Soluble Hla Antigens, Anti-Hla Antibodies, and Antiidiotypic Antibodies in the Circulation of Renal Transplant Recipients

Suciu‐Foca, Nicole; Reed, Elaine F.; D’Agati, Vivette D.; Ho, Eric K.; Cohen, David J.; Benvenisty, Alan I.; McCabe, Robert E.; Brensilver, Jeffrey M.; King, Donald W.; Hardy, Mark A.

doi:10.1097/00007890-199103000-00011

Cited by 152 publications

(51 citation statements)

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“…The addition of neutralizing anti-bFGF Abs had no effect on class Imediated tyrosine phosphorylation of the 60-kDa protein (Fig. 1A, lanes [7][8][9][10]. Furthermore, treatment of ECs directly with bFGF induced tyrosine phosphorylation of proteins with an approximate molecular mass of 42-44 kDa (Fig.…”

Section: A Lane 1 and B)mentioning

confidence: 99%

“…Transplant arteriosclerosis is characterized by the proliferation of intimal smooth muscle cells (SMC) 3 and endothelial cells (EC) in the walls of the arteries of the transplanted organ resulting in occlusion of the vessels and fibrosis of the graft. Anti-HLA Abs have long been implicated in the process of chronic rejection, as several studies have shown that patients developing anti-donor HLA Abs following transplantation are at increased risk of developing chronic rejection and graft loss (3)(4)(5)(6)(7)(8)(9)(10). A consistent finding in graft arteriosclerotic lesions is Ig deposits in affected vessel walls and within the media (2,11,12).…”

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confidence: 99%

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Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

Jin¹,

Singh²,

Du³

et al. 2002

The Journal of Immunology

118

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The development of chronic rejection is the major limitation to long-term allograft survival. HLA class I Ags have been implicated to play a role in this process because ligation of class I molecules by anti-HLA Abs stimulates smooth muscle cell and endothelial cell proliferation. In this study, we show that ligation of HLA class I molecules on the surface of human aortic endothelial cells stimulates phosphorylation of Src, focal adhesion kinase, and paxillin. Signaling through class I stimulated Src phosphorylation and mediated fibroblast growth factor receptor (FGFR) translocation to the nucleus. In contrast, Src kinase activity was not involved in class I-mediated transfer of FGFR from cytoplasmic stores to the cell surface. Inhibition of Src protein kinase activity blocked HLA class I-stimulated tyrosine phosphorylation of paxillin and focal adhesion kinase. Furthermore, HLA class I-mediated phosphorylation of the focal adhesion proteins and FGFR expression was inhibited by cytochalasin D and latrunculin A, suggesting a role for the actin cytoskeleton in the signaling process. These findings indicate that anti-HLA Abs have the capacity to transduce activation signals in endothelial cells that may promote the development of chronic rejection.

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Section: A Lane 1 and B)mentioning

confidence: 99%

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confidence: 99%

Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

Jin¹,

Singh²,

Du³

et al. 2002

The Journal of Immunology

118

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“…The Prolongation of graft survival in recipients of hyperimmune serum who do not hyperacutely reject their cardiac allografts could be due to the weli-described phenomenon of antiidiotypic antibody production which prevents acute rejection temporarily [14][15][16]. Why some recipients of HyS undergo hyperacute rejection while others have prolonged survival with passive enhancement is unclear.…”

Section: Discussionmentioning

confidence: 99%

Use of Donor Serum to Prevent Passive Transfer of Hyperacute Rejection

Wang

Geissler

Fechner

et al. 1994

Journal of Surgical Research

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Organ transplantation in presensitized recipients continues to be contraindicated for heart and kidney recipients due to the risk of hyperacute rejection, which has no known treatment at this time. We tested whether donor serum, which contains solubie MHC class I antigen, is able to neutralize the effect of antidonor antibody in the recipient and prevent hyperacute or accelerated rejection. A rat model of passive immunization was used to test the role of anti-donor antibody in hyperacute rejection. Seven of 10 recipients of hyperimmune serum (HyS), derived from Lewis rats (ETI 1 ) following 3 ACI (RT1") skin grafts, developed hyperacute or accelerated rejection. intravenous injec* tion of ACI serum prior to the HyS administration prevented hyperacute rejection in all recipients tested. When third-party (Wistar-Furth, RTl tt ) serum was given to Lewis rats injected with HyS, hyperacute rejection was not abrogated. When examining the mechanism of this effect, a simple antibody blocking phenomenon was found to be unlikely since flow cytometry analysis showed that ACI serum needed to be present at >256-fold excess compared to HyS to block anti-ACI antibody binding to RTl.A'-f-cells by 50%. We tested whether the RT1.A* class I antigen in ACI serum had other biologic properties that resulted in the prolonged graft survivah However, removal of RT1.A* antigen from ACI serum prior to use in the passive transfer model did not abrogate the graft Prolongation observed previously. These data suggest that components of donor serum other than MHC class I antigen may be useful for preventing the antibody-mediated component of hy per acute rejection. ® 199-1 Acndemie Frew, Inc.

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“…term survival remains chronic rejection, a slow and insidious process that often takes years for completion (17,18). Chronic rejection has been associated with the production of lymphokines and cytokines damaging the intima of the vessels and inducing the proliferation and differentiation of alloantibody-producing B cells (17,18).…”

Section: Discussionmentioning

confidence: 99%

Contribution of direct and indirect recognition pathways to T cell alloreactivity

1993

Human Immunology

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SummaryT cells from an HLA-DRll/DR12 responder were stimulated in mixed lymphocyte culture with cells carrying the DR1 antigen. After priming, T cells proliferated in response to both DR1-positive-stimulating cells and a peptide derived from a polymorphic region of the HLA-DRBI*0101 chain presented by responder's antigen-presenting cells (APC). The dominant epitope recognized by the primed T cells corresponded to residue 21-42 and was presented by the responder's HLA-DR12 antigen. The DR1 peptide-reactive T cells express T cell receptor V33. The results demonstrate that allopeptides derived from the processing and presentation of donor major histocompatibility complex molecules by host-derived APC trigger alloreactivity. The frequency of T cells engaged in the indirect pathway of allorecognition is about 100-fold lower than that of T cells participating in the direct recognition of native HLA-DR antigen. However, indirect allorecognition may play an important role in chronic allograft rejection, a phenomenon that is mediated by the activation of T helper cells and of alloantibody-producing B cells.T wo pathways of antigen recognition have been considered in T cell responses to MHC alloantigens (1-4). A direct pathway involves T cells capable of recognizing alloantigens as intact molecules on the surface of allogeneic stimulator cells. The TCRs recognize, in this case, unknown peptides bound in the groove of allogeneic MHC molecules and/or adjacent epitopes of the aUogeneic MHC molecule. The precursor frequency of T cells involved in the direct recognition pathway is extremely high, with estimates of 1-5% of T cells exhibiting blastogenic responses to allogeneicstimulating cells in MLC (2). There is ample evidence that the direct pathway of allorecognition is the principal contributor to antigraft cytotoxic T cell responses mediating early rejection episodes. The very high number of precursor T cells participating in direct aUorecognition has been attributed to molecular mimicry resulting from the engagement of TCRs whose innate reactivity was for a complex formed by a self-MHC molecule with an endogenous or exogenous peptide (5-9).The indirect pathways of allorecognition has come into focus more recently, with the realization that this pathway may explain T helper cell-dependent cytotoxic T cell and alloantibody responses (10-13). In this pathway, T cells recognize graft MHC alloantigens that have been processed and presented by host APC. Indirect recognition is restricted by the host MHC class II molecule, which has bound a peptide derived from the processing of an allogeneic MHC molecule that is, therefore, the classical pathway of conventional antigen recognition by CD4 T cells (10-16). The involvement of alloantigen-specific CD4 T helper cells, as mediators of alloantibody generation, suggests that the indirect pathway plays an essential role in chronic rejection, e.g., in the steady but continuous attrition (2-5%/yr) of organ allografts late after transplantation (17,18).In previous studies we have shown th...

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Soluble Hla Antigens, Anti-Hla Antibodies, and Antiidiotypic Antibodies in the Circulation of Renal Transplant Recipients

Cited by 152 publications

References 0 publications

Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

Use of Donor Serum to Prevent Passive Transfer of Hyperacute Rejection

Contribution of direct and indirect recognition pathways to T cell alloreactivity

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