title: Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation.
abstract: Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2(Tg) ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2(-/-) mice. Immune characterization showed fgl2(Tg) T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2(Tg) Tregs had increased immunosuppressive activity compared with fgl2(+/+) Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2(Tg) recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2(Tg) recipients without any immunosuppression. Tolerant fgl2(Tg) grafts had increased numbers and proportions of Tregs and tolerant fgl2(Tg) mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2(Tg) recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg-to-T cell ratio and acceptance of fully mismatched allografts.
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Institute of Medial Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Bartczak
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Chruscinski
authors.affiliation: Mesoblast, New York, NY.
authors.forename: M
authors.initials: M
authors.lastname: Mendicino
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of General Surgery and Organ Transplantation, First Hospital, China Medical University, Shen Yang, Liao Ning, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: He
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.|The GI, Hepatology and Nutrition Division, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Amir
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Khattar
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Sadozai
authors.affiliation: Cancer Research Division, Sunnybrook Health Science Centre and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: C G
authors.initials: CG
authors.lastname: Lobe
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Adeyi
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Phillips
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Gorczynski
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: D
authors.identifier: 0000-0003-4468-8276
authors.initials: D
authors.lastname: Grant
authors.affiliation: Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G A
authors.initials: GA
authors.lastname: Levy
mesh_terms: D000818:Animals; D005340:Fibrinogen / Q000502:physiology*; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C490637:Fgl2 protein, mouse; D005340:Fibrinogen