Plasma cell targeting to prevent antibody-mediated rejection

Abstract

Plasma cells (PCs) are the major source of pathogenic allo- and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However, significant recent clinical progress has been made with the use of second-generation proteasome inhibitors (PIs). PIs provide efficient elimination of plasmablast-mediated humoral responses; however, long-lived bone marrow (BM) resident PCs (LLPCs) demonstrate therapeutic resistance, particularly to first-generation PIs. In addition, durability of antibody (Ab) reduction still requires improvement. More recent clinical trials have focused on conditions mediated by LLPCs and have included mechanistic studies of LLPCs from PI-treated patients. A recent clinical trial of carfilzomib (a second-generation irreversible PI) demonstrated improved efficacy in eliminating BM PCs and reducing anti-HLA Abs in chronically HLA-sensitized patients; however, Ab rebound was observed over several weeks to months following PI therapy. Importantly, recent murine studies have provided substantial insights into PC biology, thereby further enhancing our understanding of PC populations. It is now clear that BMPC populations, where LLPCs are thought to primarily reside, are heterogeneous and have distinct gene expression, metabolic, and survival signatures that enable identification and characterization of PC subsets. This review highlights recent advances in PC biology and clinical trials in transplant populations. Plasma cells (PCs) are the major source of pathogenic allo- and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However, significant recent clinical progress has been made with the use of second-generation proteasome inhibitors (PIs). PIs provide efficient elimination of plasmablast-mediated humoral responses; however, long-lived bone marrow (BM) resident PCs (LLPCs) demonstrate therapeutic resistance, particularly to first-generation PIs. In addition, durability of antibody (Ab) reduction still requires improvement. More recent clinical trials have focused on conditions mediated by LLPCs and have included mechanistic studies of LLPCs from PI-treated patients. A recent clinical trial of carfilzomib (a second-generation irreversible PI) demonstrated improved efficacy in eliminating BM PCs and reducing anti-HLA Abs in chronically HLA-sensitized patients; however, Ab rebound was observed over several weeks to months following PI therapy. Importantly, recent murine studies have provided substantial insights into PC biology, thereby further enhancing our understanding of PC populations. It is now clear that BMPC populations, where LLPCs are thought to primarily reside, are heterogeneous and have distinct gene expression, metabolic, and survival signatures that enable identification and characterization of PC subsets. This review highlights recent advances in PC biology and clinical trials in transplant populations. Rejection has long been known to be a major, if not the most important factor determining renal allograft survival. In the 2000s, our group and others presented evidence indicating that antibody-mediated rejection (AMR) and mixed acute rejection (MAR; defined as coexisting T cell–mediated rejection [TCMR] and AMR) had a much greater negative effect on allograft survival than TCMR alone.1Everly MJ Everly JJ Arend LJ et al.Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.Am J Transplant. 2009; 9: 1063-1071Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Recognition that the presence of a humoral component in rejection (either as AMR or MAR) was a major negative prognostic factor for renal allograft survival has led to recognition that traditional antihumoral therapies (plasmapheresis and intravenous immune globulin [IVIG]) provide inadequate therapeutic approaches. A possible explanation for the inability of IVIG-based therapies to provide optimal long-term renal allograft survival after AMR is that they are known to have negligible effects on reducing HLA antibody levels. Data supporting these observations in part derive from a study in which the effects of traditional antihumoral desensitization agents on splenic populations were analyzed.2Ramos EJ Pollinger HS Stegall MD Gloor JM Dogan A Grande JP. The effect of desensitization protocols on human splenic B-cell populations in vivo.Am J Transplant. 2007; 7: 402-407Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar In this study, patients with pretransplant HLA antibodies underwent desensitization with a splenectomy also performed at the time of transplant. Analysis of these spleens for effects of various agents (IVIG, plasmapheresis, rituximab, and antithymocyte globulin) revealed that IVIG did not deplete either B cells or plasma cells, that rituximab depleted immature B cells, mature B cells, and had a partial effect on memory B cells. None of the agents significantly depleted plasma cells, which are the source of antibody production. Similarly, a study from Hopkins evaluated IVIG-based desensitization regimens in very highly HLA-sensitized kidney transplant candidates who were on dialysis. Modern, solid phase multiplexed assays were utilized to analyze the effects on HLA antibody levels and demonstrated minimal effects in reducing HLA antibody levels.3Alachkar N Lonze BE Zachary AA et al.Infusion of high-dose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients.Transplantation. 2012; 94: 165-171Crossref PubMed Scopus (46) Google Scholar Recognition of the limited capacity of IVIG to reduce HLA antibody levels in chronically HLA-sensitized patients has led to an increased focus on developing agents that can significantly reduce HLA antibody levels. This article will focus on recent clinical and experimental advances that may inform and improve approaches for plasma cell (PC) targeting to prevent AMR. Such approaches will have potentially broad application, beyond AMR to other conditions in which pathogenic PCs drive human disease. As with most Ab responses, AMR can be either de novo, in which antigen-inexperienced naïve B cells expand and differentiate into memory B cells and/or Ab-producing cells, or anamnestic, in which memory B cells are stimulated in an antigen-specific or nonantigen-specific manner to produce a marked burst in plasmablast (PB) generation and donor-specific anti-HLA Ab (DSA). To date, to our knowledge, proteasome inhibitors (PIs) have only been used to prevent anamnestic AMR, not de novo AMR. Prevention of de novo AMR would likely require long-term maintenance immunosuppression using PIs, something that has not yet been attempted. PIs have been used to prevent anamnestic AMR based on the premise that higher DSA levels pretransplant are associated with higher AMR risk,4Lefaucheur C Loupy A Hill GS et al.Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.J Am Soc Nephrol. 2010; 21: 1398-1406Crossref PubMed Scopus (625) Google Scholar and that reduction in DSA levels prior to transplant will reduce AMR risk and also the risk of immediate DSA-mediated allograft injury at the time of transplantation and reperfusion of the transplanted kidney. Typically, naïve B cells give rise to PCs as a result of exposure to antigen either via germinal center (GC) reactions or extrafollicular responses in secondary lymphoid organs. Importantly, GC reactions give rise to PCs producing the highest affinity antibodies, with the greatest degree of class switching (and therefore pathogenic potential via complement activation and FcR interactions).5Methot SP Di Noia JM. Molecular mechanisms of somatic hypermutation and class switch recombination.Adv Immunol. 2017; 133: 37-87Crossref PubMed Scopus (139) Google Scholar In the GC, control of fate decisions (that is, the decisions between death and survival and either memory B cell or PC development) is controlled by a complex and incompletely understood set of gene regulatory events that include transcription factors such as BLIMP, BCL6, Pax5, IRF4, and IRF8 among others.6Singh H Glasmacher E Chang AB Vander LB. The molecular choreography of IRF4 and IRF8 with immune system partners.Cold Spring Harb Symp Quant Biol. 2013; 78: 101-104Crossref PubMed Scopus (16) Google Scholar Once committed to PC generation, B cells activate >100 genes, many of which are unfolded protein response (UPR) genes.7Malhotra JD Kaufman RJ. The endoplasmic reticulum and the unfolded protein response.Semin Cell Dev Biol. 2007; 18: 716-731Crossref PubMed Scopus (782) Google Scholar,8Obeng EA Carlson LM Gutman DM Harrington Jr, WJ Lee KP Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells.Blood. 2006; 107: 4907-4916Crossref PubMed Scopus (862) Google Scholar A large number of UPR genes are activated by spliced (activated) XBP-1 and promote the synthesis of prodigious amounts of rough ER and Golgi apparatus that are requisite for large-scale translation of Ig transcripts, immunoglobulin folding (which requires ATP), cysteine bonding (also requires ATP), glycosylation, and packaging of antibody molecules for secretion. This “rewiring” enables mature PCs to produce several thousand antibody molecules per thereby the PC substantial and an antibody a for the unfolded protein Immunol. PubMed Scopus Google in the gene regulatory B cell Immunol. 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