title: Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice.
abstract: Islet cell transplantation as a therapy for type 1 diabetes has been limited by progressive graft loss. Significant immunosuppression including T-cell ablation has been used in an attempt to limit islet rejection. Here, we show that CD3(+) lymphocytes depleted of alloreactive T cells selected from a mixed lymphocyte reaction (MLR), where responder BALB/c splenocytes stained with carboxyfluorescein succinimidyl ester (CFSE) were stimulated with irradiated C57BL/6 splenocytes for 5 days, infused into diabetic immunodeficient mice are capable of restoring a broad T-cell repertoire and specifically do not reject islet transplants from the strain (C57BL/6) used in the original depletion. These mice demonstrate reconstitution with CD4(+) and CD8(+) T cells, the capacity to reject third-party grafts (CBA), and restoration of interferon-γ (IFN-γ) responses to third-party alloantigens. Over time, both forkhead box P3-positive (Foxp3(+)) T regulatory cells (Tregs) and γδ T cells expand, suggesting a role for peripheral tolerance, in addition to the initial depletion of alloreactive T cells, in long-term islet graft survival. Our results suggest that immune restoration with CD3(+) lymphocytes where alloreactive T cells are removed can restore cognate immunity without islet allograft loss and recurrence of diabetes.
authors.affiliation: Centre for Kidney Research, the Children's Hospital at Westmead, the University of Sydney, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: G Y
authors.initials: GY
authors.lastname: Zhang
authors.forename: Y M
authors.initials: YM
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Watson
authors.forename: S
authors.initials: S
authors.lastname: Yi
authors.forename: W J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: S I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007371:Interferon-gamma