ABSTRACT
Pathologic changes associated with chronic kidney disease - mineral and bone disorder (CKD-MBD) begin early in the course of renal disease and are typically progressive, despite the use of traditional therapies. A wide variety of potentially severe consequences are associated with the progression of this disease. These sequalae include parathyroid hyperplasia, parathyroidectomy, bone pain, fractures, vascular calcification, and cardiovascular events, with each independently associated with an increased risk for death. Nurses should be aware of the complications associated with CKD-MBD and the need to simultaneously achieve recommended targets for iPTHi, calcium, phosphorous, and the calcium-phosphorous product to increase the likelihood of arresting disease progression.
Subject(s)
Bone Density , Bone Diseases/etiology , Kidney Failure, Chronic/physiopathology , Calcinosis , Calcium/metabolism , Disease Progression , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/metabolism , Parathyroid Hormone/metabolism , Phosphorus/metabolism , Vitamin D/metabolismABSTRACT
IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4-6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Cell Movement/drug effects , Chemokine CXCL10/antagonists & inhibitors , Chemokine CXCL10/immunology , Animals , Antibodies, Monoclonal/pharmacokinetics , Arthritis, Experimental/pathology , Arthritis, Experimental/therapy , Bronchoalveolar Lavage Fluid/cytology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/drug effects , Cell Movement/immunology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Female , Graft Rejection/prevention & control , Heart Transplantation/immunology , Inflammation/pathology , Inflammation/therapy , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Mice, Inbred Strains , Mice, SCID , Precursor Cells, B-Lymphoid/cytology , Precursor Cells, B-Lymphoid/drug effects , Treatment OutcomeABSTRACT
Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders of humans and animals often initiated by oral intake of an infectious agent. Current evidence suggests that infection occurs initially in the lymphoid tissues and subsequently in the central nervous system (CNS). The identity of infected lymphoid cells remains controversial, but recent studies point to the involvement of both follicular dendritic cells (FDC) and CD11c(+) lymphoid dendritic cells. FDC generation and maintenance in germinal centers is dependent on lymphotoxin alpha (LT-alpha) and LT-beta signaling components. We report here that by the oral route, LT-alpha -/- mice developed scrapie while LT-beta -/- mice did not. Furthermore, LT-alpha -/- mice had a higher incidence and shorter incubation period for developing disease following inoculation than did LT-beta -/- mice. Transplantation of lymphoid tissues from LT-beta -/- mice, which have cervical and mesenteric lymph nodes, into LT-alpha -/- mice, which do not, did not alter the incidence of CNS scrapie. In other studies, a virus that is tropic for and alters functions of CD11c(+) cells did not alter the kinetics of neuroinvasion of scrapie. Our results suggest that neither FDC nor CD11c(+) cells are essential for neuroinvasion after high doses of RML scrapie. Further, it is possible that an as yet unidentified cell found more abundantly in LT-alpha -/- than in LT-beta -/- mice may assist in the amplification of scrapie infection in the periphery and favor susceptibility to CNS disease following peripheral routes of infection.