title: Inhibition of cathepsin S reduces allogeneic T cell priming but not graft-versus-host disease against minor histocompatibility antigens.
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 → 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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Hisaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Ivison
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kajiwara
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.forename: Matthew
authors.initials: M
authors.lastname: Yan
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dutz
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000276:immunology; D004151:Dipeptides / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007274:Injections, Intraperitoneal; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013450:Sulfones / Q000008:administration & dosage*; D014184:Transplantation, Homologous
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; C532594:N-morpholinourea-leucine-homophenylalanine-phenyl-vinylsulfone; D013450:Sulfones; D002403:Cathepsins; C028217:cathepsin S