Purpose

Cytomegalovirus (CMV) infection accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants. Sphingolipid metabolism plays an immunomodulatory role in transplant rejection, and may be synergistic with CMV-accelerated CR. We aim to identify lipidomic phenotypes associated with CMV-accelerated cardiac CR.

Methods

RCMV latently infected (infection 6mo pretransplant) F344 rat donor hearts were heterotopically transplanted into CMV-naïve Lewis recipients. Transplant recipients were immunosuppressed with CsA for 10 days to prevent acute rejection. The time to CR and degree of TVS based on neointimal index (NI) scoring were assessed. Transcriptomics was performed on allograft and native hearts to assess changes in host gene expression. UPLC-MS-Based top-down/bottom-up lipidomics analyses were performed on rat native and graft hearts and human heart allograft recipient biopsy samples to explore global lipidomic changes associated with CR.

Results

Rodent recipients of CMV latently infected hearts rejected earlier than uninfected controls (POD54 v 90; p=0.01) and had more severe TVS (NI=63 v 50; p=0.01). To identify pathways that were dysregulated in CMV accelerated CR, transcriptomics of native vs allograft hearts was performed. Genes involved in sphingolipid and ceramide biogenesis were upregulated, suggesting a pathway for cardiac damage in CMV-accelerated CR. Lipidomics analysis identified 260 lipid features (p<0.05) differentiating native from allograft hearts and 815 (p<0.05), including Sphingosine (p<0.04), differentiating RCMV-infected allograft hearts from uninfected allografts. Native hearts, naïve allografts, and CMV-latently infected allografts could be distinguished based on their lipid profiles. Similar lipidomics analysis of human allograft heart biopsies identified 162 lipid features that segregated samples from patients undergoing mild rejection vs no rejection (p<0.05).

Conclusions

Dynamic lipid profiles reflect patterns of cardiac damage and rejection. During CR, allograft hearts accumulate cardiotoxic sphingolipid and ceramide metabolites that contribute to the rejection process. These rejection-associated lipids represent biomarkers of cardiac rejection that may facilitate the development of targeted antirejection medications.

CITATION INFORMATION: Burg J, Andoh T, Haese N, Kreklywich C, Watters K, Metz T, Orloff S, Streblow D. CMV-Accelerated Cardiac Allograft Rejection Is Associated with Dysregulation of Sphingolipid Metabolomics. Am J Transplant. 2016;16 (suppl 3).

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