Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss

Gao, Baofeng; Moore, Chris; Porcheray, Fabrice; Rong, Chunshu; Abidoglu, Cem; DeVito, Julie; Paine, Rosemary; Girouard, Timothy C.; Saidman, Susan L.; Schoenfeld, David; Levin, Bruce; Wong, Waichi; Elias, Nahel; Schuetz, Christian; Rosales, Ivy A.; Fu, Yue; Zorn, Emmanuel

doi:10.1111/ajt.12763

Cited by 48 publications

(62 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These two subclasses are complement-fixing, pointing to a possible pathogenic role for these Nabs by complement-mediated graft damage. However, in contrast to our findings in renal transplant patients [10], we did not observe any association between pre-transplant IgG Nabs and rejection.…”

Section: Discussioncontrasting

confidence: 99%

See 1 more Smart Citation

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

See

Clerkin

Kennel

et al. 2017

The Journal of Heart and Lung Transplantation

View full text Add to dashboard Cite

Background Pre-transplant sensitization is a limiting factor in solid organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed the generation of Nabs following VAD implantation in pre-transplant sera and examined their contribution to the cardiac allograft outcome. Methods IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant (OHT) recipients, including 128 VAD and 78 no-VAD patients. Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by ELISA. Results No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared to no-VAD patients. This increase was likely due to presence of VAD, as revealed by lower serum IgG Nabs levels before implantation. Lastly, elevated pre-transplant IgG Nabs level was associated with the development of primary graft dysfunction in this patient series. Conclusions Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support the idea of a broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with the development of primary graft dysfunction suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.

show abstract

Section: Discussioncontrasting

confidence: 99%

“…In previous studies we reported the implication of antibodies reactive to apoptotic cells in AMR following kidney transplantation [10]. These latter antibodies are known as natural antibodies (Nabs) as they are presumed to develop spontaneously in healthy individuals without the need for prior immunization [11].…”

Section: Introductionmentioning

confidence: 99%

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

See

Clerkin

Kennel

et al. 2017

The Journal of Heart and Lung Transplantation

View full text Add to dashboard Cite

show abstract

“…However, a recent study from our lab suggests otherwise. Using serum samples collected pre-transplant from 300 kidney transplant recipients, we found a significant correlation between the presence of polyreactive antibodies cross-reactive to apoptotic cells and late kidney graft loss 14 . Furthermore, the serum reactivity to apoptotic cells was almost exclusively attributable to IgG1 and IgG3, which displayed complement activation properties.…”

Section: Discussionmentioning

confidence: 93%

“…All serum specimens were collected prior to transplantation as part of the patients’ standard clinical care. The detailed characteristics of the patient population have been reported in a previous publication 14 . A succinct summary is provided in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Evidence to Support a Contribution of Polyreactive Antibodies to HLA Serum Reactivity

et al. 2016

View full text Add to dashboard Cite

Background Assessing the serum reactivity to HLA is essential for the evaluation of transplant candidates and the follow-up of allograft recipients. In this study, we look for evidence at the clonal level that polyreactive antibodies cross-reactive to apoptotic cells and multiple autoantigens can also react to HLA and contribute to the overall serum reactivity. Methods We immortalized B cell clones from the blood of two kidney transplant recipients and characterized their reactivity to self-antigens, apoptotic cells as well as native, denatured and cryptic HLA determinants using ELISA, immunofluorescence, flow cytometry and Luminex assays. We also assessed the reactivity of 300 pre-transplant serum specimens to HLA and apoptotic cells. Results We report here 4 distinct B cell clones cross-reactive to self and HLA class I. All 4 clones reacted to numerous HLA class I alleles but did not appear to target canonical “shared” epitopes. In parallel experiments, we observed a strong correlation between IgG reactivity to HLA and apoptotic cells in pre-transplant serum samples collected from 300 kidney transplant recipients. Further analysis revealed that samples with higher reactivity to apoptotic cells displayed significantly higher class I percent PRA compared to samples with low reactivity to apoptotic cells. Conclusions We provide here 1) proof of principle at the clonal level that human polyreactive antibodies can cross-react to HLA, multiple self-antigens and apoptotic cells and 2) supportive evidence that polyreactive antibodies contribute to overall HLA reactivity in the serum of patients awaiting kidney transplant.

show abstract

“…This is in contrast to kidney transplantation cohorts, where highly immunized patients are often observed (15). This low immunization grade can be explained by the fact that no retransplantation patients are present in our cohort.…”

Section: Discussionmentioning

confidence: 81%

Antibodies against Apoptotic Cells Present in End-stage Lung Disease Patients Do Not Correlate with Clinical Outcome after Lung Transplantation

et al. 2017

View full text Add to dashboard Cite

Antibodies against HLA and non-HLA are associated with transplantation outcome. Recently, pretransplant serum IgG antibody levels against apoptotic cells were found to correlate with kidney allograft loss. We investigated the presence of these antibodies in lung transplantation (LTx) patients and evaluated the correlation of pre-LTx serum levels of IgG antibodies against apoptotic cells with LTx outcome. These cells included donor lung endothelial cells (ECs) obtained from lung perfusion fluid collected during LTx procedure. Cells were isolated, expanded in vitro, and analyzed as targets for antiapoptotic cell reactivity. Cultured cells exhibited EC morphology and were CD31+, CD13+, and vWF+. End-stage lung disease patients showed elevated serum IgG levels against apoptotic lung EC (p = 0.0018) compared to healthy controls. Interestingly, the levels of circulating antibodies directed against either apoptotic Jurkat cells or apoptotic lung ECs did not correlate, suggesting a target cell specificity. We observed no correlation between chronic or acute rejection and pre-LTx serum levels of antiapoptotic antibodies. Also, these levels did not differ between matched patients developing chronic rejection or not during follow-up or at the time of diagnosis, as they remained as high as prior to transplantation. Thus, circulating levels of antiapoptotic cell antibodies are elevated in end-stage lung disease patients, but our data do not correlate with outcome after LTx.

show abstract

Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss

Cited by 48 publications

References 47 publications

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation

Evidence to Support a Contribution of Polyreactive Antibodies to HLA Serum Reactivity

Antibodies against Apoptotic Cells Present in End-stage Lung Disease Patients Do Not Correlate with Clinical Outcome after Lung Transplantation

Contact Info

Product

Resources

About