title: Long-term prevention of chronic allograft rejection by regulatory T-cell immunotherapy involves host Foxp3-expressing T cells.
abstract: Despite the use of immunosuppressive drugs, chronic allograft rejection remains a major hurdle in transplantation medicine. Induction of specific immunologic tolerance to antigens expressed by the graft would avoid its eventual functional loss and the severe side effects of paralyzing the immune system. We previously showed that donor-specific regulatory T-lymphocytes prevent rejection of fully allogeneic bone marrow (BM) grafts in mice. Thus generated hematopoietic chimeras then accepted skin and heart allografts of the same donor. We noticed that injected regulatory T-cells (Tregs) disappeared with time and investigated the mechanisms involved in the nevertheless long-term persistence of allograft tolerance. Using Tregs that can be depleted in vivo with diphtheria toxin, we show that injected cells are required for induction but not for maintenance of tolerance to BM allografts. We observed progressive deletion of donor-specific T-lymphocytes, accounting at least in part for maintenance of tolerance. Toxin-induced depletion of administered as well as host Tregs did not affect hematopoietic chimerism but it led to rapid loss of skin allografts. Therefore, our data show that newly generated host Tregs can prevent chronic allograft rejection. Long-lasting tolerance to allografts is thus achieved.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1043, Toulouse, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Pasquet
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douet
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnoli
authors.forename: Joost P M
authors.initials: JP
authors.lastname: van Meerwijk
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013995:Time; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse