title: Impact of Human Mutant TGFβ1/Fc Protein on Memory and Regulatory T Cell Homeostasis Following Lymphodepletion in Nonhuman Primates.
abstract: Transforming growth factor β1 (TGFβ1) plays a key role in T cell homeostasis and peripheral tolerance. We evaluated the influence of a novel human mutant TGFβ1/Fc (human IgG4 Fc) fusion protein on memory CD4+and CD8+T cell (Tmem) responses in vitro and their recovery following antithymocyte globulin (ATG)-mediated lymphodepletion in monkeys. TGFβ1/Fc induced Smad2/3 protein phosphorylation in rhesus and human peripheral blood mononuclear cells and augmented the suppressive effect of rapamycin on rhesus Tmem proliferation after either alloactivation or anti-CD3/CD28 stimulation. In combination with IL-2, the incidence of CD4+CD25hiFoxp3hiregulatory T cells (Treg) and Treg:Th17 ratios were increased. In lymphodepleted monkeys, whole blood trough levels of infused TGFβ1/Fc were maintained between 2 and 7 μg/mL for 35 days. Following ATG administration, total T cell numbers were reduced markedly. In those given TGFβ1/Fc infusion, CD8+T cell recovery to predepletion levels was delayed compared to controls. Additionally, numbers of CD4+CD25hiCD127loTreg increased at 4-6 weeks after depletion but subsequently declined to predepletion levels by 12 weeks. In all monkeys, CD4+CD25hiFoxp3hiTreg/CD4+IL-17+cell ratios were reduced, particularly after stopping TGFβ1/Fc infusion. Thus, human TGFβ1/Fc infusion may delay Tmem recovery following lymphodepletion in nonhuman primates. Combined (low-dose) IL-2 infusion may be required to improve the Treg:Th17 ratio following lymphodepletion.
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A
authors.initials: A
authors.lastname: Perez-Gutierrez
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: H S
authors.initials: HS
authors.lastname: Abdulkerim
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: T L
authors.initials: TL
authors.lastname: Sumpter
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: K A
authors.initials: KA
authors.lastname: Reimann
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, 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
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M B
authors.initials: MB
authors.lastname: Ezzelarab
mesh_terms: D000818:Animals; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008212:Lymphocyte Depletion / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D011961:Receptors, Fc; D053773:Transforming Growth Factor beta1
keywords: T cell biology; animal models: nonhuman primate; basic (laboratory) research/science; fusion proteins and monoclonal antibodies; immune regulation; immunobiology; immunosuppressant; immunosuppression/immune modulation; tolerance