Granzyme B Inhibition by Tofacitinib Blocks the Pathology Induced by CD8 T Cells in Cutaneous Leishmaniasis.
J Invest Dermatol
; 141(3): 575-585, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-32738245
ABSTRACT
In cutaneous leishmaniasis, the immune response is not only protective but also mediates immunopathology. We previously found that cytolytic CD8 T cells promote inflammatory responses that are difficult to treat with conventional therapies that target the parasite. Therefore, we hypothesized that inhibiting CD8 T-cell cytotoxicity would reduce disease severity in patients. IL-15 is a potential target for such a treatment because it is highly expressed in human patients with cutaneous leishmaniasis lesions and promotes granzyme Bâdependent CD8 T-cell cytotoxicity. Here we tested whether tofacitinib, which inhibits IL-15 signaling by blocking Jak3, might decrease CD8-dependent pathology. We found that tofacitinib reduced the expression of granzyme B by CD8 T cells in vitro and in vivo systemic and topical treatment, with tofacitinib protecting mice from developing severe cutaneous leishmaniasis lesions. Importantly, tofacitinib treatment did not alter T helper type 1 responses or parasite control. Collectively, our results suggest that host-directed therapies do not need to be limited to autoimmune disorders and that topical tofacitinib application should be considered a strategy for the treatment of cutaneous leishmaniasis disease in combination with antiparasitic drugs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Pirimidinas
/
Linfocitos T Citotóxicos
/
Leishmaniasis Cutánea
/
Granzimas
/
Antiparasitarios
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Invest Dermatol
Año:
2021
Tipo del documento:
Article