title: CTLA4-Ig preserves thymus-derived T regulatory cells.
abstract: BACKGROUND
  CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway and are used in clinical trials for diseases featuring exaggerated T-cell reactivity including autoimmune diseases and allograft rejection. However, because CTLA4-Ig has been suspected to interfere with T regulatory (Treg) cell homeostasis and function, recently, substantial concerns on CTLA4-Ig's potentially antitolerogenic effects have been raised.
  
  
  METHODS
  We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers, frequencies and function in an in vitro murine major histocompatibility complex mismatched setting using C57BL/6 bone marrow-derived dendritic cells as stimulators of allogeneic Balb/c Foxp3 T cells, which allowed for tracing Treg cells in a straightforward fashion.
  
  
  RESULTS
  The presence of CTLA4-Ig in mixed leukocyte reactions-while dampening the global proliferative response of allostimulated Balb/c T cells-resulted in a relative increase of the frequency of thymus-derived CD4CD25Foxp3 Treg cells with intact suppressive activity. This relative increase was caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas the proliferative capacity of Treg cells in cell cultures remained unaffected. Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in these cells.
  
  
  CONCLUSIONS
  Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencies and function in vitro.
authors.affiliation: 1 Division Transplantation Immunology, Children's Cancer Research Institute, Vienna, Austria. 2 Division of Transplantation, Department of Surgery, Medical University Vienna, Austria. 3 Address correspondence to: Sarah Ahmadi, M.Sc., Children's Cancer Research Institute, Zimmermannplatz 10, A-1090 Vienna, Austria.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ahmadi
authors.forename: Markus A
authors.initials: MA
authors.lastname: Hölzl
authors.forename: Edda
authors.initials: E
authors.lastname: Mayer
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.forename: Andreas
authors.initials: A
authors.lastname: Heitger
mesh_terms: D000069594:Abatacept; D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D018796:Immunoconjugates / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D053645:Interleukin-2 Receptor alpha Subunit; D000069594:Abatacept