Harnessing expressed SNV and single-cell RNA sequencing to define immune cell chimerism in the rejecting kidney transplant

In solid organ transplantation, donor-derived immune cells are assumed to decline with time after surgery. Whether donor leukocytes persist within kidney transplants or play any role in rejection is unknown, however, in part because of limited techniques for distinguishing recipient from donor cells.

The combination of exome sequencing with single-cell RNA sequencing can reveal the recipient versus donor origin of each immune cell within human kidney allografts. This approach greatly improves upon previous techniques used to identify and describe leukocyte chimerism within a complex organ, such as Y chromosome identification for sex-mismatched transplants. Exome sequencing and single-cell RNA sequencing of single nucleotide variants indicated that donor-origin macrophages may contribute to the alloimmune response through antigen presentation and signaling, whereas donor-origin T cells remain quiescent. Therefore, teaming these techniques can paint a portrait of the chimerism that may lie behind rejection of a donor kidney.

There is donor and recipient chimerism of
macrophages and lymphocytes in the transplanted kidney

(A) The Demuxlet pipeline used to resolve the origin of cells from each biopsy. (B) Uniform Manifold Approximation and Projection (UMAP) visualization of 81,139 cells grouped by recipient (red) or donor (green) origin. Inset highlights macrophages (5027 cells) and lymphocytes (3647 cells) grouped by recipient or donor origin.

Malone AF, Wu H, Fronick C, Fulton R, Gaut JP, Humphreys BD. (2002)  Harnessing Expressed Single Nucleotide Variation and Single Cell RNA Sequencing To Define Immune Cell Chimerism in the Rejecting Kidney Transplant. J Am Soc Nephrol [published online ahead of print]. [abstract]

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