Acute Vascular Rejection and Accommodation: Divergent Outcomes of the Humoral Response to Organ Transplantation

Williams, Josie M.; Holzknecht, Zoie E.; Plummer, Timothy B.; Lin, Song; Brunn, Gregory J.; Platt, Jeffrey L.

doi:10.1097/01.tp.0000140770.81537.64

Cited by 80 publications

(59 citation statements)

References 45 publications

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“…Furthermore, our findings that phosphorylation of Akt is most prominent when EC are treated with low concentrations of anti-class I Ab are in accordance with previous studies showing exposure of EC to subsaturating concentrations of anti-HLA Ab increases the expression of Bcl-2 and Bcl-x L and renders the EC refractory to cell lysis (10,16,17). Therefore, similar to anti-ABO Ab, anti-HLA Ab can induce the expression of antiapoptotic proteins that may promote a state of accommodation in the allograft (35). Our studies confirm and extend these findings by identifying FAK as a key upstream tyrosine kinase controlling anti-HLA Ab-mediated prosurvival signaling.…”

Section: Discussionsupporting

confidence: 73%

RNA Interference Elucidates the Role of Focal Adhesion Kinase in HLA Class I-Mediated Focal Adhesion Complex Formation and Proliferation in Human Endothelial Cells

Jin¹,

Korin²,

Zhang³

et al. 2007

The Journal of Immunology

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Ligation of class I molecules by anti-HLA Ab stimulates an intracellular signaling cascade resulting in endothelial cell (EC) survival and proliferation, and has been implicated in the process of chronic allograft rejection and transplant-associated vasculopathy. In this study, we used small interfering RNA blockade of focal adhesion kinase (FAK) protein to determine its role in class I-mediated organization of the actin cytoskeleton, cell survival, and cell proliferation in primary cultures of human aortic EC. Knockdown of FAK appreciably inhibited class I-mediated phosphorylation of Src at Tyr418, p85 PI3K, and Akt at both Thr308 and Ser473 sites. FAK knockdown also reduced class I-mediated phosphorylation of paxillin at Try118 and blocked class I-induced paxillin assembly into focal contacts. FAK small interfering RNA completely abrogated class I-mediated formation of actin stress fibers. Interestingly, FAK knockdown did not modify fibroblast growth factor receptor expression induced by class I ligation. However, FAK knockdown blocked HLA class I-stimulated cell cycle proliferation in the presence and absence of basic fibroblast growth factor. This study shows that FAK plays a critical role in class I-induced cell proliferation, cell survival, and focal adhesion assembly in EC and may promote the development of transplant-associated vasculopathy.

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Section: Discussionsupporting

confidence: 73%

RNA Interference Elucidates the Role of Focal Adhesion Kinase in HLA Class I-Mediated Focal Adhesion Complex Formation and Proliferation in Human Endothelial Cells

Jin¹,

Korin²,

Zhang³

et al. 2007

The Journal of Immunology

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“…Especially as BGA persist in all of our recipients of ABO-incompatible renal allografts, such longer term studies are needed to determine whether diffuse C4d staining without evidence of rejection truly reflects a state of graft accommodation, in which the organ continues to function well despite the presence of antibodies directed against it. 23 The finding of diffuse PTC C4d staining without histologic evidence of rejection on one or more early protocol biopsies did not preclude later development of AMR, although the latter was rare in this study. Only one of 21 group A patients compared with three of 12 group B patients developed AMR, although this difference did not reach statistical significance and no grafts in either group were lost to AMR.…”

Section: Discussionmentioning

confidence: 44%

“…Inhibition of the complement cascade distal to C4 cleavage by factors such as decay-accelerating factor, CD59, and heparan sulfate may play a vital role in determining whether grafts exposed to such antibody develop AMR or show accommodation. 23,33,34 Indeed, recent studies in a heart xenograft model similar to that noted already demonstrated elevated expression of decay-accelerating factor, CD59, and Crry (a rodent complement regulatory protein) on capillary endothelial cells of accommodating grafts. 34 The regulation of expression of these factors in human allografts and how this is affected by binding of antibodies against blood group and HLA antigens expressed on the graft remain important areas for future study.…”

Section: Discussionmentioning

confidence: 99%

C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts

Haas

Segev

Racusen

et al. 2009

Journal of the American Society of Nephrology

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C4d deposition in peritubular capillaries is a specific marker for the presence of antidonor antibodies in renal transplant recipients and is usually associated with antibody-mediated rejection (AMR) in conventional allografts. In ABO-incompatible grafts, however, peritubular capillary C4d is often present on protocol biopsies lacking histologic features of AMR; the significance of C4d in this setting remains unclear. For addressing this, data from 33 patients who received ABO-incompatible renal allografts (after desensitization) were retrospectively reviewed. Protocol biopsies were performed at 1 and/or 3 and 6 mo after transplantation in each recipient and at 12 mo in 28 recipients. Twenty-one patients (group A) had strong, diffuse peritubular capillary C4d staining without histologic evidence of AMR or cellular rejection on their initial protocol biopsies. The remaining 12 patients (group B) had negative or weak, focal peritubular capillary C4d staining. Three grafts (two in group B) were lost but not as a result of AMR. Excluding these three patients, serum creatinine levels were similar in the two groups at 6 and 12 mo after transplantation and at last follow-up; however, recipients in group A developed significantly fewer overall chronic changes, as scored by the sum of Banff chronic indices, than group B during the first year after transplantation. These results suggest that diffuse peritubular capillary C4d deposition without rejection is associated with a lower risk for scarring in ABO-incompatible renal allografts; the generalizability of these results to conventional allografts remains unknown.

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“…In any case, C4d deposition in ABO-incompatible grafts can be seen routinely without features of AHR and therefore is of limited value. Perhaps deposition of later complement components (C5b or MAC) or absence of heparan sulfate and syndecan-4-phosphate will show more correlation with injury, as has been reported in xenografts (53). C4d deposition also occurs in 2 to 26% of histologically normal ABO-compatible grafts, the higher frequency found in HLA-presensitized patients (8,54) ( Figure 5).…”

Section: Accommodationmentioning

confidence: 72%

Antibody-Mediated Renal Allograft Rejection

Colvin

2007

Journal of the American Society of Nephrology

486

441

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Alloantibodies to HLA class I or II and other antigens expressed by endothelium cause a variety of effects on renal transplants, ranging from acute to chronic rejection, and even apparent graft acceptance (accommodation). Recognition of these conditions and appropriate therapy requires demonstration of C4d in biopsies, commonly confirmed by tests for circulating alloantibody. Substantial practical experience by pathologists in the interpretation and pitfalls of C4d stains are reviewed along with considerations of the clinical significance and pathologic mechanisms of the different effects of antibody on the endothelium of the renal allograft. Clinical trials will be needed to ascertain the optimal treatment for the newly appreciated conditions chronic humoral rejection and accommodation.

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Acute Vascular Rejection and Accommodation: Divergent Outcomes of the Humoral Response to Organ Transplantation

Abstract: These findings suggest that control of complement may underlie accommodation, at least in part, and raise the possibility that this control and possibly other protective mechanisms could be exerted by heparan sulfate.

Cited by 80 publications

References 45 publications

RNA Interference Elucidates the Role of Focal Adhesion Kinase in HLA Class I-Mediated Focal Adhesion Complex Formation and Proliferation in Human Endothelial Cells

RNA Interference Elucidates the Role of Focal Adhesion Kinase in HLA Class I-Mediated Focal Adhesion Complex Formation and Proliferation in Human Endothelial Cells

C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts

Antibody-Mediated Renal Allograft Rejection

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