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1.
Am J Transplant ; 15(5): 1205-18, 2015 May.
Article in English | MEDLINE | ID: mdl-25808553

ABSTRACT

Transplant vasculopathy is associated with neointimal accumulation of recipient-derived mesenchymal stem cells. Increased circulating levels of LG3, a C-terminal fragment of perlecan, were found in renal transplant patients with vascular rejection. Here, we evaluated whether LG3 regulates the migration and homing of mesenchymal stem cells and the accumulation of recipient-derived neointimal cells. Mice were transplanted with a fully-MHC mismatched aortic graft followed by intravenous injection of recombinant LG3. LG3 injections increased neointimal accumulation of α-smooth muscle actin positive cells. When green fluorescent protein (GFP)-transgenic mice were used as recipients, LG3 injection favored accumulation of GFP+ cells to sites of neointima formation. LG3 increased horizontal migration and transmigration of mouse and human MSC in vitro and led to increased ERK1/2 phosphorylation. Neutralizing ß1 integrin antibodies or use of mesenchymal stem cells from α2 integrin-/- mice decreased migration in response to recombinant LG3. Reduced intima-media ratios and decreased numbers of neointimal cells showing ERK1/2 phosphorylation were found in α2-/- recipients injected with recombinant LG3. Collectively, our results suggest that LG3, through interactions with α2ß1 integrins on recipient-derived cells leading to activation of ERK1/2 and increased migration, favors myointimal thickening.


Subject(s)
Graft Rejection/pathology , Heparan Sulfate Proteoglycans/chemistry , Integrin alpha2beta1/metabolism , Mesenchymal Stem Cells/cytology , Neointima/pathology , Vascular Grafting , Animals , Aorta/pathology , Aorta/transplantation , Blood Vessel Prosthesis , Carotid Intima-Media Thickness , Cell Movement , Extracellular Signal-Regulated MAP Kinases/metabolism , Green Fluorescent Proteins/metabolism , Humans , Integrin beta1/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Myocytes, Smooth Muscle/cytology , Phenotype , Protein Structure, Tertiary , Rats , Recombinant Proteins/metabolism
2.
Am J Transplant ; 13(4): 861-874, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23432943

ABSTRACT

Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n=15) versus those with acute tubulo-interstitial rejection (ATIR) (n=15) or stable graft function (n=30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p<0.05 for both mediators). Elevated pretransplant anti-LG3 titers (OR: 4.62, 95% CI: 1.08-19.72) and pretransplant donor-specific antibodies (DSA) (OR 4.79, 95% CI: 1.03-22.19) were both independently associated with AVR. To address the functional role of anti-LG3 antibodies in AVR, we turned to passive transfer of anti-LG3 antibodies in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice. Neointima formation, C4d deposition and allograft inflammation were significantly increased in recipients of an ischemic aortic allograft passively transferred with anti-LG3 antibodies. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling.


Subject(s)
Graft Rejection/immunology , Heparan Sulfate Proteoglycans/immunology , Immunoglobulin G/blood , Vascular Diseases/immunology , Adult , Animals , Antigens/immunology , Aorta/pathology , Apoptosis , Case-Control Studies , Endothelial Cells/pathology , Female , Graft Rejection/blood , Humans , Immunization, Passive , Immunoglobulin G/immunology , Inflammation/pathology , Kidney/blood supply , Kidney/pathology , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle Aged , Recombinant Proteins/immunology , Retrospective Studies , Vascular Diseases/blood
3.
APMIS ; 103(10): 714-20, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8534430

ABSTRACT

A glycoprotein present in Chlamydia trachomatis, serotype L1, elementary bodies (EBs) was earlier found to bind the lectin from Galanthus nivalis (GNA). In the present paper we investigate the interaction of GNA with chlamydial EBs and its effect on in vitro infectivity. The binding affinity was studied with 125I-GNA lectin. Within 15 min about 80% maximal binding was obtained. The chlamydia-GNA interaction was inhibited by alpha-methylmannoside, causing a decrease of about 50% at 1 mM. Curve fit analyses indicated two types of binding sites for GNA on the EBs. The affinity to these differed by a factor of 15. The influence of the lectin on the ability of C. trachomatis to infect McCoy cells was also investigated. There was a GNA-dependent inhibition with a 50% reduction in the number of intracellular inclusions at 0.2 microM of the lectin. The findings indicate the presence of terminal mannose structures on the chlamydial surface at or in the proximity of the cell-binding domains. Mannose-binding proteins of eukaryotic cells could be important for the initial uptake of EBs.


Subject(s)
Chlamydia Infections/prevention & control , Chlamydia trachomatis/metabolism , Lectins/pharmacology , Animals , Cell Line , Chlamydia Infections/metabolism , Galanthus , Glycoproteins/metabolism , Lectins/metabolism , Plant Lectins , Plants/metabolism , Radioligand Assay
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