Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.
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.
Perruccio
Katia
K
Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Policlinico Monteluce, Via Brunamonti 51-06122 Perugia, Italy.
Tosti
Antonella
A
Burchielli
Emanuela
E
Topini
Fabiana
F
Ruggeri
Loredana
L
Carotti
Alessandra
A
Capanni
Marusca
M
Urbani
Elena
E
Mancusi
Antonella
A
Aversa
Franco
F
Martelli
Massimo F
MF
Romani
Luigina
L
Velardi
Andrea
A
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
D007519:Isoantigens