Liver Transplant Speeds Immune Cell Aging

Liver Transplant Speeds Immune Cell Aging
MedPage Today
Published: April 29, 2010

Accelerated lymphocyte senescence may contribute to the increased rates of cardiovascular disease, cancer, and infections seen in liver transplant recipients, researchers said.

Compared with immune cells taken from healthy volunteers, those in liver transplant recipients had significantly shorter telomeres, reported Graeme J.M. Alexander, MA, MD, of the University of Cambridge in England, and colleagues in the May issue of Liver Transplantation.

Action Points

* Explain to interested patients that liver transplant recipients are at increased risk for infections, cardiovascular events, and certain cancers.


* Explain that these risks have traditionally been attributed to the immunosuppressant drugs that transplant recipients must take to prevent organ rejection, but this study suggests that increased aging of their immune cells may also play a role.



Shortened T cell telomeres, in turn, were significantly correlated with hepatocellular carcinoma at transplantation and postoperative diagnosis of skin tumors, the researchers also found.

The increased rates of cardiovascular disease, cancer, and infections have traditionally been attributed to the immunosuppressant regimens that transplant recipients must take, according to Alexander.

"An alternative and not exclusive hypothesis is that liver transplant recipients develop premature immune senescence which is also associated with these same pathologies, perhaps consequent to chronic alloantigenic stimulation," he said in a press release.

Aging of the immune cells has been observed in people as they get older, and is believed to contribute to their increased susceptibility to infections and other diseases. Telomere shortening may be a factor, because it limits cells' ability to proliferate, a critical function for immune cells when called upon to fight infection.

To test the alternate hypothesis, Alexander and colleagues drew blood samples from 97 healthy liver transplant recipients and 41 age- and sex-matched healthy controls. Their transplants had been performed at least three years previously. Reasons varied: alcoholic cirrhosis, hepatitis B and C infections, and different types of primary liver failure.

Among all lymphocytes in the samples from transplant recipients, the mean telomere length was 115.12 mfi, compared with 122.95 mfi in the healthy controls (P=0.004).

Alexander and colleagues indicated that the difference corresponded to about four years of effective additional aging in the patients.

The differences in telomere length varied among T-cell subsets.

CD8-positive 57-negative cells, for example, showed a 9.93-mfi deficit in the transplant recipients relative to controls (P=0.003), representing a 5.16-year increase in effective cell age.

On the other hand, telomeres in CD4-positive 45RO-positive cells were only 1.50 mfi shorter in patients versus controls (P=0.13), or just 0.78 years "older."

The researchers also examined cell-surface markers of immaturity and senescence. For six out of 10 lymphocyte subtypes, those from transplant recipients appeared significantly older than cells from controls.

"Taken together, these observations suggest that liver transplant recipients have more lymphocytes with a cell-surface phenotype of increased aging than controls and that immature lymphocytes from liver transplant recipients are biologically older than those from controls," Alexander and colleagues wrote.

They also noted that the rates of cellular aging over time appeared to be the same in patients and controls, indicating that the transplant recipients had a lower "baseline age."

The clinical significance of these findings was less clear from the study's limited data.

Skin tumors found after transplant were associated with shorter telomere length (β coefficient -7.35, SD 0.43). But post-transplant cardio- and cerebrovascular events were too rare in the sample to determine whether they were associated with telomere length or other cell senescence markers, the researchers said.

In accompanying editorial, Janet M. Lord, BSc, PhD, of the University of Birmingham in England, also bemoaned the skimpy data on patient-centered outcomes.

"Longitudinal studies will be required to determine if the T cells in graft recipients continue to age at an accelerated rate ... and if this is associated with an increased incidence of malignancy and infections," she wrote.

If such outcomes are confirmed, Lord suggested, lymphocyte telomere length could become a useful prognostic indicator for post-transplant complications and morbidities.