Induction of donor-specific tolerance to allogeneic hepatocytes by allogeneic bone marrow transplantation

Yoshida, Noritoshi; Kawahara, Toshiyasu; Futagawa, Shunji

doi:10.1016/s1386-6346(02)00326-1

Cited by 5 publications

(3 citation statements)

References 28 publications

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“…Another factor to consider is bone marrow transplantation (BMT), which could contribute to successful HT by providing tolerance against the allogeneic cells 8. Transplanted rodent hepatocytes can engraft permanently in syngeneic hosts,9, 10 whereas following allogeneic transplantation, hepatocytes are usually quickly rejected by T cell–dependent mechanisms 11.…”

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confidence: 99%

Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells

et al. 2008

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The lack of adequate donor organs is a major limitation to the successful widespread use of liver transplantation for numerous human hepatic diseases. A desirable alternative therapeutic option is hepatocyte transplantation (HT), but this approach is similarly restricted by a shortage of donor cells and by immunological barriers. Therefore, in vivo expansion of tolerized transplanted cells is emerging as a novel and clinically relevant potential alternative cellular therapy. Toward this aim, in the present study we established a new mouse model that combines HT with prior bone marrow transplantation (BMT). Donor hepatocytes were derived from human alpha(1)-antitrypsin (hAAT) transgenic mice of the FVB strain. Serial serum enzyme-linked immunosorbent assays for hAAT protein were used to monitor hepatocyte engraftment and expansion. In control recipient mice lacking BMT, we observed long-term yet modest hepatocyte engraftment. In contrast, animals undergoing additional syngeneic BMT prior to HT showed a 3-to 5-fold increase in serum hAAT levels after 24 weeks. Moreover, complete liver repopulation was observed in hepatocyte-transplanted Balb/C mice that had been transplanted with allogeneic FVB-derived bone marrow. These findings were validated by a comparison of hAAT levels between donor and recipient mice and by hAAT-specific immunostaining. Taken T o date, orthotopic liver transplantation remains the only therapeutic option for many acute and chronic end-stage liver diseases. However, donor organs are limited and can be used to treat only one patient at a time. Thus, great efforts are underway to explore new strategies for parenchymal liver cell replacement. Hepatocyte transplantation (HT) is currently the most promising option as hepatocytes have been proven to possess tremendous in vivo expansion capability, require little pretransplant manipulation, and may permit the distribution of cells from a single donor organ to multiple recipients. However, because of technical restraints, only a limited number of hepatocytes can be transplanted at a time; moreover, donor cells may be subject to immune surveillance. This raises an urgent need to develop novel strategies to induce tolerance and to select donor cells for in vivo expansion.Recent studies in the field of HT have concentrated on animal models for liver repopulation and on the determination of intrinsic factors driving the in vivo expansion of

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confidence: 99%

Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells

et al. 2008

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“…According to the site of allogenic HCTx, some studies have used the spleen or subrenal capsules (26,28,41), while other studies used the liver (13,24,35,39). Because the expansion of transplanted cells in sufficient numbers is necessary to compensate for the impaired host liver functions, the liver might be an ideal site not only as a physiological site for hepatocytes to function, but also contain sufficient space for the transplanted hepatocytes to expand.…”

Section: Discussionmentioning

confidence: 99%

“…Hematopoietic reconstitution by bone marrow transplantation (BMTx) has been shown to provide host tolerance in various models of transplantation (14). It has been demonstrated that when host bone marrow is reconstituted by donor BMTx after lethal irradiation, allogenic HCTx is feasible between the mouse strains expressing the disparate major histocmpatibility complex (MHC) (26,41). In this setting, hepatocytes of the third-party mouse strains were rejected, thus indicating that donor-specific immunotolerance was important for the successful engraftment of allogenic hepatocytes (26).…”

Section: Introductionmentioning

confidence: 99%

Replacement of Liver Parenchyma in Analbuminemic Rats with Allogenic Hepatocytes is Facilitated by Intrabone Marrow-Bone Marrow Transplantation

et al. 2011

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Although hepatocyte transplantation (HCTx) is expected to become a useful therapy for human liver diseases, allogenic hepatocytes still tend to be rejected within a short period due to host immunosurveillance. In the present study, we investigated the effect of prior bone marrow transplantation (BMTx) for the engraftment of allogenic hepatocytes using the analbuminemic rat transplantation model. The hepatocytes of Lewis (LEW) rats were not accepted in the liver of retrorsine (RS)/partial hepatectomy (PH)-treated analbuminemic F344 (F344-alb) rats, which express the disparate major histocompatibility complex (MHC) against that of LEW rats. Prior BMTx with the LEW bone marrow cells (BMCs) after sublethal irradiation achieved acceptance and repopulation of LEW hepatocytes in the liver of the RS/PH-treated F344-alb rats, associated with elevation of serum albumin. The replacement of hepatic parenchyma with albumin positive (Alb(+)) donor hepatocytes and elevation of serum albumin levels were dependent on the bone marrow reconstitution by donor BMCs, which was more efficiently achieved by intrabone marrow (IBM)-BMTx than by intravenous (IV)-BMTx. Our results demonstrate that efficient bone marrow reconstitution by IBM-BMTx enables the replacement of the hepatic parenchyma with allogenic hepatocytes in RS/PH-treated analbuminemic rats without immunosuppressants.

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Natural antibody-mediated graft rejection in xenotransplantation

Kawahara

2004

Juntendo Medical Journal

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Induction of donor-specific tolerance to allogeneic hepatocytes by allogeneic bone marrow transplantation

Cited by 5 publications

References 28 publications

Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells

Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells

Replacement of Liver Parenchyma in Analbuminemic Rats with Allogenic Hepatocytes is Facilitated by Intrabone Marrow-Bone Marrow Transplantation

Natural antibody-mediated graft rejection in xenotransplantation

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