title: Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey.
abstract: To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy "3(rd)-party" donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease.
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Zyrafete
authors.initials: Z
authors.lastname: Kuçi
authors.affiliation: Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bönig
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.affiliation: Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany.
authors.forename: Milica
authors.initials: M
authors.lastname: Bunos
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Germany.
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Janssen
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany University Hospital Centre Zagreb, Clinical Department of Transfusion and Transplantation Biology, Division of Cellular Therapy, Zagreb, Croatia.
authors.forename: Marijana
authors.initials: M
authors.lastname: Škifić
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Michel
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Eising
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany Great Ormond Street Hospital, Department of Hematology/Oncology, London, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lucchini
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Bakhtiar
authors.affiliation: University Children's Hospital Heidelberg, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.affiliation: University Children's Hospital Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.affiliation: University Children's Hospital Essen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Basu
authors.affiliation: University Children's Hospital München-Schwabing, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: von Luettichau
authors.affiliation: University Children's Hospital Ulm, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Children's Hospital, Medizinische Hochschule Hannover, Germany.
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jarisch
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Soerensen
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Emilia
authors.initials: E
authors.lastname: Salzmann-Manrique
authors.affiliation: Institute of Transfusion Medicine and German Red Cross Blood Center Frankfurt, Frankfurt am Main, Germany.
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany selim.kuci@kgu.de peter.bader@kgu.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.affiliation: University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany selim.kuci@kgu.de peter.bader@kgu.de.
authors.forename: Selim
authors.initials: S
authors.lastname: Kuçi
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000209:etiology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008875:Middle Aged; D011379:Prognosis; D012720:Severity of Illness Index; D013256:Steroids / Q000627:therapeutic use; D016019:Survival Analysis; D014019:Tissue Donors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D013256:Steroids