Durable engraftment of major histocompatibility complex–incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide

Blood ◽  
2001 ◽  
Vol 98 (12) ◽  
pp. 3456-3464 ◽  
Author(s):  
Leo Luznik ◽  
Sanju Jalla ◽  
Laura W. Engstrom ◽  
Robert Iannone ◽  
Ephraim J. Fuchs
Keyword(s):  
Stem Cells ◽  
Major Histocompatibility Complex ◽  
Total Body Irradiation ◽  
Low Dose ◽  
Cytotoxic T Cell ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Total Body ◽  
Marrow Cells

Abstract Treatment of leukemia by myeloablative conditioning and transplantation of major histocompatibility complex (MHC)–mismatched stem cells is generally avoided because of the high risk of graft rejection or lethal graft-versus-host disease (GVHD). This study shows that MHC-incompatible cells can engraft stably after nonmyeloablative conditioning with immunosuppressive chemotherapy and low-dose total body irradiation (TBI). Long-term mixed hematopoietic chimerism, clonal deletion of donor-reactive T cells, and bidirectional cytotoxic T-cell tolerance were achieved by transplanting MHC-mismatched marrow cells into recipients conditioned with pretransplantation fludarabine or cyclophosphamide (Cy), 50 to 200 cGy TBI on day −1, and Cy 200 mg/kg intraperitoneally on day 3. In this model, long-term donor chimerism was proportional to the dose of TBI or donor marrow cells. Pretransplantation fludarabine and posttransplantation Cy were both required for alloengraftment, but the drugs had additional effects. For example, fludarabine sensitized host stem cells to the toxicity of TBI, because animals conditioned with both agents had higher chimerism than animals conditioned with TBI alone (P < .05). Also, posttransplantation Cy attenuated lethal and nonlethal GVH reactions, because F1 recipients of host-reactive, parental spleen cells survived longer (P < .05) and had lower donor cell chimerism (P < .01) if they received posttransplantation Cy than if they did not. Finally, delayed infusions of donor lymphocytes into mixed chimeras prolonged survival after leukemia challenge (P < .0001) without causing lethal GVHD. These results indicate that stable engraftment of MHC-incompatible cells can be induced after fludarabine-based, nonmyeloablative conditioning and that it serves as a platform for adoptive immunotherapy with donor lymphocyte infusions.

scholarly journals Major Histocompatibility Complex Restriction Between Hematopoietic Stem Cells and Stromal Cells In Vivo

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Futoshi Hashimoto ◽  
Kikuya Sugiura ◽  
Kyoichi Inoue ◽  
Susumu Ikehara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Graft Failure ◽  
Major Histocompatibility ◽  
Hematopoietic Stem ◽  
Histocompatibility Complex ◽  
Colony Forming Units

Graft failure is a mortal complication in allogeneic bone marrow transplantation (BMT); T cells and natural killer cells are responsible for graft rejection. However, we have recently demonstrated that the recruitment of donor-derived stromal cells prevents graft failure in allogeneic BMT. This finding prompted us to examine whether a major histocompatibility complex (MHC) restriction exists between hematopoietic stem cells (HSCs) and stromal cells. We transplanted bone marrow cells (BMCs) and bones obtained from various mouse strains and analyzed the cells that accumulated in the engrafted bones. Statistically significant cell accumulation was found in the engrafted bone, which had the same H-2 phenotype as that of the BMCs, whereas only few cells were detected in the engrafted bones of the third-party H-2 phenotypes during the 4 to 6 weeks after BMT. Moreover, the BMCs obtained from the MHC-compatible bone showed significant numbers of both colony-forming units in culture (CFU-C) and spleen colony-forming units (CFU-S). These findings strongly suggest that an MHC restriction exists between HSCs and stromal cells.

Expression and Regulation of Major Histocompatibility Complex on Neural Stem Cells and Their Lineages

2008 ◽  
Vol 17 (1) ◽  
pp. 53-66 ◽  
Author(s):  
Lan Yin ◽  
Sai-Li Fu ◽  
Gui-Ying Shi ◽  
Ying Li ◽  
Jian-Qiang Jin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Major Histocompatibility Complex ◽  
Neural Stem Cells ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Growth factor treatment prior to low-dose total body irradiation increases donor cell engraftment after bone marrow transplantation in mice

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 312-317 ◽  
Author(s):  
Estelle J. K. Noach ◽  
Albertina Ausema ◽  
Jan H. Dillingh ◽  
Bert Dontje ◽  
Ellen Weersing ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factors ◽  
Low Dose ◽  
Donor Cell ◽  
Hematopoietic Growth Factors ◽  
Cell Engraftment ◽  
Total Body

Abstract Low-toxicity conditioning regimens prior to bone marrow transplantation (BMT) are widely explored. We developed a new protocol using hematopoietic growth factors prior to low-dose total body irradiation (TBI) in recipients of autologous transplants to establish high levels of long-term donor cell engraftment. We hypothesized that treatment of recipient mice with growth factors would selectively deplete stem cells, resulting in successful long-term donor cell engraftment after transplantation. Recipient mice were treated for 1 or 7 days with growth factors (stem cell factor [SCF] plus interleukin 11 [IL-11], SCF plus Flt-3 ligand [FL], or granulocyte colony-stimulating factor [G-CSF]) prior to low-dose TBI (4 Gy). Donor cell chimerism was measured after transplantation of congenic bone marrow cells. High levels of donor cell engraftment were observed in recipients pretreated for 7 days with SCF plus IL-11 or SCF plus FL. Although 1-day pretreatments with these cytokines initially resulted in reduced donor cell engraftment, a continuous increase in time was observed, finally resulting in highly significantly increased levels of donor cell contribution. In contrast, G-CSF treatment showed no beneficial effects on long-term engraftment. In vitro stem cell assays demonstrated the effect of cytokine treatment on stem cell numbers. Donor cell engraftment and number of remaining recipient stem cells after TBI were strongly inversely correlated, except for groups treated for 1 day with SCF plus IL-11 or SCF plus FL. We conclude that long-term donor cell engraftment can be strongly augmented by treatment of recipient mice prior to low-dose TBI with hematopoietic growth factors that act on primitive cells.

scholarly journals Major Histocompatibility Complex–Matched Arteries Have Similar Patency to Autologous Arteries in a Mauritian Cynomolgus Macaque Major Histocompatibility Complex–Defined Transplant Model

2019 ◽  
Vol 8 (15) ◽  
Author(s):  
John P. Maufort ◽  
Jacqueline S. Israel ◽  
Matthew E. Brown ◽  
Steve J. Kempton ◽  
Nicholas J. Albano ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Small Diameter ◽  
Induced Pluripotent Stem Cell ◽  
Major Histocompatibility ◽  
Arterial Grafts ◽  
Histocompatibility Complex ◽  
Induced Pluripotent

Background Arterial bypass and interposition grafts are used routinely across multiple surgical subspecialties. Current options include both autologous and synthetic materials; however, each graft presents specific limitations. Engineering artificial small‐diameter arteries with vascular cells derived from induced pluripotent stem cells could provide a useful therapeutic solution. Banking induced pluripotent stem cells from rare individuals who are homozygous for human leukocyte antigen alleles has been proposed as a strategy to facilitate economy of scale while reducing the potential for rejection of induced pluripotent stem cell–derived transplanted tissues. Currently, there is no standardized model to study transplantation of small‐diameter arteries in major histocompatibility complex–defined backgrounds. Methods and Results In this study, we developed a limb‐sparing nonhuman primate model to study arterial allotransplantation in the absence of immunosuppression. Our model was used to compare degrees of major histocompatibility complex matching between arterial grafts and recipient animals with long‐term maintenance of patency and function. Unexpectedly, we (1) found that major histocompatibility complex partial haplomatched allografts perform as well as autologous control grafts; (2) detected little long‐term immune response in even completely major histocompatibility complex mismatched allografts; and (3) observed that arterial grafts become almost completely replaced over time with recipient cells. Conclusions Given these findings, induced pluripotent stem cell–derived tissue‐engineered blood vessels may prove to be promising and customizable grafts for future use by cardiac, vascular, and plastic surgeons.

scholarly journals Long-Term Quantitative Biodistribution and Side Effects of Human Mesenchymal Stem Cells (hMSCs) Engraftment in NOD/SCID Mice following Irradiation

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Sabine François ◽  
Benoit Usunier ◽  
Luc Douay ◽  
Marc Benderitter ◽  
Alain Chapel
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Total Body Irradiation ◽  
Human Mesenchymal Stem Cells ◽  
Scid Mice ◽  
Human Mscs ◽  
Long Term Treatment ◽  
Total Body

There is little information on the fate of infused mesenchymal stem cells (MSCs) and long-term side effects after irradiation exposure. We addressed these questions using human MSCs (hMSCs) intravenously infused to nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice submitted to total body irradiation (TBI) or local irradiation (abdominal or leg irradiation). The animals were sacrificed 3 to 120 days after irradiation and the quantitative and spatial distribution of hMSCs were studied by polymerase chain reaction (PCR). Following their infusion into nonirradiated animals, hMSCs homed to various tissues. Engraftment depended on the dose of irradiation and the area exposed. Total body irradiation induced an increased hMSC engraftment level compared to nonirradiated mice, while local irradiations increased hMSC engraftment locally in the area of irradiation. Long-term engraftment of systemically administered hMSCs in NOD/SCID mice increased significantly in response to tissue injuries produced by local or total body irradiation until 2 weeks then slowly decreased depending on organs and the configuration of irradiation. In all cases, no tissue abnormality or abnormal hMSCs proliferation was observed at 120 days after irradiation. This work supports the safe and efficient use of MSCs by injection as an alternative approach in the short- and long-term treatment of severe complications after radiotherapy for patients refractory to conventional treatments.

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