title: Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients.
abstract: The ability of regulatory T cells (Treg) to prolong allograft survival and promote transplant tolerance in lymphodepleted rodents is well established. Few studies, however, have addressed the therapeutic potential of adoptively transferred, CD4(+) CD25(+) CD127(-) Foxp3(+) (Treg) in clinically relevant large animal models. We infused ex vivo-expanded, functionally stable, nonselected Treg (up to a maximum cumulative dose of 1.87 billion cells) into antithymocyte globulin-lymphodepleted, MHC-mismatched cynomolgus monkey heart graft recipients before homeostatic recovery of effector T cells. The monkeys also received tacrolimus, anti-interleukin-6 receptor monoclonal antibodies and tapered rapamycin maintenance therapy. Treg administration in single or multiple doses during the early postsurgical period (up to 1 month posttransplantation), when host T cells were profoundly depleted, resulted in inferior graft function compared with controls. This was accompanied by increased incidences of effector memory T cells, enhanced interferon-γ production by host CD8(+) T cells, elevated levels of proinflammatory cytokines, and antidonor alloantibodies. The findings caution against infusion of Treg during the early posttransplantation period after lymphodepletion. Despite marked but transient increases in Treg relative to endogenous effector T cells and use of reputed "Treg-friendly" agents, the host environment/immune effector mechanisms instigated under these conditions can perturb rather than favor the potential therapeutic efficacy of adoptively transferred Treg.
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M B
authors.initials: MB
authors.lastname: Ezzelarab
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI.
authors.forename: R W
authors.initials: RW
authors.lastname: Wiseman
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M A
authors.initials: MA
authors.lastname: Nalesnik
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: J K
authors.initials: JK
authors.lastname: Bhama
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: D K C
authors.initials: DK
authors.lastname: Cooper
authors.affiliation: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D016027:Heart Transplantation; D007156:Immunologic Memory / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology*; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D007518:Isoantibodies
keywords: T cell biology; animal models: nonhuman primate; basic (laboratory) research/science; heart transplantation/cardiology; immune regulation; immunobiology; lymphocyte biology; translational research/science