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

Abstract

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.

Factors influencing transfusion‐associated HLA sensitization in patients bridged to heart transplantation using ventricular assist device

“…Production of non‐specific antibodies associated with VAD has been attributed to bystander activation of B cells due to a “pro‐inflammatory” environment caused by turbulent blood flow and reactivity to the VAD. Non‐specific antibodies can cause positive reactions in cellular crossmatch and alloantibody immunoassays, though their clinical significance appears to be limited . Consistent with this, we observe non‐specific antibodies as evidenced by high background in solid‐phase immunoassays and cellular crossmatching, though the effects of these are limited by routine use of EDTA serum treatment in solid‐phase immunoassay and DTT serum treatment in cellular crossmatch.…”

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens

“…21 In this study, we focused on anti-AT1R, 3 anti-ETAR 22,23 and NAbs. 24,25 Although none of these candidates clearly identified our patients with AMVR compared with stable KTRs, the more surprising result was that they were all correlated with each other. Indeed, we identified a strong correlation (r 2 =0.82) between anti-AT1R and anti-ETAR Abs, a finding that was also reported previously in the context of heart 22 and renal transplantation.…”

An unusual case of anemia in a cardiac transplant recipient

“…However, due its ability to bind to these select progenitor cells, the anti‐M antibody has been implicated in development of delayed transfusion reactions, hemolytic disease of the newborn, and red cell aplasia through inhibition of red cell precursor growth . Blood transfusions are a known risk factor for blood‐group antibody development . Considering the clinical history, the development of an anti‐M antibody is not surprising.…”

“…6,7 Blood transfusions are a known risk factor for blood-group antibody development. 8 Considering the clinical history, the development of an anti-M antibody is not surprising. The fact that our patient's antibody functioned at warm temperatures suggests that it could have played a role in the development of anemia.…”