title: Inducible costimulator (ICOS) up-regulation on activated T cells in chronic graft-versus-host disease after dog leukocyte antigen-nonidentical hematopoietic cell transplantation: a potential therapeutic target.
abstract: BACKGROUND
  Inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4 and CD8 T cells after their activation. ICOS functions as an essential immune regulator and ICOS blockade is a potential approach to immune modulation in allogeneic transplantation. Here, we describe the expression profile of ICOS in dogs and determine whether ICOS expression is up-regulated during chronic graft-versus-host disease (GVHD) and host-versus-graft reactions in the canine hematopoietic cell transplantation model.
  
  
  METHODS
  Monoclonal antibodies (mAbs) against cell surface-expressed ICOS were produced and tested in vitro for suppression of canine mixed leukocyte reactions (MLR). Expression of ICOS on CD3 cells was evaluated by flow cytometry using peripheral blood, lymph nodes, and splenocytes obtained from dogs undergoing graft-versus-host and host-versus-graft reactions.
  
  
  RESULTS
  Canine ICOS was expressed in an inducible pattern on T cells activated by concanavalin A, anti-CD3 mAb in combination with anti-CD28 mAb, and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in MLR using peripheral blood mononuclear cells from dog leukocyte antigen-nonidentical dogs. Immunosuppressive effects of ICOS blockade were observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig or cyclosporine. ICOS expression was significantly up-regulated on T cells in dogs undergoing graft rejection or chronic GVHD after allogeneic hematopoietic cell transplantation.
  
  
  CONCLUSIONS
  These studies suggest that ICOS plays a role in graft rejection and GVHD in an outbred animal model, and ICOS blockade may be an approach to prevention and treatment of chronic GVHD.
authors.affiliation: Transplantation Biology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.forename: Carol
authors.initials: C
authors.lastname: Loretz
authors.forename: Diane
authors.initials: D
authors.lastname: Stone
authors.forename: Marco
authors.initials: M
authors.lastname: Mielcarek
authors.forename: George E
authors.initials: GE
authors.lastname: Sale
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Rezvani
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004285:Dogs; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D060889:Inducible T-Cell Co-Stimulator Protein; D007519:Isoantigens