title: Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation.
abstract: Experimental studies have shown that rabbit antithymocyte polyclonal globulin (ATG) can expand human CD4+CD25++Foxp3+ cells (Tregs). We investigated the major biological effects of a self-manufactured rabbit polyclonal anti-rat thymoglobulin (rATG) in vitro, as well as its effects on different peripheral T-cell subsets. Moreover, we evaluated the allogeneic suppressive capacity of rATG-induced Tregs in an experimental rat renal transplant model. Our results show that rATG has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T-cell depletion. Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets, directly proportional to the rATG dose used, but not of the effector memory T cells, which required significantly higher rATG doses. After rATG administration, we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats, leading to an increase in the Treg/T effector ratio. Importantly, rATG-induced Tregs displayed a strong donor-specific suppressive capacity when assessed in an antigen-specific allogeneic co-culture. All of these results were associated with better renal graft function in rats that received rATG. Our study shows that rATG has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post-transplant homeostatic proliferation.
authors.affiliation: Laboratory of Experimental Nephrology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Nephrology Department, Hospital General de México, Mexico City, México; Renal Transplant Unit, Department of Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdez-Ortiz
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Inés
authors.initials: I
authors.lastname: Llaudó
authors.forename: Marcella
authors.initials: M
authors.lastname: Franquesa
authors.forename: Gema
authors.initials: G
authors.lastname: Cerezo
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
authors.forename: Ricardo
authors.initials: R
authors.lastname: Correa-Rotter
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000737:chemistry*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002469:Cell Separation; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D010641:Phenotype; D011817:Rabbits; D051381:Rats; D051437:Renal Insufficiency / Q000601:surgery; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; C512542:thymoglobulin
keywords: Tregs; homeostatic proliferation; kidney transplantation; rabbit antithymocyte polyclonal globulin