Limited Efficacy of Immunosuppressive Strategy in Transplant Patients Associated with Immunoproteosome

The limited efficacy of a proteosome inhibitor-based immunosuppressive strategy in highly HLA-sensitized transplant recipients has been associated with the immunoproteosome.

Surgery circa 1922. Source: United States Library of Congress

Antibodies targeting the transplanted graft, known as donor-specific antibodies (DSA), are a barrier to graft acceptance and can exert a damaging effect on transplanted tissue.

Since highly HLA-sensitized transplant recipients are not responsive to current anti-DSA therapies, more recent treatment approaches have incorporated proteosome inhibitors which disrupt the activity of bone marrow plasma cells (BMPCs) that produce DSA over the long-term. However, for poorly-characterized reasons, this immunosuppressive strategy has shown only limited efficacy.

A recent study published in the American Journal of Transplantation sought to better define the mechanisms underlying resistance to this treatment strategy. Researchers from the United States and Germany profiled the transcriptome of a particular subset of BMPCs that survived therapy with the proteosome inhibitor Carfilzomib.

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The BMPCs were found to express higher levels of genetic transcripts encoding a specialized version of the proteosome known as the immunoproteosome, and in addition, beared higher levels of the corresponding functionally active protein and other proteins that support immunoproteosome activity.

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While the proteosome-resistant BMPCs exhibited decreased sensitivity to the proteosome inhibitors carfilzomib, bortezomib, and ixazomib, they were more sensitive to ONX-0914, an inhibitor specific to the immunoproteosome.

The researchers then demonstrated that the exposure of BMPCs derived from HLA-sensitized to Carfilzomib in vitro increased the expression level of a subunit of the immunoproteosome, suggesting that treatment with proteosome inhibitors promotes a response involving the immunoproteosome. Further research may lead to more effective immunosuppressive treatments for HLA-sensitized transplant recipients.

Woodle ES, Tremblay S, Brailey P, et al. (2020) Proteasomal adaptations underlying carfilzomib‐resistance in human bone marrow plasma cells. The American Journal of Transplantation, 20(2), 399-410.