title: Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.
abstract: Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Henry
authors.initials: H
authors.lastname: Barreras
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Bader
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Copsel
authors.affiliation: Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Casey O
authors.initials: CO
authors.lastname: Lightbourn
authors.affiliation: Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Pfeiffer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Altman
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida; Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida. Electronic address: rlevy@med.miami.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Levy
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007136:Immunoglobulins / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000637:transplantation*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology
chemical_list: D007136:Immunoglobulins; D007376:Interleukin-2; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
keywords: Graft-versus-host disease (GVHD); Hematopoietic stem cell transplantation (HSCT); Interleukin-2 (IL-2); T regulatory cells (Treg); Tumor necrosis factor receptor superfamily 25 (TNFRSF25)