Inhibition of cathepsin S reduces allogeneic T cell priming but not graft-versus-host disease against minor histocompatibility antigens.
Biol Blood Marrow Transplant
; 18(4): 546-56, 2012 Apr.
Article
em En
| MEDLINE
| ID: mdl-22178962
ABSTRACT
Cathepsin (Cathepsin) S, L, and B proteases mediate antigen presentation on major histocompatibility complex (MHC) class II by degrading the invariant chain Ii, which blocks peptide loading. The ability of the Cathepsin S inhibitor LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone phenyl) to impede antigen presentation has led its development as a therapy for autoimmune diseases. There is substantial evidence that donor T cell recognition of host minor histocompatibility antigens (miHA) and subsequent destruction of host tissue mediates graft-versus-host disease (GVHD). We hypothesized that enzymes involved in antigen presentation may play a role in the development of GVHD. Using the C57BL/6 â BALB.B minor mismatch acute GVHD (aGVHD) model, we found that the cathepsin S activity of spleens from allogenetically transplanted mice were significantly increased 1 week after transplantation compared with syngeneic mice. Although LHVS decreased T cell priming responses against both single OVA antigen and miHA in vitro, LHVS did not reduce the severity of aGVHD. In fact, LHVS exacerbated a CD4(+)-T cell-dependent model of GVHD similar to chronic GVHD. This suggests that cytokines rather than T cells may mediate much of the damage in the aGVHD model and that therapeutics based on inhibition of antigen presentation for GVHD must be approached with caution.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonas
/
Linfócitos T CD4-Positivos
/
Catepsinas
/
Transplante de Medula Óssea
/
Apresentação de Antígeno
/
Dipeptídeos
/
Doença Enxerto-Hospedeiro
Limite:
Animals
Idioma:
En
Revista:
Biol Blood Marrow Transplant
Assunto da revista:
HEMATOLOGIA
/
TRANSPLANTE
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Canadá