Transplant Biology Program

The Transplant Biology Program is shaping the science and clinical practice of transplantation.

Current Research in the Transplant Biology Program

One subject of research conducted in the Transplantation Biology Program concerns the development of novel approaches to replacing the function of organs and tissues that have been destroyed or that suffer inherited or acquired defects in function. For example, members of the program pioneered the genetic engineering of animals to facilitate xenotransplantation of animal organs and tissues into human patients for treatment of disease. Members of the program also pioneered efforts, including genetic engineering, to use of animals as biological vessels in which human stem cells that could be coaxed and nurtured to generate human organs and tissues for transplantation.

Another subject of research in the Transplantation Biology Program concerns the discovery of genetic and acquired factors that govern the success and failure of organ transplants. As one example, members of the program discovered the set of processes through which normal tissues acquire resistance to injury caused by immunity, inflammation and physical injury. These processes, called accommodation, are observed in organ transplants and cancers and work is now directed at devising therapeutics that would elicit accommodation in transplantation and autoimmunity and suppress it in cancer.

Recently, members of the program have discovered several complexes of genes and proteins that govern the balance between immunity and tolerance. These discoveries are presently being tested for ability to distinguish transplant recipients especially likely to suffer rejection from recipients that may experience stable graft function and absence of rejection for long periods of time. The discoveries have also been used to design therapeutics that might decrease the propensity for damaging immune responses in transplantation and other therapeutics that might amplify the intensity of immunity in cancer and infectious disease.

Recognizing that infection by mutable virus remains a serious menace to humanity, members of the program explore the mechanism of immunoglobulin somatic hypermutation to fashion a dynamic vaccine against HIV (the “mutable” vaccine). The mutable vaccine produces variants of antigens in vaccinated individuals which in turn evoke immunity. With time hosts develop broadly reactive immunity that will anticipate natural variants of the virus upon infection blocking viral diversification and allowing sterilizing immunity to develop.

Research in the program spans multiple disciplines—immunology, physiology, infectious disease, genetics, stem cell biology and experimental surgery—and addresses a broad range of questions, for example:

  • What controls the pathogenicity of immunity in normal tissues?
  • How do foreign cells and microorganisms activate the immune system, and how does the activated immune system control the growth of microorganisms and injure transplants?
  • How might stem cells, xenografts and organogenesis augment rather than replace the function of failing organs?

The Problem

Some 36,000 organ transplants were performed in the United States in 2018, while well over 100,000 critically ill patients wait for suitable organs to become available. Although medical progress vastly extends longevity, aging of the population will inevitably make the shortage of human organs for transplantation more severe. This shortage was and is likely to remain the preeminent challenge in transplantation and it sparks widespread efforts to find alternatives to reliance on human organs for treatment of organ failure.

Those patients fortunate enough to receive a human organ transplant, nevertheless experience a high risk of failure of the transplanted organ and other complications. All or nearly all transplants elicit immune responses in recipients that can injure or destroy the transplant (that is rejection) or that make the transplant paradoxically inured to injury. Since it has been impossible to know which transplants would suffer rejection and which would be spared, it has been necessary to treat all transplant recipients with high doses of expensive and potentially toxic immunosuppressive drugs.

The discovery by members of this program of genes that govern the pathogenicity of transplant immunity make it possible to imagine we may soon be able to identify recipients at low risk of rejection, potentially allowing the doses of immunosuppression to be safely lowered in these individuals. The discovery may also identify recipients at risk of severe rejection and thus potentially in need of more frequent monitoring and more aggressive treatment. The discovery also encourages the testing of therapeutics devised by members of the program to potentially may shift the aggressiveness of immune responses toward those observed in recipients with stable grafts.