By Liz Highleyman

William Gelson from University of Cambridge and colleagues investigated whether liver transplant recipients demonstrate features of immune senescence, or reduced immune function due to immune cell exhaustion.

Immune senescence is a normal process associated with aging, the study authors noted as background, but it may be accelerated in people who undergo liver transplants due to chronic hepatitis B or C, liver cancer, heavy alcohol use, or other causes of severe liver disease.

The researchers examined lymphocytes (a class of white blood cells including B-cells, T-cells, and natural killer cells) collected from 97 liver transplant recipients and 41 sex- and age-matched control subjects. The transplant patients had well-established grafts (donor livers) for at least 3 years.

Using flow cytometry, the investigators measured expression of a variety of T-cell markers that reflect activity and senescence, including killer cell lectin-like receptor subfamily G member 1, CD27, CD28, CD45RO, CD57, and CD127. Length of lymphocyte telomeres was assessed by flow-fluorescence in situ hybridization.

Telomeres are region of repeated DNA at the end of chromosomes. Lymphocytes have a finite lifespan. As a cell goes through the cycle of division and maturation, its telomeres become progressively shorter, until finally the cell "burns itself out" and can no longer divide to produce new cells, a state known as replicative senescence. Outside the transplant setting, the authors noted, immune cells with shortened telomeres have been linked to cardiovascular disease, blood malignancies, and infections.

Results

	T-cell lymphocytes from liver transplant recipients expressed more phenotypic markers of maturity than cells from control subjects.
	Lymphocyte telomeres were significantly shorter in transplant recipients compared with control subjects (115.12 vs 122.95 mfi, respectively; P = 0.004).
	Telomere length differences between the transplant and control groups varied among types of T-cells (e.g., 9.93 mfi less for CD57 negative CD8 cells; 1.50 mfi less for CD45RO positive CD4 cells).
	Telomere length was positively associated with markers of T-cell maturity and negatively associated with markers of immaturity.
	Naive as well as experienced memory T-cells showed greater aging in transplant recipients.
	Other factors independently associated with markers of lymphocyte maturity were older age and history of cytomegalovirus (CMV) infection.
	Factors independently associated with shorter lymphocyte telomeres were older age, hepatocellular carcinoma (HCC) at the time of transplantation, and skin cancers developing after transplantation.
	Transplant patients with normal liver biochemistry (e.g., normal ALT) had more immature CD8 T-cells.

Based on these findings, the researchers concluded, "lymphocytes from liver transplant recipients are older biologically than lymphocytes from age-matched and sex-matched controls."

"Hepatocellular carcinoma at transplantation, subsequent skin malignancy, and previous cytomegalovirus infection are associated with lymphocyte senescence in liver transplant recipients," they continued.

The study authors estimated that the difference in telomere length between transplant recipients and control subjects represented about 6 additional years of aging for patients with HCC and 4 additional years for those with post-transplant skin cancer. However, they found that the rate of aging did not appear to differ significantly in the transplant and control groups.

As to reasons for this association, "one possibility is that patients with more naive lymphocytes may respond to the complications of transplantation more effectively than those who have an exhausted immune system, or conversely that those patients with healthy grafts have had fewer complications and therefore have not worn out their immune system," they speculated.

These findings suggest that weakened immunity leading to infections and cancers in transplant patients may be attributable to aging and exhaustion of protective lymphocytes, as well as immunosuppressive drugs used to prevent organ rejection.

In an accompany editorial, Janet Lord from the University of Birmingham wrote, "If accelerated T-cell immunosenescence does indeed reflect chronic activation of the adaptive immune system, then shortened telomeres or increased markers of T-cell maturation may represent good indicators of patients likely to develop more postgraft complications. As graft recipients are now surviving much longer, we can anticipate that such prognostic indicators will be useful in the long-term management of these patients."

Department of Medicine, Centre for Applied Medical Statistics, and Department of Surgery, University of Cambridge, Cambridge, UK; Department of Immunology, University College London, London
UK.

7/16/10

References

W Gelson, M Hoare, S Vowler, and others. Features of immune senescence in liver transplant recipients with established grafts. Liver Transplantation 16(5): 577-587 (Abstract). May 2010.

JM Lord. An aged T cell phenotype: A prognostic indicator in liver transplant recipients? (Editorial). Liver Transplantation 16(5): 548-549. May 2010.