Organ transplants and HLA genes

SIGNIFICANCE: Organ transplantation has saved the lives of countless people. Although the success rate for organ transplantation continues to improve, many barriers remain, including infection after transplantation, the development of malignancy following solid organ transplantation, and the phenomenon of transplant rejection. Transplant rejection is caused by an immune response by the organ recipient to molecules on the transplanted organs that are coded for by the human leukocyte antigen (HLA) gene complex. Additionally, inadequate organ supply remains a barrier; for example, in 2023, there were more than 103 patients on the transplant waiting list and only 23,286 donors.

Transplantation

The replacement of damaged organs by transplantation was one of the great success stories of modern medicine in the latter decades of the twentieth century. During the 1980s, the success rates for heart and kidney transplants showed marked improvement and, most notably, the one-year survival for pancreas and liver transplants rose from 20 percent and 30 percent to 70 percent and 75 percent, respectively. According to a 2022 report from Scientific Registry of Transplant Recipients (SRTR) Scientific Registry of Transplant Recipients the one-year survival rate for people who received kidney transplants in 2013–2015 was 97.1 percent; over five years that figure was 88.8 percent. For liver transplants, the one-year survival rate was 91.4 percent and the five-year rate was 81.4 percent. In addition, the survival rate for heart transplants was 90.7 percent over one year and 80.6 percent over five years. These increases in organ survival were largely attributable to improvements in a few aspects of the transplantation protocol that directly reduced tissue rejection: the development of more accurate methods of tissue typing that allowed better tissue matching of donor and recipient, the use of a living donor versus a cadaveric donor, and the discovery of more effective and less toxic antirejection drugs. In fact, these changes helped make transplantation procedures so common by the 1990s that the low number of donor organs became a major limiting factor in the number of lives saved by this procedure.

Rejection and the Immune Response

The rejection of transplanted tissues is associated with genetic differences between the donor and recipient. Relatedly, patients with HLA matching organs have better survival rates. For example, transplants from haploidentical sibling or parental donors have about half the organ survival rates (twelve to fourteen years) when compared with transplanted patients that received an HLA-identical organ donor (twenty-five years). Transplants of tissue within the same individual, called autografts, are never rejected. Thus the grafting of blood vessels transplanted from the leg to an individual’s heart during bypass operations are never in danger of being rejected. On the other hand, organs transplanted between genetically distinct humans tend to undergo clinical rejection within a few days to a few weeks after the procedure. During the rejection process, the transplanted tissue is gradually destroyed and loses its function. When examined under the microscope, tissue undergoing rejection is observed to be infiltrated with a variety of cells, causing its destruction. These infiltrating cells are part of the recipient’s immune system, which recognizes molecules on the transplant as foreign to the body and responds to them as they would to a disease-causing, pathogenic organism.

The human immune response is a complex system of cells and secreted proteins that has evolved to protect the body from invasion by pathogens. Immune mechanisms are directed against molecules or parts of molecules called antigens. The ultimate function of the immune response is to recognize pathogen-associated antigens as foreign to the body and to eliminate and destroy the organism, thus resolving the disease. On the other hand, the immune response is prevented, under most circumstances, from attacking the antigens expressed on the tissues of the body in which they originate. The ability to distinguish between self and foreign antigens is critical to protecting the body from pathogens and to the maintenance of good health.

A negative consequence of the ability of the immune system to discriminate between self and foreign antigens is the recognition and destruction of transplants. The antigens associated with transplants are recognized as foreign in the same fashion as pathogen-associated antigens, and many of the same immune mechanisms used to kill pathogens are responsible for the destruction of the transplant. The molecules on the transplanted tissues recognized by the immune system are called histocompatibility antigens. The term “histocompatibility” refers to the fact that transplanted organs are often not compatible with the body of a genetically distinct recipient. All vertebrate animals have a cluster of genes that code for the most important histocompatibility antigens, called the major histocompatibility complex (MHC).

MHC Polymorphism, HLA Genes, and Tissue Typing

Each MHC locus is highly polymorphic, meaning that many different alleles exist within a population (members of a species sharing a habitat). The explanation for the of histocompatibility antigens is related to the actual function of these molecules within the body. Clearly, histocompatibility molecules did not evolve to induce the rejection of transplants, despite the fact that this characteristic led to their discovery and name.

Histocompatibility molecules function by regulating immunity against foreign antigens. Each allele codes for a protein that allows the immune response to recognize a different set of antigens. Many pathogens, including the viruses associated with influenza and acquired immunodeficiency syndrome (AIDS), undergo genetic mutations that lead to changes in their antigens, making it more difficult for the body to make an immune response to the virus. The existence of multiple MHC alleles in a population, therefore, ensures that some individuals will have MHC alleles allowing them to mount an immune response against a particular pathogen. If an entire population lacked these alleles, their inability to respond to certain pathogens could threaten the very existence of the species. The disadvantage of MHC polymorphism, however, is the immune response to the donor’s histocompatibility antigens that causes organ rejection.

The human leukocyte antigen (HLA) gene complex is located on chromosome 6 in humans. Six important histocompatibility antigens are coded for by the HLA complex: the A, B, C, DR, DP, and DQ alleles. Differences in HLA antigens between the donor and recipient are determined by tissue typing. For many years, tissue typing was performed using antibodies specific to different HLA alleles. The MHC class I-related chain (MICA) is the product of an HLA-related, polymorphic gene. Genetic interest has grown regarding MICA antigens, which have been reported to be distinct from those of the HLA system. Antibodies against these alleles may also affect the outcome of organ transplants, but this hypothesis still remains to be conclusively proven. Antibodies are proteins secreted by the cells of the immune system that are used in the laboratory to identify specific antigens. As scientists began to clone the genes for the most common HLA alleles in the 1980’s and 1990’s, however, it appeared that direct genetic analysis would eventually replace or at least supplement these procedures.

Current genetic transplant techniques involve balancing the matching of HLA versus another similar technique involving avoiding mismatches. For example, when matching an organ donor to a recipient, the avoidance of mismatches is used in preference to matching of HLA antigens. Fewer differences in these antigens between donor organ and recipient mean a better prognosis for transplant survival. A report from the United Network for Organ Sharing (UNOS) database evaluated more than 7,600 patients with HLA-matched and 81,000 patients with HLA-mismatched kidney transplants. The HLA-matched transplants had longer allograft half-lives (12.5 versus 8.6 years) and increased ten-year survival (52 versus 37 percent). Therefore, closely related individuals who share many of their histocompatibility alleles are usually preferred as donors. However, timing of transplantation is also important and can affect survival, and so mismatched donors are sometimes used. If a family member is unavailable for organ donation, worldwide computer databases such as UNOS, SRTR, and the Organ Procurement and Transplantation Network (OPTN) are used to match potential donors with recipients, who are placed on a waiting list based on the severity of their disease.

Additional genetics research has been ongoing to ameliorate the current organ deficit. For example, two areas of interest involve the manipulation and engineering of transgenic animals for organ transplantation, which have been investigated through xenografts along with drug-induced reprogramming of mature animal cells to cells that are more embryonic (immature) in nature. These embryonic cells may then be genetically engineered to eventually produce modified cells immunologically compatible with humans. Researchers could then create or grow organs that could be used for transplantation.

Immunosuppressive Antirejection Drugs

One important medical breakthrough responsible for the increased success of organ transplantation involves the discovery and successful use of antirejection drugs, most of which act by suppressing the immune response to the transplanted tissue. Immunosuppressive drugs are often given in high doses for the first few weeks after transplantation or during a rejection crisis, but the dosage of these drugs is usually reduced thereafter to avoid their toxic effects.

Cyclosporine is one effective drug and has largely been responsible for the increased efficacy of liver, pancreas, lung, and heart transplantation procedures. However, cyclosporine has limitations in that it can cause kidney damage when given in high doses. More recently, many new immunosuppressive drugs have been discovered and developed for clinical use in transplantation. Two more commonly used drugs, Tacrolimus (FK 506) and mycophenolate mofetil (MMF), have replaced the use of cyclosporine at many hospital institutions but still have many unwanted side effects. Azathioprine, which is now also used less frequently due to the introduction of cyclosporine, is associated with bone marrow toxicity. However, azathioprine is still used as part of a combined cyclosporine-azathioprine regimen or combined with prednisolone. New combinations such as with the medications tacrolimus and mycophenolate are often used as an attempt to reduce the toxicity caused by both drugs. Other advances in immune therapies include the medications leflunomide, sirolimus (SRL), and everolimus. Currently, monoclonal antibodies daclizumab and basiliximab are often used at initiation of transplantation, which target specific on T helper cells and significantly reduce the chance of immediate or acute transplant rejection.

Nonetheless, despite advances in therapies, the search for more effective and less toxic antirejection drugs continues. Most patients will have to remain on some type of antirejection therapy for the remainder of their lives. Additionally, individuals receiving immunosuppressive therapy have other concerns outside of the toxicity of the drugs themselves. Transplant recipients will have an impaired ability to mount an immune response to pathogens, and their susceptibility to infections, developing cancers, and a variety of other diseases (for example, cardiovascular) will be increased. Thus transplant recipients must take special precautions to avoid exposure to potential pathogens, especially when receiving high doses of the drugs. Alternatives to medications, such as genetic manipulation of the dendritic cell, have been explored to suppress the immune response of organ rejection. Likewise, other genetic target molecules include cardiacmyosin, phospholipids, ribosomal antigens, intercellular adhesion molecule-1, and vimentin but these molecules are still far from being targeted for daily use in clinical organ transplantation.

Key Terms

• allelesthe two alternate forms of a gene at the same locus on a pair of homologous chromosomes
• antigensmolecules recognized as foreign to the body by the immune system, including molecules associated with disease-causing organisms (pathogens)
• dendritic cella cell that presents and processes antigen material on its surface to other cells of the immune system
• haploidenticalhaving the same alleles at a set of closely linked genes on one chromosome
• histocompatibility antigensmolecules expressed on transplanted tissues that are recognized as foreign by the immune system, causing rejection of the transplant; the most important histocompatibility antigens in vertebrates are coded for by a cluster of genes called the major histocompatibility complex (MHC)
• locus (pl.loci) the location of a gene on a chromosome
• polymorphismthe presence of many different alleles for a particular locus in individuals of the same species
• transgenicliving things that possess added or manipulated DNA from another species (for example, a transgenic mouse with a cystic fibrosis gene, as such animals can assist scientists in understanding and perhaps treating a particular disease); other genes can be changed so that an animal’s organs are coated with human antigens or chemical markers, which could potentially allow for xenotransplantation without rejection
• xenotransplantationa tissue transplant between two unique or different species; animal-to-human organ transplants have not yet been carried out successfully

Bibliography

Boros, B., and J. Bromberg. “De Novo Autoimmunity After Organ Transplantation: Targets and Possible Pathways.” Human Immunology 69 (2008): 383–88. Print.

Browning, Michael, and Andrew McMichael, eds. HLA and MHC: Genes, Molecules, and Function. New York: Academic Press, 1999. Print.

"Data and Trends." UNOS, 2024, unos.org/data/. Accessed 5 Sept. 2024.

Ehser, S., J. Chuang, C. Kleist, et al. “Suppressive Dendritic Cells as a Tool for Controlling Allograft Rejection in Organ Transplantation: Promises and Difficulties.” Human Immunology 69 (2008): 165–73. Print.

Foster, B. J., et al. "Impact of HLA Mismatch at First Kidney Transplant on Lifetime with Graft Function in Young Recipients." American Journal of Transplantation 14.4 (2014): 876–85. Print.

Halloran, P. “Immunosuppressant Drugs for Kidney Transplantation.” New England Journal of Medicine 351 (2004): 2715–29. Print.

Israni, A. K. "OPTN/SRTR 2020 Annual Data Report: Introduction." Wiley Online Library, 10 Mar. 2022, doi.org/10.1111/ajt.16974. Accessed 5 Sept. 2024.

Janeway, Charles A., Paul Travers, et al. Immunobiology: The Immune System in Health and Disease. 5th rev. ed. Philadelphia: Taylor & Francis, 2001. Print.

Lechler, Robert I., et al. “The Molecular Basis of Alloreactivity.” Immunology Today 11 (March, 1990). Print.

Liu, Siqi, et al. "Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation." Frontiers in Immunology, vol. 13, 13 June 2022, doi.org/10.3389/fimmu.2022.902093. Accessed 6 Sept. 2024.

Mak, T., and M. Saunders. The Immune Response: Basic and Clinical Principles. San Diego: Elsevier Academic Press, 2006. Print.

Rudolph, Colin D., and Abraham M. Rudolph, eds. Rudolph’s Pediatrics. 21st ed. New York: McGraw-Hill Medical, 2003. Print.

Sasaki, Mutsuo, et al., eds. New Directions for Cellular and Organ Transplantation. New York: Elsevier Science, 2000.

Scientific American 269 (September, 1993).

Snyder, Thomas M., et al. "Universal Noninvasive Detection of Solid Organ Transplant Rejection." Proceedings of the National Academy of Sciences 108.15 (2011): 6229–34. Print.

Stastny, P. "Introduction: What We Know About Antibodies Produced by Transplant Recipients Against Donor Antigens Not Encoded by HLA Genes." Human Immunology 74.11 (2013): 1421–24. Print.