title: Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells.
abstract: Previous work has demonstrated that both rapamycin (RAPA) and IL-2 enhance CD4⁺CD25⁺Foxp3⁺ regulatory T-cell (Treg) proliferation and function in vitro. We investigated whether the combination of RAPA plus IL-2 could impact acute GVHD induction after bone marrow transplantation (BMT). RAPA plus IL-2 resulted in improved survival and a reduction in acute GVHD lethality associated with an increased expansion of donor type CD4⁺Foxp3⁺ Tregs and reduced CD4⁺CD25⁻ conventional T cells (Tcons). RAPA plus IL-2, but not either drug alone, increased both expansion of donor natural Tregs and conversion of induced Tregs from donor CD25⁻ Tcons while IL-2 alone increased conversion of Tregs from CD25⁻ Tcon. RAPA plus IL-2 treatment resulted in less production of IFN-γ and TNF, cytokines known to be important in the initiation of acute GVHD. These studies indicate that the pharmacologic stimulation of T cells with IL-2 and the suppression of Tcon proliferation with RAPA result in a selective expansion of functional Tregs and suppression of acute GVHD.
authors: Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Medical Research Institute, Pusan National University Hospital, Busan, Korea.
authors: Ho-Jin
authors: HJ
authors: Shin
authors: Jeanette
authors: J
authors: Baker
authors: Dennis B
authors: DB
authors: Leveson-Gower
authors: Aaron T
authors: AT
authors: Smith
authors: Emanuela I
authors: EI
authors: Sega
authors: Robert S
authors: RS
authors: Negrin
mesh_terms: D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000187:drug effects* / Q000276:immunology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020123:Sirolimus