Prenatal tolerance induction: relationship between cell dose, marrow T-cells, chimerism, and tolerance.
It was reported that the dose of self-antigens can determine the consequence of deletional tolerance and donor T cells are critical for tolerance induction in mixed chimeras. This study aimed at assessing the effect of cell doses and marrow T cells on engraftment and tolerance induction after prenatal bone marrow transplantation. Intraperitoneal cell transplantation was performed in FVB/N (H-2K(q)) mice at gestational day 14 with escalating doses of adult C57BL/6 (H-2K(b)) marrows. Peripheral chimerism was examined postnatally by flow cytometry and tolerance was tested by skin transplantation. Transplantation of light-density marrow cells showed a dose response. High-level chimerism emerged with a threshold dose of 5.0 x 10(6) and host leukocytes could be nearly replaced at a dose of 7.5-10.0 x 10(6). High-dose transplants conferred a steady long-lasting donor-specific tolerance but were accompanied by >50% incidence of graft-versus-host disease. Depletion of marrow T cells lessened graft-versus-host disease to the detriment of engraftment. With low-level chimerism, tolerance was a graded phenomenon dependent upon the level of chimerism. Durable chimerism within 6 months required a threshold of > or = 2% chimerism at 1 month of age and predicted a 50% chance of long-term tolerance, whereas transient chimerism (<2%) only caused hyporesponsiveness to the donor. Tolerance induction did not succeed without peripheral chimerism even if a large amount of injected donor cells persisted in the peritoneum. Neither did an increase in cell doses or donor T-cell contents benefit skin graft survivals unless it had substantially improved peripheral chimerism. Thus, peripheral chimerism level can be a simple and straightforward test to predict the degree of prenatal immune tolerance.
Chen
Jeng-Chang
JC
Department of Surgery, Chang Gung Children's Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. bx9619@cgmh.org.tw
Chang
Ming-Ling
ML
Huang
Shiu-Feng
SF
Chang
Pei-Yeh
PY
Muench
Marcus O
MO
Fu
Ren-Huei
RH
Ou
Liang-Shiou
LS
Kuo
Ming-Ling
ML
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002452:Cell Count; D017637:Clonal Deletion; D005260:Female; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011237:Predictive Value of Tests; D011247:Pregnancy; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018183:Transplantation Chimera / Q000196:embryology / Q000276:immunology*; D019172:Transplantation Conditioning; D014181:Transplantation Immunology