Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.
BACKGROUND
To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model.


METHODS
Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides.


RESULTS
Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen.


CONCLUSIONS
These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
J P
JP
Vella
C
C
Magee
L
L
Vos
K
K
Womer
H
H
Rennke
C B
CB
Carpenter
W
W
Hancock
M H
MH
Sayegh
D000818:Animals; D000917:Antibody Formation; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000032:analysis; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation; D051381:Rats; D011917:Rats, Inbred Lew
D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies; D007519:Isoantigens