Tolerance in liver transplantation: Biomarkers and clinical relevance

Table 1 Biomarkers of tolerance in liver transplantation

Biomarker	Description	Study before or during IS withdrawal	Ref.
Dendritic cells
pCD/mCD ratio	Tolerant patients have elevated pDC/mDC ratio. No differences between tolerant patients vs healthy controls	No	[134,150]
mDCs/pCD ratio	Elevated mDC/pCD associated with late rejection	No	[151]
PD-L1/CD86 ratio	Elevated PD-L1/CD86 expression on DCs in tolerant patients	No	[152]
DC HLA-G expression	Elevated on mDC	No	[153]
T cells
Regulatory T cells	Increase of peripheral CD4+CD25high cells and RNA FoxP3 over time during weaning	Yes	[40,43,44,133]
	Increase in T regs in liver biopsy of tolerant patients
Natural killer	Increase in Tolerant patients	Yes	[154]
Soluble factors
Serum HLA-G	Normal or elevated serum HLA-G levels associated to normal liver	No	[155-157]
Anti-donor antibodies	Absent in tolerant patients	No	[150]
Cell proliferation
Phytohemagglutinin SI	SI < 20 and > 10 yr since LT 100% tolerance	Yes	[158]
Genetic profile
Cytokine gene polymorphism	Low TNF-alpha and high/intermediate IL-10 production in OT	No	[159]
Gene transcripts	Enriched from NK, CD4+CD25+ FoxP3+, γδTCR+ and δ1TCR+	No	[42,43,160]
Genes related to iron homeostasis in liver graft	Enriched in tolerant patients (CDHR2, MIF, PEBP1, SOCS1, TRF)	Yes	[140]

DC: Dendritic cell; mDC: Monocytoid dendritic cell; LT: Liver transplantation; pDC: plasmacytoid dendritic cell; SI: Stimulation index.

Table 2 Impact of immunosuppression withdrawal on preexisting complications in liver transplantation

Author (year)	Ref.	No. of patients	Rational for IS withdrawal	Description of impact on preexisting complications	Impact on preexisting complications in tolerant patients
Mazariegos	[144]	95	Chronic IS-related toxicity	Yes	No changes in renal function or hypertension. Higher survey scores of patients well being
(1997)
Devlin	[2]	18	Chronic IS-related toxicity	No	-
(1998)
Takatsuki	[161]	63	30 PTLD	No	-
(2001)
Eason	[162]	18	Patients who expressed a desire to discontinue IS	No	-
(2005)
Tryphonopoulos	[163]	104	Role of DBMI in IS withdrawal in LT	No	-
(2005)
Orlando	[146]	34	Impact of IS withdrawal on HCV disease in LT	Yes	Less cardiovascular or infectious diseases
(2008)
Pons	[148]	22	Chronic IS-related toxicity	Yes	Renal function, hypertension, hypercholesterolemia, hyperuricemia, hypertension and diabetes control improved
(2009)
Feng	[147]	20	Chronic IS-related toxicity	Yes	No changes in comorbidities
(2012)
de la Garza	[158]	22	Chronic IS-related toxicity	No	-
(2013)
Benitez	[145]	102	Chronic IS-related toxicity	Yes	No changes in comorbidities
(2013)

IS: Immunosuppression; PTLD: Post-transplant lymphoproliferative disorder; HCV: Hepatitis C virus; LT: Liver transplantation; DBMI: Donor bone marrow infusion.