title: Skin allograft maintenance in a new synchimeric model system of tolerance.
abstract: Treatment of mice with a single donor-specific transfusion plus a brief course of anti-CD154 mAb uniformly induces donor-specific transplantation tolerance characterized by the deletion of alloreactive CD8+ T cells. Survival of islet allografts in treated mice is permanent, but skin grafts eventually fail unless recipients are thymectomized. To analyze the mechanisms underlying tolerance induction, maintenance, and failure in euthymic mice we created a new analytical system based on allo-TCR-transgenic hemopoietic chimeric graft recipients. Chimeras were CBA (H-2(k)) mice engrafted with small numbers of syngeneic TCR-transgenic KB5 bone marrow cells. These mice subsequently circulated a self-renewing trace population of anti-H-2(b)-alloreactive CD8+ T cells maturing in a normal microenvironment. With this system, we studied the maintenance of H-2(b) allografts in tolerized mice. We documented that alloreactive CD8+ T cells deleted during tolerance induction slowly returned toward pretreatment levels. Skin allograft rejection in this system occurred in the context of 1) increasing numbers of alloreactive CD8+ cells; 2) a decline in anti-CD154 mAb concentration to levels too low to inhibit costimulatory functions; and 3) activation of the alloreactive CD8+ T cells during graft rejection following deliberate depletion of regulatory CD4+ T cells. Rejection of healed-in allografts in tolerized mice appears to be a dynamic process dependent on the level of residual costimulation blockade, CD4+ regulatory cells, and activated alloreactive CD8+ thymic emigrants that have repopulated the periphery after tolerization.
authors.affiliation: Program in Immunology and Virology, and Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: N N
authors.initials: NN
authors.lastname: Iwakoshi
authors.forename: T G
authors.initials: TG
authors.lastname: Markees
authors.forename: N
authors.initials: N
authors.lastname: Turgeon
authors.forename: T
authors.initials: T
authors.lastname: Thornley
authors.forename: A
authors.initials: A
authors.lastname: Cuthbert
authors.forename: J
authors.initials: J
authors.lastname: Leif
authors.forename: N E
authors.initials: NE
authors.lastname: Phillips
authors.forename: J P
authors.initials: JP
authors.lastname: Mordes
authors.forename: D L
authors.initials: DL
authors.lastname: Greiner
authors.forename: A A
authors.initials: AA
authors.lastname: Rossini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood; D001803:Blood Transfusion; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002999:Clone Cells; D006224:Cricetinae; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA / Q000235:genetics* / Q000276:immunology*; D008822:Mice, Transgenic; D018448:Models, Immunological; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D023201:CD40 Ligand