Successful Allogeneic Bone Marrow Transplantation (BMT) by Injection of Bone Marrow Cells via Portal Vein: Stromal Cells as BMT-Facilitating Cells

Fan, Tianxue; Hisha, Hiroko; Jin, Tienan; Chen, Yú; Lian, Zhe‐Xiong; Guo, Shubin; Cui, Yunze; Feng, Biao; Yang, Guoxiang; Li, Qing; Ikehara, Susumu

doi:10.1634/stemcells.19-2-144

Cited by 40 publications

(22 citation statements)

References 25 publications

(36 reference statements)

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“…46,49 Similarly, allogeneic MSCs may attenuate graft-versus-host disease complicating allogeneic marrow transplantation. 31,39,50 Although a substantive body of literature buttresses the notion that MSCs are immunosuppressive, 31-34 as we have also here demonstrated in vitro ( Figure 2C), it is not yet clearly proven that MHC-mismatched MSCs are universally immunoprivileged.In this study, we confirmed our previously published findings 28,29 that primary murine MSCs retrovirally gene-modified to deliver Epo engender a significant and prolonged rise in Hct when implanted in syngeneic mice. Of greater note, however, are our results indicating that MHC class I-and class II-mismatched murine MSCs are not immunoprivileged, as the implantation of C57Bl/6-derived Epo ϩ MSCs in allogeneic Balb/c recipient mice led to their in vivo rejection.…”

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confidence: 68%

Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice

Eliopoulos

Stagg

Lejeune

et al. 2005

Blood

503

418

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It has been suggested that marrow stromal cells (MSCs) may be immunoprivileged and can engraft in allogeneic recipients with intact immune systems. We determined if the implantation of murine MSCs engineered to release erythropoietin (Epo) would be feasible in major histocompatibility complex (MHC)-mismatched allogeneic mice without immunosuppression, and we monitored hematocrit (Hct) as a reporter of MSC graft survival. MSCs from C57Bl/6 mice were engineered to release murine Epo (Epo ؉ MSCs) and implanted subcutaneously in either syngeneic C57Bl/6 mice or MHC-mismatched Balb/c mice. In syngeneic recipients, the Hct rapidly rose from baseline level and remained higher than .88 (88%) for more than 200 days. However, in MHCmismatched recipient Balb/c mice, the Hct rose transiently and rapidly declined to baseline values. Repeat implantations in these same mice were associated with an acquired refractoriness in the Hct response consistent with alloimmunization to donor Epo ؉ MSCs. Allogeneic MSC implants had an increased proportion of host-derived lymphoid CD8 ؉ , natural killer T (NKT), and NK infiltrating cells compared with syngeneic controls, and splenocytes isolated from Balb/c mice that had received implants also displayed a significant interferon-gamma (IFN␥) response to C57Bl/6 MSCs in vitro. These IntroductionBone marrow stromal cells (MSCs), 1 also sometimes referred to as mesenchymal stem cells, are promising for regenerative medicine due to their innate ability to differentiate into various cell types. [2][3][4][5] Thus, autologous MSCs and their genetically engineered progeny have potential use in several preclinical regenerative medicine scenarios, such as cardiovascular regeneration, 6-14 brain and spinal cord regeneration, 15,16 as well as bone and cartilage repair. [17][18][19][20][21][22][23] Furthermore, genetically engineered MSCs may operate as cellular vehicles for the delivery of therapeutic proteins in hereditary and acquired metabolic, endocrine, and malignant diseases. 4,[24][25][26][27][28][29][30] In vitro studies on human, baboon, and murine MSCs have revealed that MSCs are immunosuppressive. [31][32][33][34] Depending upon the experimental circumstances, suppression of mixed lymphocyte reaction (MLR) in vitro between major histocompatibility complex (MHC)-mismatched stimulator and responder cells by MSCs appears to arise from both contact-dependent 35 and soluble factors including, but not limited to, [36][37][38] hepatocyte growth factor (HGF) and transforming growth factor ␤1 (TGF-␤1). 32 However, alternative experimental settings suggest that MSCs may also behave as nonprofessional antigen-presenting cells (APCs). 39,40 In support of their in vivo immunosuppressive features are the observations that allogeneic MSCs may prolong skin allograft survival in immunocompetent baboons, 31 prevent the rejection of allogeneic B16 mouse melanoma cells in immunocompetent C3H mice, 34 and attenuate graft-versus-host disease in mice and humans. 38,41 The sum of these observations supports the...

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confidence: 68%

Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice

Eliopoulos

Stagg

Lejeune

et al. 2005

Blood

503

418

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“…28 These findings suggest that the PV injection of donor whole BMCs (including donor stromal cells) creates a suitable microenvironment in the liver, and that this facilitates the proliferation of donor HSCs in collaboration with MHC-matched donor stromal cells. Indeed, we have very recently found that donorderived cells trapped in the liver play a crucial role in the success of BMT 36 ; when adherent cell-depleted BMCs were injected, 75% of recipients died within 90 days, whereas all the recipients injected with adherent cell-depleted BMCs with cultured stromal cells survived more than 80 days. 37 Although this method is effective, there are risks associated with the abdominal section, and supplemental IV injection is required.…”

Section: Discussionmentioning

confidence: 99%

Intra–bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice

Kushida

Inaba

Hisha

et al. 2001

Blood

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246

309

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Intractable autoimmune diseases in chimeric resistant MRL/lpr mice were treated by a new bone marrow transplantation (BMT) method consisting of fractionated irradiation, 5.5 Gy ؋ 2, followed by intrabone marrow (IBM) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice (5.5 Gy ؋ 2 ؉ IBM). In MRL/lpr mice treated with this method, the number of donor-derived cells in the bone marrow, spleen, and liver rapidly increased (almost 100% donor-derived cells by 14 days after the treatment), and the number of donorderived hemopoietic progenitor cells concomitantly increased. Furthermore, donorderived stromal cells were clearly detected in the cultured bone pieces from MRL/lpr mice treated with 5.5 Gy ؋ 2 ؉ IBM. All the recipients thus treated survived more than 1 year (> 60 weeks after birth) and remained free from autoimmune diseases. Autoantibodies decreased to almost normal levels, and abnormal T cells (

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“…27 It is well documented that donor stromal cells are essential for successful allogenic BMT. 28 In our model, we transplanted whole BM rather than a selected population of BMC, and we delivered BM directly into the natural BM microenvironment. The advantage of this approach lies in the fact that unselected BMC contain stem cells, progenitor cells, stromal cells and their precursors, all of which facilitate donor-cell engraftment.…”

Section: Discussionmentioning

confidence: 99%

Donor–origin cell engraftment after intraosseous or intravenous bone marrow transplantation in a rat model

Klimczak

Ünal

Jankowska

et al. 2007

Bone Marrow Transplant

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We compared the effects of intraosseous BMT with those of standard i.v. BMT on the efficacy on donor-cell engraftment into the BM and lymphoid organs across an MHC barrier in rats. Twenty-four intraosseous and 24 i.v. BMTs were performed from 48 ACI (RT1 a ) donors to 48 Lewis (RT1 l ) recipients. Each transplant group received either intraosseous or i.v. BMT. Groups I and II served as controls without immunosuppression (n ¼ 16); groups III and IV received cyclosporine monotherapy (n ¼ 16); and V and VI received ab-TCR monoclonal antibody and cyclosporine A (ab-TCR/CsA) for 7 days (n ¼ 16). In each group, four rats received 35 Â 10 6 transplanted bone marrow cells (BMCs) and four received 70 Â 10 6 cells. All animals survived without GVHD. Mean (7s.d.) donorcell engraftment into BM of recipients after intraosseous BMT was 7.9% (71.3%) in recipients receiving ab-TCR-CsA and 70 Â 10 6 BMCs, and 4.2% (71.4%) in recipients after i.v. transplantation. The seeding efficacy of donor cells into lymphoid tissue was greater after intraosseous BMT and ab-TCR-CsA than after standard i.v. transplantation. In our model, intraosseous BMT facilitated donor-cell engraftment under short-term immunodepletive ab-TCR/CsA protocol, which resulted in a temporary state of immune unresponsiveness.

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Successful Allogeneic Bone Marrow Transplantation (BMT) by Injection of Bone Marrow Cells via Portal Vein: Stromal Cells as BMT-Facilitating Cells

Abstract: ABSTRACT

Cited by 40 publications

References 25 publications

Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice

Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice

Intra–bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice

Donor–origin cell engraftment after intraosseous or intravenous bone marrow transplantation in a rat model

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