Increasing donor chimerism and inducing tolerance to islet allografts by post-transplant donor lymphocyte infusion.
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.
Liu
Baolin
B
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.
Hao
Jianqiang
J
Pan
Yisheng
Y
Luo
Bin
B
Westgard
Britt
B
Heremans
Yves
Y
Sutherland
David E R
DE
Hering
Bernhard J
BJ
Guo
Zhiguang
Z
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
D001786:Blood Glucose