Evidence That Apoptosis of Activated T Cells Occurs in Spontaneous Tolerance of Liver Allografts and Is Blocked by Manipulations Which Break Tolerance1

Abstract

Taken together, these findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.

Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

“…Conversely, the activation of T cells in rejecting kidney transplants occurred later and appeared not to lead to their apoptotic death. 59 The pattern of infiltration of tolerant compared with rejecting grafts supported these findings, with an early rapid increase in T cells and IL-2 receptor-expressing cells in tolerant liver grafts that peaked on day 3. 65 This was accompanied by extensive apoptosis of activated T cells in the infiltrate and recipient lymphoid tissues, 59 followed by a decline in activated cells in the tolerant liver grafts by day 5 and thereafter.…”

“…59 The pattern of infiltration of tolerant compared with rejecting grafts supported these findings, with an early rapid increase in T cells and IL-2 receptor-expressing cells in tolerant liver grafts that peaked on day 3. 65 This was accompanied by extensive apoptosis of activated T cells in the infiltrate and recipient lymphoid tissues, 59 followed by a decline in activated cells in the tolerant liver grafts by day 5 and thereafter. 65 Conversely, there was an inexorable increase in the numbers of T cells and activated cells in the rejecting grafts that was slower than in the tolerant livers, but eventually culminated in much greater levels of activation and irreversible rejection.…”

“…5 Either of these treatments that broke tolerance resulted in significantly reduced apoptosis early after liver transplantation in both the graft and recipient lymphoid tissues. 59 Apoptosis of infiltrating T cells is not restricted to liver allograft tolerance and has been shown in other transplant models. In murine heart allografts, there was prominent apoptosis of cells in the perivascular infiltrates of recipients that had been treated to prevent acute rejection with anti-CD4 antibody.…”

“…This local increase in Th1 cytokines in recipient lymphoid tissues was also absent in renal or skin transplants that were rejected. 58,59 We subsequently showed that mRNA for interferon-␥ and IL-2 is derived from recipient, not donor cells, mainly of the CD4 phenotype. 46,60 …”

“…64,65 Apoptosis was not confined to grafts of liver-tolerant recipients, but also occurred in recipient lymphoid tissues. 59,66 Detailed analysis of the liver-infiltrating cells by flow cytometry analysis showed that many of the infiltrating leukocytes were apoptotic, whereas few apoptotic cells could be detected in the infiltrate of rejecting kidney allografts in the same strain combination. 59 Apoptotic cells were concentrated in the activated T-cell population of the recipient, suggesting that activation of infiltrating T cells preceded their death in liver tolerance, a mechanism that resembles activation-induced cell death (AICD).…”