Antibody‐Mediated Rejection in Human Cardiac Allografts: Evaluation of Immunoglobulins and Complement Activation Products C4d and C3d as Markers

Rodríguez, E. René; Skojec, Diane V.; Tan, Carmela D.; Zachary, Andrea A.; Kasper, Edward K.; Conte, John V.; Baldwin, William M.

doi:10.1111/j.1600-6143.2005.01074.x

Cited by 153 publications

(138 citation statements)

References 23 publications

(24 reference statements)

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“…C4d deposition is particularly prevalent in patients sensitized by previous transplants, pregnancies or blood transfusions. Although C4d has been widely studied in renal transplants, relatively few studies have examined the value of C4d as a correlate of antibody-mediated rejection in human cardiac transplants (9)(10)(11). In addition to C4d, Fishbein and coworkers (12) have emphasized an association between antibody-mediated rejection and accumulations of macrophages in capillaries of endomyocardial biopsies.…”

Section: Introductionmentioning

confidence: 99%

C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

Minami

Murata

Lee

et al. 2006

American Journal of Transplantation

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Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complementactivating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days.

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Section: Introductionmentioning

confidence: 99%

C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

Minami

Murata

Lee

et al. 2006

American Journal of Transplantation

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“…Circulating anti-HLA Abs are also associated with late loss of kidney, heart, lung, and liver grafts, including the development of chronic rejection (6,7). Graft endothelial cells are the primary targets of donor-reactive Abs during AHR, and C4d staining of capillaries in endomyocardial biopsies correlates with the presence of circulating anti-donor Abs and ongoing AHR (8,9). The use of C4d staining in graft biopsies has improved diagnosis of AHR and led to the recognition that the incidence of AHR is more prevalent than previously thought (10 -12).…”

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confidence: 99%

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Nozaki

Amano

Bickerstaff

et al. 2007

The Journal of Immunology

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Rejected MHC-mismatched cardiac allografts in CCR5−/− recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5−/− recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5−/− (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-γ, whereas CD4 T cells producing IL-4 were increased in CCR5−/− recipients. Numbers of donor-reactive CD8 T cells producing IFN-γ were reduced 60% in CCR5−/− recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5−/− allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1−/− recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5−/− recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in μMT−/−/CCR5−/− recipients. These results indicate that the donor-specific Ab produced in CCR5−/− heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.

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“…The vascular endothelium is a major target of antibody-mediated rejection (7)(8)(9)(10). Low titers of antibodies are associated with endothelial cell swelling, platelet aggregation, and macrophage accumulation (4,5).…”

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Antibody to human leukocyte antigen triggers endothelial exocytosis

Yamakuchi

Kirkiles-Smith

Ferlito

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Although antibodies to HLA play a role in the pathogenesis of diseases processes such as rejection of transplanted organs, the precise mechanisms by which antibodies cause tissue injury are not completely understood. We hypothesized that antibodies to host tissues cause inflammation in part by activating endothelial exocytosis of granules that contain prothrombotic mediators such as von Willebrand Factor (VWF) and proinflammatory mediators such as P-selectin. To test this hypothesis, we treated human endothelial cells with murine monoclonal antibody W6/32 to HLA class I and then measured exocytosis by the release of VWF and the externalization of P-selectin. Antibody to HLA activates endothelial exocytosis in a dose-dependent manner over time. The biologically active complement split product, C5a, adds a slight but significant increase to antibody induction of exocytosis. Antibody to HLA alone or with C5a did not damage the cells. Cross-linking of HLA appears to play a role in the ability of antibody to activate exocytosis, because the W6/32 monovalent Fab fragment did not activate VWF release, but the bivalent F(ab) 2 was effective in triggering exocytosis. To explore the in vivo effects of antibody upon graft injury, we infused W6/32 F(ab)2 antibody to human HLA into severe combined immunodeficient/beige mice that had been transplanted with human skin grafts. Antibody to HLA activated exocytosis and inflammation in human skin grafts. Our data show that antibody to host antigens can activate human endothelial cell exocytosis and leukocyte trafficking. By triggering vascular inflammation, antibody activation of exocytosis may play a role in transplant rejection.nitric oxide ͉ rejection ͉ transplant ͉ vasculopathy ͉ Weibel-Palade body

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Antibody‐Mediated Rejection in Human Cardiac Allografts: Evaluation of Immunoglobulins and Complement Activation Products C4d and C3d as Markers

Cited by 153 publications

References 23 publications

C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Antibody to human leukocyte antigen triggers endothelial exocytosis

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