Intrathymic Immune Modulation Prevents Acute Rejection but Not the Development of Graft Arteriosclerosis (Chronic Rejection)1

Abstract

Intrathymic immune modulation does not abolish alloreactivity, and despite induction of long-lasting graft survival, this procedure does not prevent and may even facilitate the development of GAD.

Predominant expression of the Th2 response in chronic cardiac allograft rejection

“…1A and Table 1). These findings are consistent with our previous studies [39] and a recent study demonstrating that intrathymic immune modulation with allogeneic cells prevented acute but not chronic rejection [20]. Allografts with delayed rejection (1 5-82 days; IZ = 6) showed dense mononuclear cell infil- tration, moderate-to-severe myocardial fibrosis, severe vascular proliferative lesions, and lesions related to acute episodes of allograft rejection, such as vasculitis, interstitial hemorrhage, and myocardial necrosis (Fig.…”

Origin of neointimal endothelium and α-actin–positive smooth muscle cells in transplant arteriosclerosis

“…Recently, we reported that after intrathymic immune modulation the intragraft cytokine profile in long-term allografts (>200 days) has shifted from a Th1 type (high IL-2 and IFN-γ) toward a Th3 or Tr1 type (high IFN-γ, TGF-β, and IL-10; no IL-2) profile. This altered immune response might preserve graft endothelium, but it does not prevent the development of TA (30). Studying human kidney biopsies, Lagaaij et al recently suggested a correlation between the degree of EC replacement by recipient-derived endothelium and the severity of vascular rejection (16).…”

“…CsA (Sandoz Pharma AG, Basel, Switzerland) was injected intramuscularly on days 1, 2, and 3 after transplantation (15 mg/kg). Cardiac allografts thus transplanted show significantly prolonged graft survival but eventually develop TA indicative of CTD (30).…”

“…Cardiac transplantation following intrathymic immune modulation resulted in development of severe TA in the CAs (30). To study whether EC replacement by recipient-derived ECs had also taken place in these cardiac allografts, recipient and donor MHC class I-specific staining was performed.…”

“…Second, we used a cardiac transplant model in which MHC-incompatible cardiac allografts are transplanted following intrathymic immune modulation and short-term immunosuppression (29). Cardiac allograft survival is significantly prolonged, but development of TA in the coronary artery (CA) tree cannot be prevented, resembling clinical outcome after cardiac transplantation (30). Using both transplant models we analyzed the origin of neointimal ECs and VSM cells, using MHC class I haplotype-specific immunohistochemistry and two independent PCR-based analyses (31,32).…”