operational tolerance post liver transplants

One of the interesting groups of patients that I have come across in the last 1 1/2 years are the patients who receive liver transplant and over time develop "operational tolerance" of their graft, meaning that they are able to wean off immunosuppressive agents over time.  Operational tolerance is defined clinically as the "lack of acute or chronic rejectionn and graft survival with normal function and histology in an immunosuppressant-free, immunocompetent host." 

Anectodally, we see this most commonly with teenagers who have become non-compliant with their immunosuppressive regiments.  And of the solid organ transplants, liver transplants are most likely to become tolerated by the host's immune system.  In general, children are more likely than adults to develop operational tolerance.  In the literature, 3-20% of patients may be able to wean successfully off of immunosuppressants.

This brings the questions--why do some patients reject the graft and others become tolerant?  How can we predict which patients will develop operational tolerance?

A study in Brussels observed that pediatric patients who developed operational tolerance had higher levels of IL-10 and decreased TNF-alpha and IFN-gamma levels soon after transplant (2 hours, 1 day and 4 days).  This could potentially identify a cytokine profile that could possibly predict patients who would become tolerant.  Other studies have suggested that there is an elevated number of T regs in patients who develop tolerance (this would correlate with higher amounts of IL-10, which is produced by T regs as we are aware). 

T regs express CD4/CD25 and the transcription factor FoxP3.  There are studies that suggest that FoxP3 can also be induced by peripheral T cells that are CD4+/CD25-.

This study (Pons et al) set out to monitor T cells in patients s/p liver transplant as immune suppression was weaned.  They selected 12 adults who had:  received a liver 2+ years prior to the start of the study, were 1+ years past a rejection episode, and had no evidence of autoimmune liver disease or viral infections.  They were monitored prospectively as their immunosuppression (cyclosporine and prednisone) was gradually weaned.  Flow cytometry was used to identify lymphocytes, and FoxP3 mRNA levels were detected by PCR.  The researchers looked at populations of T lymphocytes (CD3+CD4+, CD3+CD8+, CD3+Vdelta+), B lymphocytes (CD19+), and NK cells (CD3_CD16+CD56+) prior to withdrawal of immunosuppression and then at various periods during withdrawal of immunosuppression.  They compared these findings to another group s/p liver transplant who were immunosuppressant-dependant (ID) and another group who was healthy (H).  There was a similar profile of T regs (CD4+CD25+) in all immunosuppressed patients. 

Over the course of withdrawal of immunosuppression, 5/12 patients developed tolerance.  The percentage of CD3+, CD4+, CD8+, CD19+, CD3-CD16+CD56+, CD8+CD28- populations did not change during withdrawal (in the patients who ended up becoming tolerant and those who ended up rejecting).  However, in the group that became tolerant of their graft, T regs increased significantly during the withdrawal (beginning at the time of assessment pre-withdrawal and ending at the tolerance point).  The group who rejected did not exhibit this increase in T regs.  They noticed a similar pattern with FoxP3 mRNA expression.

This study was unable to predict (prior to immunosuppression withdrawal) which patients will become tolerant.  However, they were able to determine that T regs and FoxP3 expression dramatically changes in patients who become tolerant.

Continued research in this area will greatly influence care of patients post transplant.  In the past, it has been gold standard to continue immunosuppression, tolerating the side effect profiles of the medications.  Identifying patients who will successful become tolerant will help to titrate medications, improve quality of life, and decrease harmful side effects of the immunosuppression medications.


Pons JA et al, FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression withdrawal.  Transplantation. 2008 Nov 27;86(10):1370-8.

Orlando G et al, Operational Tolerance after Liver Transplantation.  J Hepatology 2009;50:1247-57.