Healthy Donors Exhibit a CD4 T Cell Repertoire Specific to the Immunogenic Human Hormone H2-Relaxin before Injection.
J Immunol
; 202(12): 3507-3513, 2019 06 15.
Article
en En
| MEDLINE
| ID: mdl-31101669
ABSTRACT
H2-relaxin (RLN2) is a two-chain peptide hormone structurally related to insulin with a therapeutic potential in multiple indications. However, multiple injections of human RLN2 induced anti-RLN2 Abs in patients, hampering its clinical development. As T cell activation is required to produce Abs, we wondered whether T cells specific for RLN2 might be already present in the human blood before any injection. We therefore quantified the RLN2-specific T cell repertoire using PBMCs collected from healthy donors. CD4 T cells were stimulated in multiple replicates by weekly rounds of stimulation by dendritic cells loaded with RLN2, and their specificity was assessed by IFN-γ ELISPOT. The number of specific T cell lines was used to estimate the frequency of circulating T cells. In vitro T cell response was demonstrated in 18 of the 23 healthy donors, leading to the generation of 70 independent RLN2-specific T cell lines. The mean frequency of RLN2-specific CD4 T cells was similar to that of T cells specific for known immunogenic therapeutic proteins. Using overlapping peptides, we identified multiple T cell epitopes hosted in the N-terminal parts of the α- and ß-chains and common to multiple donors, in agreement with their capacity to bind to multiple HLA-DR molecules. Our results provide important clues to the immunogenicity of RLN2 and highlight the weak central immune tolerance induced against this self-hormone.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Relaxina
/
Autoantígenos
/
Linfocitos T CD4-Positivos
/
Epítopos de Linfocito T
Límite:
Humans
Idioma:
En
Revista:
J Immunol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Francia