title: Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.
abstract: Aspergillus and cytomegalovirus are major causes of morbidity/mortality after haploidentical hematopoietic transplantation. The high degree of mismatching makes cell immunotherapy impossible as it would result in lethal graft-versus-host disease (GvHD). We generated large numbers of donor T-cell clones specific for Aspergillus or cytomegalovirus antigens. We identified clones potentially responsible for causing GvHD by screening them for cross-reactivity against recipient mononuclear cells. Non-recipient reactive, pathogen-specific clones were infused soon after transplantation. They were CD4+ and produced high levels of interferon-gamma and low levels of interleukin-10. In 46 control transplant recipients who did not receive adoptive therapy, spontaneous pathogen-specific T cells occurred in low frequency 9 to 12 months after transplantation and displayed a non-protective low interferon-gamma/high interleukin-10 production phenotype. In the 35 recipients who received adoptive therapy, one single infusion of donor alloantigen-deleted, pathogen-specific clones in the dose range of 10(5) to 10(6) cells/kg body weight did not cause GvHD and induced high-frequency T-cell responses to pathogens, which exhibited a protective high interferon-gamma/low interleukin-10 production phenotype within 3 weeks of infusion. Frequencies of pathogen-specific T cells remained stable over time, and were associated with control of Aspergillus and cytomegalovirus antigenemia and infectious mortality. This study opens new perspectives for reducing infectious mortality after haploidentical transplantations.
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Policlinico Monteluce, Via Brunamonti 51-06122 Perugia, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Perruccio
authors.forename: Antonella
authors.initials: A
authors.lastname: Tosti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Burchielli
authors.forename: Fabiana
authors.initials: F
authors.lastname: Topini
authors.forename: Loredana
authors.initials: L
authors.lastname: Ruggeri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carotti
authors.forename: Marusca
authors.initials: M
authors.lastname: Capanni
authors.forename: Elena
authors.initials: E
authors.lastname: Urbani
authors.forename: Antonella
authors.initials: A
authors.lastname: Mancusi
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
mesh_terms: D000293:Adolescent; D000328:Adult; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D001230:Aspergillus / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology; D006238:Haploidy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive; D007519:Isoantigens / Q000276:immunology; D007938:Leukemia / Q000276:immunology* / Q000601:surgery*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D016896:Treatment Outcome
chemical_list: D007519:Isoantigens