Cardiac allograft vasculopathy (CAV) is a leading cause of death in long-term heart transplant survivors. Dense B cell infiltrates are common in heart transplants with CAV. To understand the role of these cells, we conducted detailed examination of graft-infiltrating B cells with regards to their phenotype, clonality, reactivity and functional interplay with other infiltrating immune cells. We collected 55 cardiac allograft explants and confirmed the presence of CAV in all of them based on intimal thickening of intramural vessels. 93% of these explants had B cell infiltration near coronary arteries. Antibody-producing plasma cells and macrophages could also be detected in 85% and 95% of CAV explants, respectively. Significant fraction of infiltrating macrophages had an M2 phenotype (CD68+CD163+). Notably, B cell infiltrates were not associated with circulating DSA, indicating that the function of these cells was unrelated to the production of anti-HLA antibodies. To study the clonality of infiltrating B cells, we analyzed the immunoglobulin heavy chain variable region (IGVH) repertoire in 6 CAV explants using next generation sequencing. We found that certain B cell clones had undergone robust proliferation at multiple locations in the graft tissue. Lastly, we isolated and immortalized B cell clones directly from 3 fresh CAV explants and analyzed the reactivity profiles of their secreted antibodies using ELISAs and flow cytometry. Remarkably, a majority of these clones had characteristics of innate-like B cells and secreted natural antibodies reactive to multiple auto-antigens and/or to apoptotic cells. To conclude, our study revealed a high frequency of B cell infiltrates around coronary arteries in heart transplants with CAV independent of DSA. The unexpected enrichment of polyreactive innate-like B cells, among infiltrating cells, strongly supports their role in the immune reaction associated with CAV, especially in association with neighboring macrophages.

Supported by NIHAI116814, ROTRF46510926, S10RR027050-01A1.

CITATION INFORMATION: Chatterjee D, Moore C, Gao B, Clerkin K, See S, Shaked D, Rogers K, Nunez S, Veras Y, Addonizio L, Givertz M, Naka Y, Mancini D, Vasilescu R, Marboe C, Restaino S, Madsen J, Zorn E. Prevalence of Polyreactive Innate-Like B Cells Among Graft-Infiltrating B Cells in Human Cardiac Allograft Vasculopathy. Am J Transplant. 2016;16 (suppl 3).

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