Donor stem cell infusion after non-myeloablative conditioning for tolerance induction to HLA mismatched adult living-donor liver graft.
OBJECTIVE
The induction of transplantation tolerance, defined as the survival of a functioning allograft in the absence of continuing immunosuppressive therapy, would be a major advance. Clinical and experimental data have shown that transplantation tolerance could be induced by pre-transplant myeloconditioning and infusion of donor hematopoietic cells. We investigated the feasibility and safety of a protocol to induce tolerance to HLA mismatched living-donor liver graft by pre-transplant non-myeloablative conditioning followed by donor stem cells (SC) infusion, in patients with advanced liver cancers.


METHODS
Two patients with intrahepatic cancers who did not fulfill criteria for cadaver liver transplantation were included in the study. Preparative regimen consisted in cyclophosphamide and anti-thymocyte globulin, followed by infusion of purified donor CD34(+) stem cells. Living-donor liver transplantation (LDLT) using the liver right lobe was performed after hematological reconstitution, respectively 40 and 55 days after donor stem cell infusion. Immunosuppressive therapies were discontinued when liver graft function returned to normal.


RESULTS
The procedure could be completed in the two patients. No severe toxicity of the preparative regimen was observed. Neither patient presented graft versus host reaction after donor stem cell infusion. A transient macrochimerism was observed in the first case, while no chimerism could be detected in the second. Immunosuppression was discontinued, respectively 90 and 28 days, after liver transplantation, without subsequent rejection episode. In the two cases, liver function remained normal for the study period. In both patients, the period of immune reconstitution was prolonged, as illustrated by persisting low CD4(+) cell counts. Mixed lymphocyte cultures, performed after immunosuppression withdrawal, demonstrated donor specific hyporesponsiveness in the first case, but in a context of global hyporeactivity in the two patients. The first patient died from tumor recurrence 370 days after liver transplantation. The second patient is alive, 270 days after liver transplantation, but with a suspicion of tumor relapse as indicated by the reappearance of tumor marker in blood.


CONCLUSIONS
In the two cases, acceptance of HLA mismatched living-donor liver graft was obtained after non-myeloablative conditioning and donor stem cell infusion. Improving the rate of immune reconstitution appears as a priority to reduce the risk of tumor recurrence in such patients.
Donckier
Vincent
V
Medicosurgical Department of Gastroenterology, Hôpital Erasme, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
Troisi
Roberto
R
Toungouz
Michel
M
Colle
Isabelle
I
Van Vlierberghe
Hans
H
Jacquy
Caroline
C
Martiat
Philippe
P
Stordeur
Patrick
P
Zhou
Ling
L
Boon
Nathalie
N
Lambermont
Micheline
M
Schandené
Liliane
L
Van Laethem
Jean Luc
JL
Noens
Lucien
L
Gelin
Michel
M
de Hemptinne
Bernard
B
Goldman
Michel
M
D000961:Antilymphocyte Serum / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000601:surgery; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000601:surgery; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000601:surgery; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D017809:Fatal Outcome; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000601:surgery; D016031:Liver Transplantation / Q000276:immunology*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D036102:Peripheral Blood Stem Cell Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000276:immunology*
D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012333:RNA, Messenger; D003520:Cyclophosphamide; D020123:Sirolimus