Trafficking of APC from liver allografts of Flt3L-treated donors: augmentation of potent allostimulatory cells in recipient lymphoid tissue is associated with a switch from tolerance to rejection.
Livers transplanted across major histocompatibility complex (MHC) barriers in mice are normally accepted without recipient immune suppression, and induce a state of functional tolerance. However, markedly increasing functional dendritic cells (DC) in the 'passenger leucocyte' population by donor pretreatment with the hematopoietic growth factor Flt3-ligand (Flt3L; 10 microg/day for 10 days) results in acute allograft rejection. In this study, molecular, immunohistochemical and flow cytometric analysis of donor cell traffick into recipient lymphoid tissue 24 h after liver transplantation (C57BL/10 [H2b]-->C3H [H2k]) was performed. In addition, the capacity of donor-derived cells in these tissues to stimulate host T cell proliferation was examined. Reverse transcriptase polymerase chain reaction analysis revealed increases in donor genomic DNA in both thymi and spleens of mice given livers from Flt3L-treated donors compared to controls. Donor MHC class II+ (IAb+) cells in spleens were strikingly elevated (10-fold) in the former group. Two-colour flow cytometry revealed a similar increase in donor-derived H-2Kb+/I-Ab+ cells, and in the incidence of donor leucocytes expressing CD40, CD80, and CD86. CD11c+ DC comprised approximately 40% of the I-Ab+ cells in spleens of mice given livers from Flt3L-treated donors. These changes were associated with the presence, in spleens, of potent allostimulatory activity for naive recipient strain T cells, that was not observed in normal liver recipients. Elicitation of allograft rejection, associated with enhanced trafficking of stimulatory donor antigen-presenting cells (APC), in particular DC, suggests that normal liver graft survival and tolerance induction may be linked to failure/counter-regulation of APC-driven stimulation of effective anti-donor T cell responses.
Steptoe
R J
RJ
Thomas E Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pennsylvania, USA.
Li
W
W
Fu
F
F
O'Connell
P J
PJ
Thomson
A W
AW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D006084:Graft Rejection / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008099:Liver / Q000166:cytology; D016031:Liver Transplantation / Q000276:immunology*; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C084881:flt3 ligand protein