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PreprintDerechos de autor
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- BA - IGM - Preprint [85]
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PD-1 BLOCKADE EXACERBATES MYCOBACTERIUM TUBERCULOSIS INFECTION IN RHESUS MACAQUES
Autor
Kauffman, Keith D
Sakai, Shunsuke
Lora, Nickiana E
Namasivayam, Sivaranjani
Baker, Paul J
Kamenyeva, Olena
Foreman, Taylor W
Nelson, Christine E
Souza, Deivide Oliveira de
Vinhaes, Caian L.
Yaniv, Ziv
Arleham, Cecilia S Lindestam
Sette, Alessandro
Freeman, Gordon J
Moore, Rashida
the NIAID/DIR Tuberculosis Imaging Program
Sher, Alan
Barber, Katrin D Mayer
Andrade, Bruno de Bezerril
Kabat, Juraj
Via, Laura E
Barber, Daniel L
Sakai, Shunsuke
Lora, Nickiana E
Namasivayam, Sivaranjani
Baker, Paul J
Kamenyeva, Olena
Foreman, Taylor W
Nelson, Christine E
Souza, Deivide Oliveira de
Vinhaes, Caian L.
Yaniv, Ziv
Arleham, Cecilia S Lindestam
Sette, Alessandro
Freeman, Gordon J
Moore, Rashida
the NIAID/DIR Tuberculosis Imaging Program
Sher, Alan
Barber, Katrin D Mayer
Andrade, Bruno de Bezerril
Kabat, Juraj
Via, Laura E
Barber, Daniel L
Afiliación
"Múltipla ver em Notas"
Resumen en ingles
Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have
applications in the treatment of chronic infections. Here we examine the role of PD-1 during
Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with αPD-1
mAb developed worse disease and higher granuloma bacterial loads compared to isotype control
treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtbspecific
CD8 T cells. In contrast, Mtb-specific CD4 T cells in αPD-1 treated macaques were not
increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited
reduced intralesional trafficking in live imaging studies. In granulomas of αPD-1 treated animals,
multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial
loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after
PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to
associate with the composition of the intestinal microbiota prior to infection in individual
macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in
macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for
normal CD4 T cell responses
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