Intimal Thickening Develops Without Humoral Immunity in a Mouse Aortic Allograft Model of Chronic Vascular Rejection

Abstract

Background The major threat to the long-term survival of cardiac allograft recipients is the development of diffuse intimal thickening in the allograft coronary arteries through mechanisms that are poorly understood. Although antidonor antibodies have been associated with the development of this condition, a causal relationship has not been established. Methods and Results To determine whether humoral immune responses are necessary for the development of graft vascular disease, we performed abdominal aortic allografts from normal donor mice into different immunodeficient recipient mice: those lacking all donor-specific immune responses (severe combined immunodeficient [SCID] mice and recombination activating gene-1 [RAG-1]–deficient mice) and those lacking humoral immune responses alone owing to a targeted deletion of the joining region (J_H) gene segments for the immunoglobulin heavy chain. At 6 to 9 weeks after transplantation, aortic allografts in normal immunocompetent recipients showed concentric intimal thickening extending the full length of the graft (percent luminal reduction, [%LR], 31.2±9.1 [mean±SD] and 38.5±3.6 in different donor-recipient strain combinations). In contrast, syngeneic (histocompatible) aortic grafts showed a normal-appearing vessel wall (%LR, 1.6±0.7). In both SCID and RAG-1–deficient recipients, aortic allografts showed a virtual absence of neointimal formation (%LR, 3.7±2.1 and 3.8±1.6 in SCID and RAG-1–deficient recipients, respectively), indicating a critical etiological role for alloimmune responses in this model. Importantly, allografts in J_H-deficient mice showed marked intimal thickening (%LR, 35.7±7.9), with an appearance histologically indistinguishable from that of normal immunocompetent recipients. Conclusions Neointimal formation in graft vascular disease is critically dependent on alloimmune responses of the host. Humoral effector mechanisms, however, may not be required.