Table 1.
Studies for spontaneous tolerance in liver transplantation.
| Institution | Published year | Living/Cadaver | Pediatric/Adult | Study design | n | Patient with S.E. | Baseline biopsy | Time since LT (criteria) yr | IS regimen | Success rate | Acute rejection (Chronic rejection) | Graft loss | Remarks |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pittsburgh | 1993 (54) | – | – | Case series reports | 6 | Yes | No | NA | NA | NA | NA | NA | First series report from Pittsburgh |
| 1995 (55) 1997 (56) | NA | Mix | Prospective | 59 95 | No | Yes | Mean 8.4 (>5) | 14% Aza, 12% Tac 74% CsA | 18/95 (19%) | 25.4% (NR) | 0 | Two of PBC developed recurrence | |
| King's College | 1998 (57) | Cadaver | Adults | Prospective | 18 | Yes | No | Median 7 (–) | CsA and Aza | 5/18 (27.7%) | 28% (5.6%) | 1/18 (5.6%) | Fewer HLA mismatch was associated with successful withdrawal. Previous rejection history and autoimmune original disease are risk factor |
| Kyoto | 2001 (58) | Living | Pediatric | Partially prospective | 26 (63) | Partially yes | No | NA (>2) | Tac | 24/63 (38.1%) | 12% (NR) | 0 | Biopsy at 4 year after weaning showed that 2 of 11 tolerant recipients had substantial bile duct atrophy and recovered by tacrolimus reinduction |
| 2002 (59) | Living | Mix | Prospective + retrospective | 115 | Partially yes | No | NA (>2) | Tac | 16/67 (23.9%) | Non-protocol 25% Protocol 11.9% | 0 | None of clinical characteristics was identified as predictor of successful weaning | |
| Marcia | 2003 (60) | Cadaver | Adult | Prospective | 9 | No | Yes | Median 5.1 (>2) | CyA | 3/9 (33%) | 22% (NR) | 0 | Endothelial cell chimerism seems to have nothing to do with the induction of clinical tolerance in liver transplant patients |
| Stanford | 2004 (61) | NA | Pediatric | Retrospective | 38 | Yes | No | NA | Steroid+CNI (Tac92%, CyA 8%) | 8/38 (20.5%) | 55.3% (5.3%) | 2/38 (5.3%) | Two patients were retransplanted for chronic rejection |
| New Orleans | 2005 (62) | Cadaver | Adult | Prospective | 18 | No | No | (>0.5) | Tac | 1/18 (5.6%) | 61% (NR) | 0 | Early induction of operational tolerance seems to be difficult |
| Miami | 2005 (63) | Cadaver | Adult | RCT (donor BM) | 105 | No | No | Mean 4 (>3) | 85% Tac 14% CsA | 0% | 67% (1.9%) | 1/105 (0.95%) | Donor bone marrow infusion did not help successful completion of withdrawal |
| Rome | 2006 (64) 2008 (65) 2013 (66) | Cadaver | Adult | Prospective | 34 | No | Yes | Mean 5.3 (>1) | CsA monotherapy | 8/34 (23.4%) | 76.4% (NR) | 0 | All HCV related recipients |
| Israel | 2007 (67) | NA | Adult | RCT | 26 | No | No | Mean 4.3 vs. 5.0 (>2) | CsA +/–Aza, (Plednisone) | 2/26 (7.7%) | UDCA+ 43% UDCA– 75% | 0 | 3/4 AIH recipients had recurrence |
| Korea | 2009 (68) | Mix | Pediatric | Retrospective | 5 | Yes | No | Median 3.8 | NA | – | NR | 0 | Long term stable graft function and no rejection >1 yr were favorable findings for successful withdrawal |
| UCSF | 2012 (69) | Living | Pediatric | Multi-center prospective | 20 | No | Yes | Mean 7.7 (>3) | CNI monotherapy | 12/20 (60%) | 36.8% (NR) | 0 | Later initiation of IS withdrawal after transplantation and less portal inflammation and total C4d score on screening biopsy were associated with successful withdrawal |
| Pamplona | 2013 (70) | Cadaver | Adult | Prospective | 24 | Yes | Yes | Median 9.3 (>3) | NA | 15/24(62.5%) | 4.1% (41%) | 0 | Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 vs. 71 months) |
| Barcelona | 2013 (71) | Cadaver | Adult | Multi-center prospective | 102 | No | Yes | Median 8.6 (>3) | CNI mTOR inhibitor CSB | 41/102 (40.2%) | 56% (NR) | 0 | Time since transplantation, recipient age, and male gender were independent factor for successful withdrawal |
| 2014 (72) | Cadaver | Adult | Multi-center prospective | 32 | No | Yes | Median 7.2 (>3) | CNI +/–MMF or CBS | 17/34 (50%) | 44.1% (NR) | 0 | Persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses | |
| Taipei | 2015 (73) | Mix | Pediatric | Single center retrospective | 16 | No | Yes | (>1 for Tx <1, > 2 for Tx > 1) | Tac monotherapy | 5/15 (33%) | 46.7% (NR) | 0 | Early recruitment was favorable factor predicting operational tolerance |
| Chicago | 2019 (74) | Cadaver | Adult | Prospective | 15 | No | Yes | Mean 6.7 (>3) | Silorimus | 8/15 (53.3%) | 40% (NR) | 0 | mTOR inhibitor withdrawal had similarly succeeded in comparison with CNI withdrawal |
| Pennsylvania | 2019 (75) | Cadaver | Adult | Multi-center RCT | 77 | No | Yes | Median 18 (>3) | Tac (91) CsA (2), MMF(2) | 10/77 (13%) | 40.3% (NR) | 0 | Withdrawal showed likely less eventful than maintenance group |
S.E., side effect; Aza, azathioprine; Tac, tacrolimus; CsA, cyclosporine A; NR, not reported; NA, not assessed; CNI, calcineurin inhibitor; RCT, randomized control study; CSB, costimulatory blockade; MMF, mycophenolate mofetil.