title: Increasing donor chimerism and inducing tolerance to islet allografts by post-transplant donor lymphocyte infusion.
abstract: Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.
authors.affiliation: Department of Surgery, Diabetes Institute for Immunology and Transplantation, University of Minnesota, Minneapolis, MN, USA, and Department of Surgery, Second Affiliated Hospital, China Medical University, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Hao
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Pan
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.forename: Britt
authors.initials: B
authors.lastname: Westgard
authors.forename: Yves
authors.initials: Y
authors.lastname: Heremans
authors.forename: David E R
authors.initials: DE
authors.lastname: Sutherland
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Guo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000601:surgery; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011236:Prediabetic State; D018183:Transplantation Chimera; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D001786:Blood Glucose