First, this was a pilot safety study on plerixafor and bortezomib in a patient population with ESRD that was not powered to determine efficacy
First, this was a pilot safety study on plerixafor and bortezomib in a patient population with ESRD that was not powered to determine efficacy. group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a post-treatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens. Citronellal Keywords: desensitization, plasma cells, plerixafor, bortezomib, proteasome inhibitors, antibody, single-cell genomics, kidney transplant, DSA, donor-specific antibodies, HLA antibodies 1.?Introduction Despite improvements in organ availability and allocation, obtaining a well-matched kidney transplant remains challenging for patients with high degrees of human leukocyte antigen (HLA) sensitization. HLA sensitization increases the waiting time on dialysis and the associated mortality risk.1 Moreover, after transplantation, sensitized patients are at increased risk of antibody-mediated rejection (AMR), and concomitant allograft failure.2C4 To date, desensitization therapies, such as intravenous immunoglobulin and plasmapheresis, have been associated with transient reductions in anti-HLA antibody (aHLA Ab) titers, which rebound upon treatment cessation.5C7 To achieve sustained reduction in aHLA Ab, we have focused on developing plasma cell (PC)Ctargeting approaches using proteasome inhibitors (PIs) because PCs are dependent on proteasomes to degrade misfolded proteins resulting from their high rate of antibody synthesis.8C19 Although PIs deplete PCs, toxicities and aHLA Ab rebound remain a challenge.9,20 The mechanism(s) of rebound is unclear but may be owing to incomplete PC depletion, the resolution of unfolded protein responses, and/or repopulation of bone marrow (BM) plasma cells (BMPCs) by newly differentiated PCs generated after treatment.21 One approach for enhancing PC depletion is to target multiple survival pathways using multiagent regimens. During an immune response, a portion of newly generated PCs home to the BM through CXCL12 chemokine gradients. Although the mechanisms driving long-term PC survival remain incompletely understood, consensus holds that PCs reside in CXCL12-rich niches where proximity to stromal and immune cells provides prosurvival signals through cytokines and cellCcell contact.22C24 CXCR4 signaling in PCs induces the expression of the adhesion factors VLA-4 and LFA-1, which are important for physically maintaining PCs in the BM.25,26 Moreover, CXCR4 signaling promotes survival in other cell types but has not been demonstrated in PCs.27,28 Given the importance of the BM niche, we hypothesized that disrupting niche access would sensitize PCs to death by survival factor deprivation and/or PI treatment. We sought to mobilize BMPCs using the CXCR4 Citronellal antagonist, plerixafor, to interrupt the CXCR4:CXCL12 axis that recruits and retains PCs in DNM2 the Citronellal BM.29 We conducted a proof-of-concept Citronellal and safety evaluation of plerixafor alone and with bortezomib in HLA-sensitized patients awaiting kidney transplantation. 2.?Materials and methods A detailed report of materials and methods is provided in the Supplementary Materials. 2.1. Study approval The study (NCT02522572) was approved by the University of Cincinnati Institutional Review Board (#2014C4773) and conducted in accordance with the tenets of the Declaration of Helsinki. All animal experiments were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee at Cincinnati Childrens Hospital Medical Center. 3.?Results 3.1. Demographics Between 2015 and 2021, 11 participants were enrolled in the study (Fig. 1A). Group A participants 1 and 2 were re-enrolled in group B (as participants 7 [8 months after completing group A] and 5 [16.5 months after completing group A but was transplanted before starting group.