Transplantation tolerance: Of mice and men

Little is known about the effect of an individual’s immune history on their response to a donated tissue transplant. An important study by researchers at Emory University in Atlanta, Georgia, reveals that individuals harboring virally-induced memory T cells that are cross reactive with donor antigens are resistant to conventional strategies designed to induce transplant tolerance.

Enormous progress has been achieved in the field of transplantation during the past 3 decades, due in large part to the availability of effective immunosuppressive drugs. Such drugs are designed to sufficiently suppress the recipient immune response to the donor tissue without compromising the ability to fight infection. In the 50 years since the first description of tolerance to transplanted tissue in mice, researchers have strived to induce tolerance in human transplant recipients. So why the discrepancy?

In the June 16 issue of the Journal of Clinical Investigation, Christian Larsen and his colleagues demonstrated that a critical distinction between pathogen-free mice used in transplant research and nonhuman primates or human patients is their acquired immune history. The authors demonstrate that a specific threshold of memory cells is necessary to promote rejection and CD8+ central memory cells are principally responsible for mediating rejection. The data reveal that the transplantation field may have underappreciated the barrier that memory to previous viral infections in the recipient serves in the induction of tolerance.

“This study makes a strong argument for the importance of previous antigen exposure in determining the outcome of protocols designed to induce tolerance” says Harvard surgeon David Sachs, Director of the Transplantation Biology Research Center at Massachusetts General Hospital. “The data clearly support the practice of testing for potential cellular as well as humoral sensitization against the donor prior to carrying out such protocols clinically, even in cases for which there has been no known exposure to the donor antigens”. Dr. Sachs continues to explore the more general question of why it is more difficult to induce tolerance in large versus small animals in his accompanying commentary. We should expect that differences to prior antigen exposure will be only one of the potential reasons for marked differences that are encountered between mice and primates in attempts to induce tolerance to transplanted tissue. Elucidating the mechanisms of these relationships can only increase the chances of achieving complete tolerance to tissue transplantation in humans.

AUTHOR CONTACT:
Christian P. Larsen
Emory University, School of Medicine, Atlanta, Georgia, USA.
Phone: 404-727-8466
Fax: 404-727-3660
Email: clarsen@emory.org

View the PDF of this article at: https://www.the-jci.org/press/17477.pdf

ACCOMPANYING COMMENTARY:
Tolerance: Of mice and men
AUTHOR CONTACT:
David H. Sachs
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: 617-726-4065
Fax: 617-726-4067
Email: sachs@helix.mgh.harvard.edu

View the PDF of this commentary at: https://www.the-jci.org/press/18926.pdf