title: Mls-1a-induced peripheral tolerance to host minor histocompatibility antigens in radiation bone marrow chimeras. Modification of T cell repertoire associated with active suppression and permanent presentation of host antigens.
abstract: Minor histocompatibility Ag (mHAg) can be responsible for the development of graft vs host reaction (GVHR) after bone marrow transplantation. In a mouse model, B10.D2 donor immunization against Mls-1a prevents lethal GVHR developed by CD4+ T cells against DBA mHAg in irradiated (DBA/2 x B10.D2)F1 hosts. Such F1 hosts become 100% chimeric and show long term survival (LS mice). The cellular mechanisms underlying the tolerance in LS mice was investigated. It was found that a state of tolerance can be induced in thymectomized F1 hosts. Although spleen cells from LS mice are able to initiate lethal GVHR in third-party H-2k-incompatible hosts, no GVHR is observed in secondary hosts incompatible for specific DBA/2 mHAg. Mixed lymphocyte experiments in vitro confirm that T cells from LS mice are unresponsive toward specific DBA/2 mHAg, although they are able to proliferate in response to H-2 or Mls-1a Ag. The responsiveness to Mls-1a correlates with the presence of V beta 6+ cells in LS mice, probably derived from mature T cells present in the donor inoculum. The tolerance in LS mice is not due to the lack of DBA/2 mHAg presentation; instead, permanent presentation of Ag (Ag I and Ag II) previously described as being responsible for lethal GVHR is consistently observed. A significant protection against GVHR is obtained by transferring normal B10.D2 cells together with spleen cells from LS mice, clearly indicating the contribution of active suppression in the state of tolerance; this is further confirmed by in vitro results obtained in limiting dilution assays. It is concluded that tolerance in chimeric LS mice 1) is due to a peripheral (thymus-independent) mechanism; 2) is specific for mHAg; 3) correlates with unresponsiveness of the repertoire to host mHAg, without alteration of the repertoire for H-2 and Mls-1a Ag; and 4) is associated with an active suppression and with a permanent presentation of at least two mHAg responsible for GVHR mortality.
authors.affiliation: INSERM U.267 Immunogénétique des Allogreffes, Villejuif, France.
authors.forename: I
authors.initials: I
authors.lastname: Miconnet
authors.forename: M
authors.initials: M
authors.lastname: Bruley-Rosset
authors.forename: O
authors.initials: O
authors.lastname: Halle-Pannenko
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology; D007108:Immune Tolerance; D007116:Immunization, Passive; D008213:Lymphocyte Activation; D051379:Mice; D008912:Minor Histocompatibility Loci; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology*; D011828:Radiation Chimera; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
chemical_list: D016747:Minor Lymphocyte Stimulatory Antigens