Chronic GVHD Leads to Shortening of Telomeres in Subsets of Lymphoid Cells but Not in Granulocytes in Long-Term Survivors after Allogeneic HSCT.
Authors: Baerlocher Gabriela M. , Rovo Alicia , Matthey Sybille , Mueller Astrid , Daikeler Thomas , Medinger Michael , Halter Jörg , Heim Dominik , Gratwohl Alois , Tichelli Andre 
Published: October 2019

Abstract
The donor/recipient pair provides a model for evaluating telomere shortening and cell senescence in a transplant setting, since cells have the same origin but a different fate. High replicative stress on stem cells accelerates telomere shortening in all leukocytes within the first year after allogeneic hematopoietic stem cell transplantation (HSCT). Thereafter, telomere length dynamics of HSCT-recipients appear not to differ from their donors. We evaluated telomere shortening in different leukocyte subsets in very long survivors after HSCT and looked for associations with transplant events. This was a prospective, cross-sectional study in which we analyzed in a blinded way the telomere length by automated multicolor flow-FISH in 20 patients and their respective HLA-matched sibling donors. The median age at study time was 41 years for the recipients (range 5–50) and the donors (range 3–45), 65% of the patients were male. The donor was younger in 60% and a female in 35%. The median follow-up after HSCT was 17.5 years (range 12–25). Two patients (10%) received HSCT for severe aplastic anemia and 18 (90%) for a hematological malignancy. Total body irradiation (TBI) was part of the conditioning in 85% of the patients and all received bone marrow as source of stem cells. Acute graft versus host disease (GVHD) was observed in 55% of the patients and chronic GVHD in 40%. The age-matched and cell-type-specific absolute telomere length values for the recipients and the donors fell between the 1st and 99th percentile of the normal distribution. The telomere length (mean ± std) in recipients as compared to donors was significantly shorter (p < 0.01) for granulocytes (6.7 kb ± 1.0 vs 7.2 ± 0.9), CD45RA-positive T-cells (5.6 kb ± 1.2 vs 6.3 ± 1.2); memory T-cells (5.1 kb ± 0.9 vs 5.6 ± 0.9), B-cells (7.2 kb ± 1.2 vs 7.9 ± 1.1) and NK/NKT-cells (5.1 kb ± 0.8 vs 5.6 ± 1.5). The mean difference in telomere length between the pairs was in the range of 0.5–0.7 kb for each subset of leukocytes; based on the telomere length values we could predict donors and recipients in a 100 %. Age, sex, diseases, conditioning with fractionated or non-fractionated TBI and acute GVHD had no impact on relative telomere loss. Patients with chronic GVHD (n=8; p=0.04) and particularly those with extensive chronic GVHD (n=5; p=0.004) presented with significant telomere shortening in CD45RA-positive T-cells. In recipients with extensive chronic GVHD telomere shortening was also found in B-cells (p=0.04). For leukocytes there was a trend in telomere shortening over time since HSCT (p=0.06). Our results confirm and extend previous findings that peripheral blood cells have shorter telomeres in long-term recipients after allogeneic HSCT. The difference in telomere length compared to the telomere length value in the respective donor corresponds to approximately 10–15 years of cell aging. In patients with chronic GVHD with more pronounced telomere shortening in certain subsets of lymphocytes but not in granulocytes, this difference corresponds to approximately 40–60 years of cell aging. These findings are compatible with a concept of chronic GVHD as a disease of disturbed immunity and raise the question of immuno-senescence or late altered immunity in chronic GVHD.