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CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.

ABSTRACT: Background:Complementary, marrow donor-derived peripheral blood T-lymphocyte infusions enable consistent hematopoietic engraftment in lethally irradiated dog leukocyte antigen (DLA)-haploidentical littermate recipients, but at the cost of severe graft versus host disease (GVHD). Here, we explored whether CD94-selected and in vitro-expanded natural killer (NK) cells could be substituted for T-lymphocytes for enhancing marrow engraftment without causing severe GVHD. Methods:Five dogs were conditioned with 700 cGy total body irradiation followed by infusion of DLA-haploidentical donor marrow and CD94-selected, in vitro-expanded NK cells. NK cells were infused at a median of 140 000 (range 78 000-317 000) cells/kg. Results:Four dogs rejected their marrow grafts, whereas 1 dog fully engrafted and developed GVHD. We observed an increase in peripheral blood NK cells after infusion of CD94-selected, ex vivo-expanded NK in 2 dogs. Peripheral blood lymphocyte counts peaked at day 7 or 8 posttransplant in the 4 rejecting dogs, whereas in the fully engrafted dog, lymphocyte counts remained stable at suboptimal levels. Conclusions:Our study indicates NK cells can be expanded in vitro and safely infused into DLA-haploidentical recipients. Within the range of CD94-selected and expanded cells infused we concluded that they failed to both uniformly promote engraftment and avert GVHD.

SUBMITTER: Abrams K

PROVIDER: S-EPMC7673772 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.

Abrams Kraig K Graves Scott S SS Parker Maura H MH Storb Rainer R

Transplantation direct 20201116 12

<h4>Background</h4>Complementary, marrow donor-derived peripheral blood T-lymphocyte infusions enable consistent hematopoietic engraftment in lethally irradiated dog leukocyte antigen (DLA)-haploidentical littermate recipients, but at the cost of severe graft versus host disease (GVHD). Here, we explored whether CD94-selected and in vitro-expanded natural killer (NK) cells could be substituted for T-lymphocytes for enhancing marrow engraftment without causing severe GVHD.<h4>Methods</h4>Five dog ...[more]

PMID: 33225057

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Project description:There is a clinical need for developing systemic transplantation protocols for use of human skeletal stem cells (also known bone marrow stromal stem cells) (hBMSC) in tissue regeneration. In systemic transplantation studies, only a limited number of hBMSC home to injured tissues suggesting that only a subpopulation of hBMSC possesses "homing" capacity. Thus, we tested the hypothesis that a subpopulation of hBMSC defined by ability to form heterotopic bone in vivo, is capable of homing to injured bone.We tested ex vivo and in vivo homing capacity of a number of clonal cell populations derived from telomerized hBMSC (hBMSC-TERT) with variable ability to form heterotopic bone when implanted subcutaneously in immune deficient mice. In vitro transwell migration assay was used and the in vivo homing ability of transplanted hBMSC to bone fractures in mice was visualized by bioluminescence imaging (BLI). In order to identify the molecular phenotype associated with enhanced migration, we carried out comparative DNA microarray analysis of gene expression of hBMSC-derived high bone forming (HBF) clones versus low bone forming (LBF) clones.HBF clones were exhibited higher ex vivo transwell migration and following intravenous injection, better in vivo homing ability to bone fracture when compared to LBF clones. Comparative microarray analysis of HBF versus LBF clones identified enrichment of gene categories of chemo-attraction, adhesion and migration associated genes. Among these, platelet-derived growth factor receptor (PDGFR) ? and ? were highly expressed in HBF clones. Follow up studies showed that the chemoattractant effects of PDGF in vitro was more enhanced in HBF compared to LBF clones and this effect was reduced in presence of a PDGFR?-specific inhibitor: SU-16 f. Also, PDGF exerted greater chemoattractant effect on PDGFR?(+) cells sorted from LBF clones compared to PDGFR?(-) cells.Our data demonstrate phenotypic and molecular association between in vivo bone forming ability and migratory capacity of hBMSC. PDGFR? can be used as a potential marker for the prospective selection of hBMSC populations with high migration and bone formation capacities suitable for clinical trials for enhancing bone regeneration.

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CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.

Publications

CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.

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