title: Donor-specific tolerance in a murine model: the result of extra-thymic T cell deletion?
abstract: Previously, we established a murine model, that involves the engraftment of fully allogeneic T cell depleted donor bone marrow cells in sublethally irradiated and single dose anti-CD3 treated recipient mice. These mice developed permanent stable multilineage mixed chimerism and donor-specific tolerance without graft-versus-host disease. Recently, we have shown that donor-specific tolerance is not induced and/or maintained by clonal anergy, neither by a Th1/Th2 shift, nor by suppressor or other regulatory processes. In the present study, we investigated whether clonal deletion plays a role in tolerance induction in our model. We studied the kinetics of TCRVbeta8(+) T cells in BALB/c (H-2L(d+))-->dm2 (H-2L(d-)) chimeras, in which combination of mouse strains TCRVbeta8 predominates the anti-donor response. We found that TCRVbeta8(+) T cells were specifically deleted. To our surprise, this deletion was also found in mixed chimeras, thymectomized prior to the conditioning regimen. We conclude that clonal deletion plays a role in the establishment and maintenance of donor-specific tolerance, and that the thymus is not required for this process. In addition, confocal laser-scanning microscopy clearly showed the presence of abundant amounts of donor T cells and some donor antigen presenting cells in the small intestine in thymectomized chimeras and not in other organs, suggesting that T cell selection might take place in this organ in the absence of the thymus.
authors.affiliation: Laboratory for Vaccine Research, National Institute of Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: van Pel
authors.forename: Danielle W J G
authors.initials: DW
authors.lastname: van Breugel
authors.forename: Margot
authors.initials: M
authors.lastname: van Wijk
authors.forename: Sacco
authors.initials: S
authors.lastname: Luypen
authors.forename: Jose
authors.initials: J
authors.lastname: Vingerhoed
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Roholl
authors.forename: Claire J P
authors.initials: CJ
authors.lastname: Boog
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002678:Chimera / Q000276:immunology; D017637:Clonal Deletion; D007108:Immune Tolerance; D007421:Intestine, Small / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology*; D013997:Time Factors; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous