The Role of Anti-Hla Antibodies in Heart Transplantation

Suciu‐Foca, Nicole; Reed, Elaine F.; Marboe, Charles C.; Harris, Paul E.; Px, Yu; Yk, Sun; Ho, Elaine Lynn‐Ee; Rose, Eric A.; Reemtsma, K; Dw, King

doi:10.1097/00007890-199103000-00033

Cited by 188 publications

(80 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%

mentioning

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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“…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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“…Antibody mediated rejection (AMR) or vascular rejection is associated with anti HLA and antiendothelial antibody formation and has been linked to pathogenesis of CAV [6,[62][63][64]. Anti HLA antibodies can exert effects on allograft through complement dependent and independent pathways.…”

Section: Immunobiology and Pathogenesis Of Coronary Allograft Vasculomentioning

confidence: 99%

“…High levels of circulating anti-HLA antibodies are associated with poor intermediate and long term survival. Presence of anti-endothelial antibodies is a strong determinant of CAV progression [6,58,[62][63][64][65][66][67][68]. Presence of non-HLA antibodies against cardiac myosin and vimentin has also been associated with pathogenesis of CAV.…”

Section: Immunobiology and Pathogenesis Of Coronary Allograft Vasculomentioning

confidence: 99%

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

Munagala¹,

Phancao²

2018

obm.transplant

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Heart transplant remains the gold standard therapy for patients with end stage heart disease and offers improved survival and quality of life. Significant progress has been achieved in improving one-year mortality after heart transplantation. Nonetheless, longterm graft survival has not changed significantly over the past few decades. Long term survival of heart transplant recipients is limited by chronic rejection, cardiac allograft vasculopathy (CAV), and malignancy. CAV is a major contributor for graft failure and mortality after the first year of in heart transplant recipients. CAV is a proliferative vasculopathy characterized by diffuse myointimal hyperplasia and progressive narrowing of the graft vessels. Both immune dependent and independent factors have been shown to contribute to the pathogenesis of CAV. Understanding these risk factors is essential in developing preventative and therapeutic strategies. Angiography with Intravascular ultrasound has become the key diagnostic tool in the early detection of CAV as well as prognostication. Echocardiographic assessment of allograft function in conjunction with coronary angiographic findings are used in assessing the severity of CAV. Adjustment of immunosuppression and statins remain the initial steps in the management of CAV. Retransplantation is the definitive treatment for severe CAV, however, the paucity of organs along with increased mortality associated with retransplantation makes it a less desirable option. Remarkable progress has been achieved in the understanding of pathogenesis, risk factors for CAV and plaque morphology. Nevertheless, significant knowledge gaps persist in scientific understanding of risk factors, pathogenesis, prevention and treatment of CAV. Further research is warranted to fill these gaps, develop diagnostic modalities to facilitate early detection of CAV, and management strategies to Improve graft tolerance and immune modulation. This review focuses on summarizing the pathogenesis and risk factors for CAV.

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The Role of Anti-Hla Antibodies in Heart Transplantation

Cited by 188 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

Contribution of direct and indirect recognition pathways to T cell alloreactivity

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

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