title: Sensitization to minor antigens is a significant barrier in bone marrow transplantation and is prevented by CD154:CD40 blockade.
abstract: Sensitization to major histocompatibility complex (MHC) alloantigens is critical in transplantation rejection. The mechanism of sensitization to minor histocompatibility antigens (Mi-HAg) has not been thoroughly explored. We used a mouse model of allosensitization to Mi-HAg to study the Mi-HAg sensitization barrier in bone marrow transplantation (BMT). AKR mice were sensitized with MHC congenic Mi-HAg disparate B10.BR skin grafts. Adaptive humoral (B-cells) and cellular (T cells) responses to Mi-HAg are elicited. In subsequent BMT, only 20% of sensitized mice engrafted, while 100% of unsensitized mice did. In vivo cytotoxicity assays showed that Mi-HAg sensitized AKR mice eliminated CFSE labeled donor splenocytes significantly more rapidly than naïve AKR mice but less rapidly than MHC-sensitized recipients. Sera from Mi-HAg sensitized mice also reacted with cells from other mouse strains, suggesting that Mi-HAg peptides were broadly shared between mouse strains. The production of anti-donor-Mi-HAg antibodies was totally prevented in mice treated with anti-CD154 during skin grafting, suggesting a critical role for the CD154:CD40 pathway in B-cell reactivity to Mi-HAg. Moreover, anti-CD154 treatment promoted BM engraftment to 100% in recipients previously sensitized to donor Mi-HAg. Taken together, Mi-HAg sensitization poses a significant barrier in BMT and can be overcome with CD154:CD40 costimulatory blockade.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, KY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: L R
authors.initials: LR
authors.lastname: Hussain
authors.forename: Z
authors.initials: Z
authors.lastname: Zhu
authors.forename: L D
authors.initials: LD
authors.lastname: Bozulic
authors.forename: C
authors.initials: C
authors.lastname: Ding
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.forename: S T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002648:Child; D006084:Graft Rejection / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007519:Isoantigens / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000276:immunology; D018183:Transplantation Chimera
chemical_list: D019013:CD40 Antigens; D007519:Isoantigens; D015778:Minor Histocompatibility Antigens; D023201:CD40 Ligand