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The Stampede to Stockholm:
Nobel Prize-Winning Achievements in Transplantation Biology


PALI SHAH, MD
JFTC Chair
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA

pdedhiy2@jhmi.edu


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Every October, the world celebrates scientific achievements with the Nobel Prize in Medicine and Physiology. In the 50 years since the first lung and heart transplants, the evolution of cardiothoracic transplant from an experimental model to a life-saving therapy has been dependent on discoveries allowing us to harness the immune response.1 This missive reflects on the milestones in transplant immunology which have made this transformation possible and the ongoing challenges still awaiting us.

The foundation of transplant immunology dates to the 1940s where George Snell and Jean Dauset "discovered the genetic factors that determine the possibilities of transplanting tissue from one individual to another", i.e. the major histocompatibility complex.2 Building on this, the zoologist Peter Medawar observed rejection of allogeneic but not autologous skin grafts in burn patients and developed a pre-clinical model to study tolerance and rejection.3 He demonstrated that the time to allograft rejection was dependent on prior exposure and graft rejection was a systemic immune response mediated by lymphocytes. He further demonstrated that allogeneic cells introduced into a neonatal mouse would induce tolerance of an allogeneic skin graft. These fundamental insights about the potency of the immune response led to the Nobel Prize award in 1960 for Medawar and in 1980 for Snell and Dauset.

By avoiding the allogeneic immune response altogether, Joseph Murray was able to perform the first successful kidney transplant in 1954 between identical twins, eventually receiving a Nobel prize in 1990 for his work.4 While a series of twin transplants were performed worldwide in the 1950s, attempts to suppress immunity with irradiation in allogeneic settings proved lethal or ineffective, until the development of azathioprine by future Nobel Prize winner Gertrude Elion. An anti-proliferative agent which inhibited purine synthesis, the discovery of azathioprine suppressing antibody formation led to its use in the first allogeneic heart and lung transplants by Shumway and Hardy.5

Unfortunately, high rates of fatal infection and rejection limited the clinical potential of transplantation. In the 1970s, Doherty and Zinkernagel conducted Nobel prize winning work identifying how T lymphocytes recognize cognate antigens in the context of MHC.6 These findings coincided with the discovery of cyclosporine, an agent which blocked the antigen driven activation of the T lymphocyte and prevented the development of effector function.7 As we know, this agent dramatically reduced acute allograft rejection after transplantation and allowed for the first durable heart-lung and lung transplant by Drs' Reitz and Cooper in the 1980s.4 Interestingly, the discovery of the key cytokine inhibited by cyclosporin, IL-2 occurred after the use of cyclosporine in the transplant recipients.

IL-2 inhibition, anti-proliferative agents and prednisone remain the mainstay of current transplant immunosuppression today. While mortality from acute rejection has improved, chronic allograft rejection and cumulative toxicities limit the full potential of transplant. Over the past two decades, new breakthroughs in transplant immunology have identified new co-stimulatory signals, regulatory pathways, innate and even autoimmune responses. As we better understand how these mechanisms impact alloimmune responses, perhaps we will be able to come closer to the elusive state of tolerance Medawar originally described.


Disclosure Statement: the author has no financial disclosures.


References:

  1. Morris PJ. Transplantation—a medical miracle of the 20th century. N Engl J Med. Dec 23 2004;351(26):2678-2680.
  2. Raju TN. The Nobel chronicles. 1980: George Davis Snell (1903-96); Jean Baptiste Dausset (b 1916); Baruj Benacerraf (b 1920). Lancet. Nov 13 1999;354(9191):1738.
  3. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. Oct 3 1953;172(4379):603-606.
  4. Watson CJ, Dark JH. Organ transplantation: historical perspective and current practice. British journal of anaesthesia. Jan 2012;108 Suppl 1:i29-42.
  5. Hardy JD, Webb WR, Dalton ML, Jr., Walker GR, Jr. Lung Homotransplantation in Man. JAMA: the journal of the American Medical Association. Dec 21 1963;186:1065-1074.
  6. "The Nobel Prize in Physiology or Medicine 1996" http://www.nobelprize.org/nobel_prizes/medicine/laureates/1996. 1996.
  7. Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents and actions. Jul 1976;6(4):468-475.