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1.
J Infect Dis ; 216(6): 678-687, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28934427

RESUMO

Human metapneumovirus (hMPV) is a respiratory virus detected in ≥9% of allogeneic hematopoietic stem cell transplant (HSCT) recipients, in whom it can cause significant morbidity and mortality. Given the lack of effective antivirals, we investigated the potential for immunotherapeutic intervention, using adoptively transferred T cells. Thus, we characterized the cellular immune response to the virus and identified F, N, M2-1, M, and P as immunodominant target antigens. Reactive T cells were polyclonal (ie, they expressed CD4 and CD8), T-helper type 1 polarized, and polyfunctional (ie, they produced interferon γ, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, and granzyme B), and they were able to kill autologous antigen-loaded targets. The detection of hMPV-specific T cells in HSCT recipients who endogenously controlled active infections support the clinical importance of T-cell immunity in mediating protective antiviral effects. Our results demonstrate the feasibility of developing an immunotherapy for immunocompromised patients with uncontrolled infections.


Assuntos
Imunoterapia Adotiva , Metapneumovirus/imunologia , Infecções por Paramyxoviridae/terapia , Adulto , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Granzimas/imunologia , Humanos , Imunidade Celular , Hospedeiro Imunocomprometido/imunologia , Epitopos Imunodominantes/imunologia , Interferon gama/imunologia , Leucócitos Mononucleares/virologia , Masculino , Metapneumovirus/isolamento & purificação , Pessoa de Meia-Idade , Infecções por Paramyxoviridae/imunologia , Linfócitos T/virologia , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
2.
J Infect Dis ; 216(2): 153-161, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28472480

RESUMO

Parainfluenza virus type 3 (PIV3) infections are a major cause of morbidity and mortality in immunocompromised individuals, with no approved therapies. Our group has demonstrated the safety and efficacy of adoptively transferred virus-specific T cells for the prevention and treatment of a broad range of viral infections including BK virus, cytomegalovirus, adenovirus, human herpesvirus 6, and Epstein-Barr virus. However, this approach is restricted to well-characterized viruses with known immunogenic/protective T-cell target antigens, precluding extension to PIV3. We now characterize the cellular immune response to all 7 PIV3-encoded antigens in 17 healthy donors and define a hierarchy of immunogenicity based on the frequency of responding donors and the magnitude of specific cells. We show that reactive populations of both CD4+ and CD8+ T cells are capable of producing Th1-polarized effector cytokines and killing PIV3-expressing targets. Furthermore, we confirm the clinical relevance of these cells by demonstrating a direct correlation between the presence of PIV3-specific T cells and viral control in allogeneic hematopoietic stem cell transplant recipients. Taken together, our findings support the clinical use of PIV3-specific T cells produced with our Good Manufacturing Practice-compliant manufacturing process, in immunocompromised patients with uncontrolled infections.


Assuntos
Antígenos Virais/imunologia , Imunidade Celular , Leucócitos Mononucleares/virologia , Vírus da Parainfluenza 3 Humana , Infecções por Respirovirus/imunologia , Linfócitos T/imunologia , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Imunoterapia , Lactente , Masculino , Pessoa de Meia-Idade
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