The combination of primary sclerosing cholangitis and CCR5-Δ32 in recipients is strongly associated with the development of nonanastomotic biliary strictures after liver transplantation.
BACKGROUND
The role of the immune system in the pathogenesis of nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) is unclear. A loss-of-function mutation in the CC chemokine receptor 5 (CCR5-Δ32) leads to changes in the immune system, including impaired chemotaxis of regulatory T cells.


OBJECTIVE
To investigate the impact of the CCR5-Δ32 mutation on the development of NAS.


METHODS
In 384 OLTs, we assessed the CCR5 genotype in donors and recipients and correlated this with the occurrence of NAS.


RESULTS
The CCR5-Δ32 allele was found in 65 (16.9%) recipients. The cumulative incidence of NAS at 5 years was 6.5% in wild-type (Wt) recipients vs 17.2% for carriers of the CCR5-Δ32 allele (P<0.01). In recipients with CCR5-Δ32, 50% of all NAS occurred >2 years after OLT, compared with 10% in the Wt group. In multivariate regression analysis, the adjusted risk of developing NAS was four-fold higher in recipients with CCR5-Δ32 (P<0.01). The highest risk of NAS was seen in patients transplanted for primary sclerosing cholangitis (PSC), who also carried CCR5-Δ32 (relative risk 5.4, 95% confidence interval 2.2-12.9; P<0.01). Donor CCR5 genotype had no impact on the occurrence of NAS.


CONCLUSIONS
Patients with the CCR5-Δ32 mutation have a four-fold higher risk of developing NAS, compared with Wt recipients. This risk is even higher in patients with CCR5-Δ32 transplanted for PSC. Late development of NAS is significantly more present in patients with CCR5-Δ32. These data suggest that the immune system plays a critical role in the development of NAS after OLT.
Department of Surgery, University of Groningen, Groningen, the Netherlands.
Sanna
S
op den Dries
Carlijn I
CI
Buis
Jelle
J
Adelmeijer
Eric J
EJ
Van der Jagt
Elizabeth B
EB
Haagsma
Ton
T
Lisman
Robert J
RJ
Porte
D000328:Adult; D016009:Chi-Square Distribution; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000401:mortality / Q000601:surgery*; D002779:Cholestasis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D003251:Constriction, Pathologic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006085:Graft Survival; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation / Q000009:adverse effects* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D019713:Receptors, CCR5 / Q000235:genetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors
D019713:Receptors, CCR5