Local cellular immunology of experimental transplant vascular sclerosis

We have observed that most C57BL/6 (H-2b) recipients of DBA/2 (H-2d) heterotopic cardiac allografts retain their grafts for more than 60 days following treatment with anti-CD4 MAb (GK1.5), anti-VCAM-1 MAb (M/K-2), or gallium nitrate (GN). Nevertheless, many ongoing alloimmune responses are detectable more than 60 d post-transplant in these mice: (i) continuous inflammatory endothelial activation and low-grade cellular infiltration in the graft, (ii) modest frequencies of donor-reactive T cells in the graft and spleen, (iii) mRNA for various cytokines (IL-1, IL-2, IL-4, IL-6, IFN gamma, TNF alpha, TGF beta) in the graft, (iv) high levels of donor-reactive alloantibody in the circulation, (v) variable development of allogeneic chimerism in the recipient, and (vi) development of interstitial fibrosis and neointimal hyperplasia in the graft. Despite the widely differing targets of GK1.5, M/K-2, and GN, their therapeutic outcomes appear to be identical. Taken together, these observations suggest that long-term allograft survival in these experimental systems is not the result of immune acceptance, i.e. allogeneic tolerance. Although these therapies interrupt the destructive progression of acute rejection, they permit many related immune responses in the graft recipient in association with the development of chronic rejection-like histopathology.