TY - JOUR
T1 - Adoptive Immunotherapy Against Allogeneic Kidney Grafts in Dogs with Stable Hematopoietic Trichimerism
AU - Graves, Scott S.
AU - Hogan, William J.
AU - Kuhr, Christian
AU - Diaconescu, Razvan
AU - Harkey, Michael
AU - Sale, George E.
AU - Stone, Brad
AU - Georges, George E.
AU - Storb, Rainer
N1 - Funding Information:
Financial disclosure: This work was supported by National Institutes of Health grants CA78902, CA15704, and DK56465-P30 (Core Center of Excellence in Hematology). The laboratory also was supported by an award from the Joseph Steiner Krebsstifung, Bern, Switzerland and a grant from the Lupin Foundation, Metairie, Louisiana (to R.S.).
PY - 2008/11
Y1 - 2008/11
N2 - Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney-an organ ordinarily not involved in graft-versus-host reactions-can be targeted by sensitized donor lymphocytes.
AB - Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney-an organ ordinarily not involved in graft-versus-host reactions-can be targeted by sensitized donor lymphocytes.
KW - Canine
KW - Graft-versus-host disease
KW - Kidney transplantation
KW - Marrow transplantation
KW - Multiple donors
KW - Nonmyeloablative
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U2 - 10.1016/j.bbmt.2008.08.005
DO - 10.1016/j.bbmt.2008.08.005
M3 - Article
C2 - 18940673
AN - SCOPUS:53749094562
SN - 1083-8791
VL - 14
SP - 1201
EP - 1208
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 11
ER -