CHRONIC CARDIAC ALLOGRAFT REJECTION IS INDEPENDENT OF DONOR MHC CLASS II ANTIGENS

Abstract

381 Donor MHC class II antigens are expressed on the vascular endothelium during chronic rejection. However, whether expression of donor MHC class II antigens is required for chronic rejection is not known. The purpose of this study was to determine whether allografted MHC II-/- hearts which do not reject acutely in the presence of only CD4 T cells would develop chronic vascular lesions. To test this proposition, heterotopic cardiac allografts from C57BL/6 (H-2b) MHC II +/+ or MHC II-/- mice were transplanted into immune-deficient C.B-17scid (H-2d, SCID) mice. SCID mice bearing established cardiac grafts were: (1) left unreconstituted, (2) reconstituted by adoptive transfer with unfractionated lymph node cells from BALB/c (H-2d) donors (10 ×106 cells), or (3) reconstituted with purified CD4 BALB/c T cells (10× 106 cells). Hearts were monitored for rejection by daily palpation. CD4 T cells isolated by antibody column purification (Biotex) and had undetectable numbers (<0.5%) of contaminating CD8 T cells or B220 B cells by flow cytometry.RESULTS: Unreconstituted SCID mice did not reject either cardiac MHC II +/+ or MHC -/- allografts (n=10, n=6, graft survival >60 days). Adoptive transfer of unfractionated cells to SCID recipients triggered acute rejection of both MHC II+/+ allografts (n=7, days 8,9,10, 10, 11, 19, 19) and MHC-/- allografts (n=6, days 8,10,10,10,10,11). MHC II+/+ allografts in SCID mice reconstituted with purified CD4 cells rejected in a time course similar to control mice (n=10, days 8, 9, 9, 10, 10, 10, 11, 11, 16, 22). MHC II-/- allografts in SCID mice reconstituted with purified CD4 cells did not reject acutely (n=7, 4/5 grafts >60 days, p<0.005), but all developed intimal thickening and evidence of chronic rejection. Unreconstituted long term (>60 days) allografts from either MHC class II+/+ or -/- donors did not develop evidence of chronic rejection. Acutely rejecting allografts demonstrated a typical lymphocytic infiltrate but did show evidence of chronic rejection. CONCLUSIONS: 1) Donor MHC class II antigens are not required for chronic rejection of cardiac allografts. 2) CD4 T cells are sufficient for chronic rejection of allografts, independently from either CD8 T cells or B cells. 3) Furthermore, we propose that CD4-dependent chronic graft rejection can be mediated through the indirect (host APC) dependent pathway.