Review of Bortezomib Treatment of Antibody-Mediated Rejection in Renal Transplantation

Ejaz, Nazia; Alloway, Rita R.; Halleck, Fabian; Dürr, Michael; Budde, Klemens; Woodle, E. Steve

doi:10.1089/ars.2014.5892

Cited by 44 publications

(32 citation statements)

References 87 publications

(159 reference statements)

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“…Understanding the basic biology of these cells will allow for the rationale use of therapeutics (Table 1); for instance, anti-CD20 (Rituximab) should successfully curtail memory and naïve B cell responses, targeting the B cell survival factor with anti-BAFF/BLyS (anti-BAFF; belimumab) should reduce the mature B cell pool as well GC B cell responses while the combined inhibition of BAFF and APRIL with TACI-Ig; (atacicept) should additionally deplete plasma cells (70), and the depletion of short-lived ASC can be achieved with the small molecule inhibitor of proteasome, bortezomib (Velcade), which promotes plasma cell apoptosis and inhibits cell proliferation (71). Finally, comparable methodologies are being used to quantify LLPC/ASCs and memory B cells specific for alloantigens or pathogens in transplant patients.…”

Section: Discussionmentioning

confidence: 99%

Memory B Cells in Transplantation

Chong

Sciammas

2015

Transplantation

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Much of the research on the humoral response to allografts has focused on circulating serum antibodies and the long-lived plasma cells that produce these antibodies. In contrast, the interrogation of the quiescent memory B cell compartment is technically more challenging and thus has not been incorporated into the clinical diagnostic or prognostic toolkit. In this review, we discuss new technologies that have allowed this heretofore enigmatic subset of B cells to be identified at quiescence and during a recall response. These technologies in experimental models are providing new insights into memory B cell heterogeneity with respect to their phenotype, cellular function and the antibodies they produce. Similar technologies are also allowing for the identification of comparable memory alloreactive B cells in transplant recipients. While much of the focus in transplant immunology has been on controlling the alloreactive B cell population, long-term transplant patient survival is critically dependent on protection by pathogen-specific memory B cells. Techniques are also available that allow the interrogation of memory B cell response to pathogen re-encounter. Thus we are poised in our ability toinvestigate how immunosuppression affects allo- as well as pathogen-specific memory B cells, and reason that these investigation can yield new insights that will be beneficial for graft as well as patient survival.

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Section: Discussionmentioning

confidence: 99%

Memory B Cells in Transplantation

Chong

Sciammas

2015

Transplantation

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“…Rapamycin has also been shown to inhibit production of the inflammatory mediator iNOS in macrophage cell lines [89]. Bortezomib is a protease inhibitor mainly used in the treatment of AMR [90] and has also been found to block T-cell mediated responses [91, 92]. In a murine model of contact hypersensitivity, an inflammatory immune reaction mediated by T cells, Bortezomib treatment resulted in a noted reduction in macrophage infiltration [91].…”

Section: The Effects Of Immunosuppressives and Therapeutics On Macropmentioning

confidence: 99%

The divergent roles of macrophages in solid organ transplantation

Salehi

Reed

2015

Current Opinion in Organ Transplantation

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Purpose of review This review summarizes the phenotype and function of macrophages in the context of solid organ transplantation and will focus on fundamental insights into their paradoxical pro-inflammatory versus suppressive function. We will also discuss the therapeutic potential of regulatory macrophages in tolerance induction. Recent findings Macrophages are emerging as an essential element of solid organ transplantation. Macrophages are involved in the pathogenesis of ischemia reperfusion injury, as well as both acute and chronic rejection, exacerbating injury through secretion of inflammatory effectors and by amplifying adaptive immune responses. Notably, not all responses associated with macrophages are deleterious to the graft, and graft protection can in fact be conferred by macrophages. This has been attributed to the presence of macrophages with tissue-repair capabilities, as well as the effects of regulatory macrophages. Summary The explosion of new information on the role of macrophages in solid organ transplantation has opened up new avenues of research and the possibility of therapeutic intervention. However, the role of myeloid cells in graft rejection, resolution of rejection and tissue repair remains poorly understood. A better understanding of plasticity and regulation of monocyte polarization is vital for the development of new therapies for the treatment of acute and chronic transplant rejection.

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“…66 Currently, there are no US Food and Drug Administration-approved treatments for AMR, 67 and based on the success of bortezomib in killing myeloma plasma cells, proteasome inhibition was tested in cases of AMR refractory to treatment with plasmapheresis and intravenous Ig in the presence or absence of rabbit anti-thymocyte globulin or rituximab following renal transplant. 68 Bortezomib showed significant activity reducing anti-HLA antibodies by 50% within 2 weeks. 69,70 Of the agents used for treatment of AMR in renal transplant, only bortezomib was shown to induce apoptosis of plasma cells in vitro and deplete bone marrow plasma cells in 2 patients.…”

mentioning

confidence: 95%

“…69,70 Of the agents used for treatment of AMR in renal transplant, only bortezomib was shown to induce apoptosis of plasma cells in vitro and deplete bone marrow plasma cells in 2 patients. A larger trial using a bortezomibbased protocol has shown promising activity; however, not all studies have been positive, and there is no report of a randomized trial, 68 although one is being initiated. 71 Additionally results from the use of bortezomib to desensitize patients with anti-HLA antibodies prior to renal transplant have been equivocal.…”

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confidence: 99%

The Tao of myeloma

Boise

Kaufman²,

Bahlis

et al. 2014

Blood

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Multiple myeloma is a plasma cell malignancy in which significant advances have been observed during the last 15 years. Our understanding of the disease has been advanced through its molecular characterization. We have also seen improvements in patient care with the development of 2 new classes of active agents, proteasome inhibitors and immunomodulatory drugs (IMiDs), resulting in a significant improvement in overall survival of myeloma patients such that it can now be debated as to whether some subsets of myeloma patients can be cured. However, the advances in our understanding of myeloma biology occurred in parallel with advances in treatment as opposed to being directly informed by the research. Moreover, the molecular characterization of malignant plasma cells would not have predicted the effectiveness of these novel therapies. We hypothesize that proteasome inhibitors and IMiDs are highly active because malignant plasma cells are constrained by many of the characteristics of their normal counterparts and these novel therapies target both normal plasma cell biology and the cancer biology of myeloma. Thus, a better understanding of normal plasma cell biology will likely yield as many actionable targets as mapping the genomic landscape of this disease.

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Review of Bortezomib Treatment of Antibody-Mediated Rejection in Renal Transplantation

Abstract: In the next few years, new PIs are likely to be introduced and new approaches would be developed for achieving synergy with PIs. The ultimate goal will be to develop a regimen that delivers reliable, rapid, complete, and durable elimination of DSA with an acceptable safety profile.

Cited by 44 publications

References 87 publications

Memory B Cells in Transplantation

Memory B Cells in Transplantation

The divergent roles of macrophages in solid organ transplantation

The Tao of myeloma

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