In utero transplantation of hematopoietic stem cells in sheep: the role of T cells in engraftment and graft-versus-host disease.
Transplantation of hematopoietic stem cells (HSC) from adult sheep into fetal lambs results in hematopoietic chimerism and graft-versus-host disease (GVHD). To evaluate the role of T cells in HSC engraftment and GVHD we depleted adult marrow HSC of T cells and observed the incidence of chimerism and GVHD in the fetal recipients. Using a naturally occurring polymorphism of the beta-globin locus to detect engraftment, bone marrow obtained from homozygous type A hemoglobin adult sheep were transplanted (2 x 10(9) cells/kg fetal weight) into 90 days' gestation fetal lambs homozygous for type B hemoglobin. Donor HSC were T-cell depleted by treatment with antisera (raised in rabbits against sheep thymocytes) in the presence of complement. T-cell depletion resulted in significant decrease in hematopoietic colony formation by donor HSC in vitro (305 +/- 49 v 134 +/- 21 colonies/10(5) cells) that normalized by the addition of autologous T cells (433 +/- 32 colonies/10(5) cells). Marrow depleted of T cells exhibited reduced engraftment in the recipient fetuses. When T cells were added back to donor HSC (depleted of T cells) at near-normal concentrations, engraftment improved but the lambs also developed GVHD. The addition of T cells to donor HSC (depleted of T cells) at concentrations below that present in unprocessed bone marrow resulted in significant engraftment but not GVHD. T cells play an important role in both the engraftment of adult HSC in fetal recipients and the development of GVHD in chimeric newborns. The elimination of T cells prevents GVHD but markedly reduces engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)
Crombleholme
T M
TM
Department of Surgery, University of California, San Francisco.
Harrison
M R
MR
Zanjani
E D
ED
D000818:Animals; D000911:Antibodies, Monoclonal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D011247:Pregnancy; D012756:Sheep; D013601:T-Lymphocytes / Q000276:immunology*; D014180:Transplantation / Q000379:methods; D014599:Uterus
D000911:Antibodies, Monoclonal