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

• Published in: Transplant immunology 1999-03, Vol.7 (1), p.51-57
• Main Authors: Steptoe, Raymond J, Li, Wei, Fu, Fumin, O'Connell, Peta J, Thomson, Angus W
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigens, CD - immunology; B7-1 Antigen - immunology; B7-2 Antigen; CD40 Antigens - immunology; Cell Division; CHO Cells; Cricetinae; Graft Rejection - immunology; Histocompatibility Antigens Class II - immunology; Humans; Immune Tolerance - immunology; Liver - cytology; Liver Transplantation - immunology; Lymphoid Tissue - cytology; Lymphoid Tissue - immunology; Male; Membrane Glycoproteins - immunology; Membrane Proteins - administration & dosage; Membrane Proteins - immunology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Spleen - cytology; Spleen - immunology; T-Lymphocytes - cytology; Tissue Donors; Transplantation, Homologous
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/S0966-3274(99)80019-7

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 μg/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 [H2 b]→C3H [H2 k]) 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 + (IA b+) cells in spleens were strikingly elevated (10-fold) in the former group. Two-colour flow cytometry revealed a similar increase in donor-derived H2-K b+/I-A b+ cells, and in the incidence of donor leucocytes expressing CD40, CD80, and CD86. CD11c + DC comprised ∼40% of the I-A b+ 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.