A new method for tolerance induction: busulfan administration followed by intravenous injection of neuraminidase-treated donor bone marrow.
The portal venous (p.v.) administration of foreign cells induces donor-specific tolerance. Recently, we have demonstrated that the p.v. administration of donor cells elicits donor-specific tolerance across major histocompatibility complex barriers. In the present study, utilizing the intrahepatic tolerance-inducing system, we have established a new method for organ transplantation using both busulfan ([Bu] to provide a sufficient "space" for the donor hematopoietic cells to expand in the recipient) and neuraminidase ([Neu] to enhance the trapping of i.v.-injected cells in the liver). Radiolabeled bone marrow cells (BMCs) were found to exclusively accumulate in the livers of the recipients as a result of the Neu treatment. Furthermore, hematopoietic progenitors (forming hematopoietic foci) in the accumulated BMCs were retained in the recipient livers for at least 18 days. C57BL/6 (B6) mice that had been transplanted with skins of BALB/c mice immediately after the injection of BALB/c BMCs showed a 90% skin graft survival rate over 400 days as a result of using the combination of injecting 50 mg/kg Bu into the B6 mice and treatment of the BALB/c BMCs with 0.25 U/ml Neu (50 Bu + 0.25 Neu). However, the survival rate significantly decreased when either the Bu or Neu treatment was omitted. In tolerant recipients, microchimerism was observed in the various hematolymphoid organs. T cells collected from the tolerant recipients suppressed proliferative responses to the donor-alloantigens but enhanced the production of Th2 and Th3 cytokines. These findings suggest that the enhanced retention of donor BMCs in the recipient livers as a result of the Bu and Neu treatments efficiently induces tolerance induction. Therefore, this "single-day protocol" would be of great advantage for human organ transplantation.
Nagahama
T
T
The First Department of Pathology, Kansai Medical University, Osaka, Japan.
Sugiura
K
K
Lee
S
S
Morita
H
H
Adachi
Y
Y
Kwon
A H
AH
Kamiyama
Y
Y
Ikehara
S
S
D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation / Q000379:methods*; D002066:Busulfan / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000494:pharmacology*; D016038:Skin Transplantation; D018418:Th2 Cells / Q000378:metabolism; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*
D016207:Cytokines; D007166:Immunosuppressive Agents; D009439:Neuraminidase; D002066:Busulfan