Gelson from University of Cambridge and colleagues investigated
whether liver transplant recipients demonstrate features of
immune senescence, or reduced immune function due to 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.
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.
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.
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.
lymphocytes from liver transplant recipients expressed more
phenotypic markers of maturity than cells from control subjects.
telomeres were significantly shorter in transplant recipients
compared with control subjects (115.12 vs 122.95 mfi, respectively;
P = 0.004).
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
length was positively associated with markers of T-cell
maturity and negatively associated with markers of immaturity.
as well as experienced memory T-cells showed greater aging
in transplant recipients.
factors independently associated with markers of lymphocyte
maturity were older age and history of cytomegalovirus (CMV)
independently associated with shorter lymphocyte telomeres
were older age, hepatocellular carcinoma (HCC) at the time
of transplantation, and skin cancers developing after transplantation.
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."
carcinoma at transplantation, subsequent skin malignancy, and
previous cytomegalovirus infection are associated with lymphocyte
senescence in liver transplant recipients," they continued.
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.
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.
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.
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."
of Medicine, Centre for Applied Medical Statistics, and Department
of Surgery, University of Cambridge, Cambridge, UK; Department
of Immunology, University College London, London
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).
Lord. An aged T cell phenotype: A prognostic indicator in liver
transplant recipients? (Editorial). Liver Transplantation
16(5): 548-549. May 2010.