title: Indefinite mouse heart allograft survival in recipient treated with CD4(+)CD25(+) regulatory T cells with indirect allospecificity and short term immunosuppression.
abstract: CD4(+)CD25(+) regulatory T cells (Tregs) play a crucial role in controlling immune responses. It is an appealing strategy to harness Tregs for adoptive cell therapy to induce tolerance to allografts. Several approaches have been developed to expand antigen-specific Tregs. Despite the large body of experimental data from murine studies demonstrating the great potential of these cells for clinical application, Treg adoptive transfer therapy was used in immunodeficient animals or in strain combinations with limited histiocompatibility. The aim of this study was to investigate whether Treg lines can protect from allograft rejection in a fully MHC-mismatched strain combination and whether the presence of Tregs with indirect allospecificity offered an advantage compared to self-reactive Tregs. Treg lines with self-specificity or with indirect allospecificity were generated by stimulating BL/6 CD4(+)CD25(+) T cells with autologous immature DCs either unpulsed or pulsed with K(d) peptide. The Treg lines were injected into recipient mice in combination with temporary depletion of CD8(+) T cells and a short course of Rapamycin. The data demonstrate that Treg lines with indirect allospecificity can be generated and most importantly they can induce indefinite survival of BALB/c hearts transplanted into BL/6 recipients when combined with short term immunosuppression. However, the Treg lines with self-specificity were only slightly less effective. The data presented in this study demonstrate the potential of ex vivo expanded Treg lines for adoptive cell therapy to promote transplantation tolerance.
authors.affiliation: MRC Centre of Transplantation, King's College London, Guy's Campus, London, UK.
authors.forename: Julia Yuen-Shan
authors.initials: JY
authors.lastname: Tsang
authors.forename: Yakup
authors.initials: Y
authors.lastname: Tanriver
authors.forename: Shuiping
authors.initials: S
authors.lastname: Jiang
authors.forename: Eva
authors.initials: E
authors.lastname: Leung
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
authors.forename: Robert
authors.initials: R
authors.lastname: Lechler
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015704:CD4 Antigens / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D006085:Graft Survival / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology* / Q000378:metabolism; D016027:Heart Transplantation; D064532:Histocompatibility Antigen H-2D; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation
chemical_list: D015704:CD4 Antigens; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments