title: Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin.
abstract: Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4+cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4+FoxP3+Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4+Foxp3+porcine Tregs in vivo. We observed depletion of up to 70-85% of the CCR4+Foxp3+porcine Tregs in the peripheral blood and 85-91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4-cell populations including CD8α+T cells, CCR4-CD4+T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4+Foxp3+porcine Tregs in both peripheral blood and lymph nodes.
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Nalu
authors.initials: N
authors.lastname: Navarro-Alvarez
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jigesh A
authors.initials: JA
authors.lastname: Shah
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; TBRC Laboratories, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: cahuang@mgh.harvard.edu.
authors.forename: Christene A
authors.initials: CA
authors.lastname: Huang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: zwang7@mgh.harvard.edu.
authors.forename: Zhirui
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D003429:Cross Reactions; D004167:Diphtheria Toxin / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods / Q000662:veterinary*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C515354:CCR4 protein, human; D004167:Diphtheria Toxin; D000922:Immunotoxins; D054398:Receptors, CCR4
keywords: CCR4; Diphtheria toxin; Immunotoxin; MGH miniature swine; Porcine Treg