules contribute heavily to rejection responses, other antigens can play a role as well.

When transplantation was still new, the ABO blood group antigens that determine blood transfusion compatibility were common culprits in triggering rejection. In addition to being found on blood cells, these antigens are also found on “endothelial cells,” which line the insides of blood vessels. As a result, when a recipient’s circulatory system was connected to the blood vessels of a graft, an ABO mismatch would cause “hyperacute” rejection, a severe rejection reaction beginning within minutes of transplantation. This can be so rapid and destructive that surgeons can often see an affected organ turn black before their eyes [2]. Nowadays, donors and patients are tested to have matching blood types in order to guard against this. In the case of Richard Norris, the face transplant recipient, not only did physicians have to match him with a donor based on MHC variants and ABO types, but also things like bone structure and skin tone, making the matching process much more complicated.

Unfortunately, we do not yet have the technology to completely prevent rejection. Although tissue and blood typing helps us avoid the biggest sources of rejection, some incompatibilities still occur, except in the case of identical twins, where the donor and recipient are genetically identical. Therefore, all transplants eventually experience rejection reactions to some degree. Because of this, recipients usually take immunosuppressive drugs to prevent or delay organ failure. However, suppressing a patient’s immune system also increases their susceptibility to infection.

Despite efforts to prevent rejection, transplanted organs still fail at a surprising rate [3]. In the case of kidney transplants from a living donor, the 5-year survival rate of grafts was about 81%, and only 59% of grafts survived 10 years. For lung transplants, only half were still working after 5 years. By 10 years, nearly three-quarters of transplanted lungs fail. Living with a transplant is therefore far more challenging than it is made to seem in Hollywood, where many stories end happily once a donor is miraculously found and the transplant operation is performed successfully.

But despite its current limitations, there is no doubt that transplantation has improved countless lives. As the science and practice of transplantation continue to improve, it is likely that new breakthroughs will continue to be made, changing lives for the better. About one year ago, Dallas Wiens became the first recipient of a full face transplant in the US, after being disfigured and almost killed by a power-line accident. Earlier this month, he spoke at a press conference at Brigham and Women’s Hospital, where his groundbreaking surgery was performed. After one year, he has not experienced any rejection reactions, a first for transplant recipients, and he has been able to regain his sense of smell. But more importantly, Dallas can now feel his daughter’s kisses on his face, and he recalled the first time it happened, “As soon as she did I broke into tears. Tears of joy obviously at just how amazing that was after so long of not being able to feel her” [4].

Wen Allen Tseng is a PhD student in the Biological and Biomedical Sciences program at Harvard Medical School.

References

[1]  Fard, Maggie Fazeli. “Face transplant for Virginia man is lauded as most extensive in history.” The Washington Post. 27 Mar. 2012. Web. 6 Apr. 2012. <http://www.washingtonpost.com/local/face-transplant-for-virginia-man-is-lauded-as-most-extensive-in-history/2012/03/27/gIQAYvB4eS_story.html>

[2] Smith, Susan, Jean M. Goycoolea, et al. “Immunologic Aspects of Organ Transplantation: Rejection: The Allogeneic Immune Response.” Medscape. 2002. Web 7 Apr. 2012. <http://www.medscape.com/viewarticle/436533_12>

[3] “Unadjusted Graft and Patient Survival at 3 Months, 1 Year, 3 Years, 5 Years, and 10 Years.” 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999-2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD. Web. 27 Mar. 2012. <http://www.ustransplant.org/annual_reports/current/113_surv-new_dh.htm>

[4] “US face transplant patient speaks out one year on.” The Telegraph. 3 Apr. 2012. Web. 6 Apr. 2012. <http://www.telegraph.co.uk/news/worldnews/northamerica/usa/9184623/US-face-transplant-patient-speaks-out-one-year-on.html>

Read more about Dallas Wiens and see a video clip of his press conference at Brigham and Women’s Hospital in Boston (Warning: some images may be graphic): <http://www.telegraph.co.uk/news/worldnews/northamerica/usa/9184623/US-face-transplant-patient-speaks-out-one-year-on.html>

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