Acute and Chronic Vascular Rejection in Nonhuman Primate Kidney Transplantation

Abstract

A nonhuman primate (NHP) study was designed to evaluate in nonlife-supporting kidney allografts the progression from acute rejection with transplant endarteritis (TXA) to chronic rejection (CR) with sclerosing vasculopathy. Group G1 (n = 6) received high cyclosporine A (CsA) immunosuppression and showed neither TXA nor CR during 90 days posttransplantation. Group G2 (n = 6) received suboptimal CsA immunosuppression and showed severe TXA with graft loss within 46 days (median). Arterial intimal changes included infiltration of macrophages and T lymphocytes (CD3, CD4, CD8) with few myofibroblasts, abundant fibronectin/collagen IV, scant collagens I/III, high rate of cellular proliferation and no C4d accumulation along peritubular capillaries. Group G3 (n = 12) received suboptimal CsA and anti-rejection therapy (rabbit ATG + methylprednisolone + CsA) of TXA. Animals developed CR and lost grafts within 65 days (median). As compared to G2, the arterial intimal changes showed less macrophages and T lymphocytes, an increased number of myofibroblasts, abundant fibronectin/collagen IV and scar collagens I/III, C4d deposition along capillaries in 60% of animals and transplant glomerulopathy in 80% of animals.In conclusion, CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts, and progressive deposition of collagens in the intima. Our experimental design appears well suited to study events leading to CR.

Identification of platelet-derived growth factor D in human chronic allograft nephropathy

“…This finding suggests that PDGF-D, together with PDGF-A and -B, participates in the pathogenensis of transplant arteriopathy in an organized sequence of activities. This proposed scenario is consistent with the evolution of morphologic changes recently described in a non-human primate model of chronic vascular rejection which also suggest that many if not all of the cases of CAN in our series are indeed the result of chronic rejection [29]. Our findings do not identify what may be the functional role of PDGF-D that appears to be constitutively expressed by vascular medial smooth muscle cells.…”

“…Chronic allograft arteriopathy is one of the main pathological manifestations of CAN, which is characterized by neointima formation by mesenchymal cells with accumulation of sclerotic matrix in arteries [1,3]. This arteriopathy is often a consequence of rejection, as recently detailed in studies of a non human primate model of transplant rejection [29], and it is likely most of the cases of CAN included in the present study are a consequence of chronic vascular rejection. Current leading opinions about the origin of the mesenchymal neointimal cells in this arteriopathy is that they are derived either from smooth muscle cells that have migrated from the vessel media as a result of stimulation by growth factors and cytokines released during vascular injuries, or that they are derived from myofibroblasts migrating from the vascular adventitia.…”

“…These and other factors may then lead to medial smooth muscle cell or myofibroblast activation, further upregulation of PDGF-Rβ by these cells, and induction of migration to the subendothelial space. In this site these cells then may proliferate and synthesize extracellular matrix to form neointima [29]. PDGF-D may play a pivotal role in the sclerosing stages of arteriopathy.…”

Pathological Effects in Lymphoid Tissues of the Spleen, Lymph Nodes, and Peyer’s Patches in Cyclosporin-Treated Cynomolgus Monkeys

“…In contrast, germinal centers in the 100 mg/kg group were unobservable in all analyzed organs in the present study, whereas germinal centers had been clearly observed in our previous study in naive cynomolgus monkeys [14]. Wieczorek et al reported that groups which received high CsA immunosuppression showed less acute rejection with transplant endarteritis to chronic rejection with sclerosing vasculopathy than groups which received suboptimal CsA immunosuppression in nonhuman primate kidney transplantation [18]. Therefore, at the dose level of CsA in the present study, the histological changes of the lymphoid tissue were considered to be changes resulting from beneficial effects of CsA.…”

Mitochondrial DNA Diversity among Three Subpopulations of Cynomolgus Macaques (Macaca fascicularis) Originating from the Indochinese Region

“…This species is often used for biomedical research [7,21] involving infectious diseases, such as AIDS [43], influenza [17], tuberculosis [6,15], measles virus [30], western equine encephalitis virus [27], and severe acute respiratory syndrome (SARS) [1�]� neuro- [1�]� neuro-� neurological diseases, such as Alzheimer's disease [40] and Parkinson's disease [8]� reproduction [33]� regenerative medicine [31]� transplantation [4,18,25,41,42]� and immunotherapy [22,32]. In order to effectively use cynomolgus macaques for medical research, it is necessary to better understand the genetic diversity among and within the different populations.…”