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ARRA Investments in Transplantation Research

Public Health Burden
Organ transplantation is performed on patients with end-stage organ failure when all other therapies have failed. Currently, more than 25 different types of organs and tissues are routinely transplanted, offering prolonged survival and improved quality of life for those suffering from a range of diseases. Although the one-year survival rate for organ transplantation has dramatically improved over the last 25 years, significant barriers remain. These include transplant rejection, complications of long-term immune suppression, and shortage of organs and tissues available for transplant candidates.

Transplant Rejection
Rejection of transplanted organs or tissue is the main barrier for transplantation. Rejection occurs when the recipient’s immune system attacks and destroys the donor organ or tissue. It can be categorized as hyperacute (occurring within 24 hours), acute (occurring within weeks), or chronic (occurring within months). Studies on all three types of rejection are being supported by ARRA funding. Some of these studies are:
  • Devising strategies for preventing hyperacute rejection. Through xenotransplantation studies (using animal organs and tissues for human transplantation), scientists are looking at transplantation of pig-derived lungs in baboon recipients. 1
  • Identifying novel urinary biomarkers for monitoring acute kidney transplant rejection. If successful, this non-invasive assay could replace invasive kidney biopsies.2
  • Determining the mechanisms responsible for organ damage resulting in chronic kidney3 and heart4 rejection.
  • Analyzing genetic variations that may account for differing outcomes in transplant patients receiving the same immunosuppressive therapy, in order to minimize rejection. 5
Graft-Versus-Host Disease
Graft-versus-host disease (GVHD) is the major cause of bone marrow transplant-related morbidity and mortality. It occurs when immune cells present in the donor’s marrow attack the recipient’s cells. GVHD can also occur in solid organ transplantations. ARRA-funded projects studying GVHD include:
  • Investigating a novel approach using specific types of immune cells, called dendritic cells, as immunotherapy to suppress GVHD.6
  • Studying the ability of the compound, triciribine, to control GVHD in a mouse model of bone marrow transplantation. This work will be used to gain pre-clinical data necessary for designing a GVHD prevention clinical trial in humans.7
  • Collaborating with a biotechnology company to evaluate the use of their drug, TLX1001, for the prevention and treatment of GVHD in mice. If successful in animal models, human clinical trials will be pursued.8
Post-Transplant Treatments
To maintain graft survival, transplant recipients are treated with immunosuppressive drugs. Many of these therapies are nonspecific, leading to overall suppression of the immune system and increased risk of infection. Multiple ARRA-funded studies are working to devise alternative strategies for maintaining long-term graft survival, including projects to:
  • Determine the signals that immune cells require to reject transplants. This information can be used to design methods of inducing long-lasting transplant acceptance without the use of current toxic immunosuppressive medications. 9
  • Study the process by which host immune cells that confer tolerance, called regulatory T cells, are activated. From these studies, researchers hope to develop new methods for inducing tolerance by modulating a specific set of immune cells, rather than relying on non-specific immunosuppressive drugs. 10
Organ Shortage
Although the willingness to donate organs is increasing, the demand for organs is still far greater than the supply. There are currently over 100,000 people awaiting an organ transplant, and it is estimated that 19 of them will die each day due to this shortage. As a result, researchers are examining the use of xenotransplantation. ARRA-funded studies are:
  • Examining xenotransplantation in non-human primates, using pigs as the organ donors. Although researchers have discovered way to prevent immediate rejection of pig-derived organs, these organs are still rejected within three to six months. This research aims to determine the genetic mechanisms underlying chronic rejection and to test methods for preventing this response. 11
  • Devising strategies for preventing hyperacute rejection. In xenotransplantation studies, scientists are specifically looking at transplantation of pig-derived lungs in baboon recipients. 12

  1. 3U01AI066335-05S1 -- Mechanisms of GALTKO Lung Xenograft Injury -- Pierson, Richard
  2. 1R21AI075256-01A2 -- Novel Urinary Proteomic Biomarkers for Acute Renal Transplant Rejection -- Sarwal, Minnie
  3. 3U01AI070107-04S1 -- Genomics of Chronic Renal Allograft Rejection -- Murphy, Barbara
  4. 3U01AI063623-05S1 -- Novel Therapies of Chronic Allograft Dysfunction -- Sayegh, Mohamed
  5. 3U19AI070119-04W1 -- Genomics of Kidney Transplantation -- Matas, Arthur
  6. 1R01AI082318-01 -- Tolerogenic DC as Therapeutic Agents in GVHD -- Butcher, Eugene
  7. 1R21AI082498-01 -- Peripheral T Cell Tolerance by Targeting AKT -- Anasetti, Claudio
  8. 3R42AI069602-03W1 -- Inhibition of IkK to treat lethal Graft-vs.-Host Disease -- Flood, Patrick
  9. 2P01AI044644-10 -- Interactions of Protective Immunity and Transplantation Tolerance -- Larsen, Christian
  10. 3R01AI063408-05S2 -- Modulation of T Lymphocyte Regulation -- Leguern, Christian
  11. 2R01AI052079-05A2 -- Non-Human Primate Models for Human Xenotransplantation -- Kearns-Jonker, Mary
  12. 3U01AI066335-05S1 -- Mechanisms of GALTKO Lung Xenograft Injury -- Pierson, Richard

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Page Last Updated on June 30, 2018 NIH...Turning Discovery Into Health®