BTS 2013 Report – Treating antibody-mediated rejection

by Maria Dalby reporting on the presentation by Steve Woodle, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.   The future of treatment of antibody-mediated rejection (AMR) may lie in proteasome inhibition. Agents such as bortezomib have been shown to be effective for reversing AMR by targeting and depleting the main source of antibody production, namely the mature plasma cell.

Professor Steve Woodle from the University of Cincinnati has conducted several studies on the role of proteasome inhibition in transplantation; in his presentation, he suggested that one of the main advantages of using proteasome inhibitor is the opportunity for combination therapy with synergy effects.

 

Development of donor-specific HLA antibodies is a prognostic marker for graft failure in renal transplantation (1). Whilst antibody removal is known to improve survival (2), current protocols, including intravenous immunoglobulin, plasma exchange, antithymocyte globulin or rituximab, have shown inconsistent results and the effect is often transient (3).

 

Proteasomes are large enzymatic structures that are present in the cytosol of all eukaryotic cells. Their function is to help maintain cellular homeostasis by degrading mis-folded proteins, transcription factors and inhibitory molecules during the cell cycle. Proteasome inhibitors such as bortezomib are believed to exert their immunomodulatory effect through four key physiological mechanisms, namely inhibition of nuclear factor kappa B (NFkB) activity, inhibition of proliferation and induction of apoptosis via cell cycle arrest, induction of apoptosis via endoplasmic reticulum stress, and inhibition of Class I major histocompatibility complex (MHC) expression by reducing endogenous peptide production. Animal studies have shown that bortezomib has the capacity to deplete mature plasma cells (3).

 

Clinical experience with bortezomib in transplant recipients is as yet limited, but an initial report of six patients with AMR and concomitant acute cellular rejection following kidney transplantation showed that treatment with bortezomib resulted in prompt rejection reversal, marked and prolonged reductions in DSA levels, improved graft function, and prevention of recurrent rejection for at least five months (4). A further study demonstrated that bortezomib was superior to intravenous immunoglobulin, antithymocyte globulin and rituximab for inducing apoptosis of human bone marrow-derived plasma cells and subsequently block antibody production (5). Data from more recent studies at Professor Woodle’s centre indicates that bortezomib is effective not only on refractory AMR but also as primary therapy for removing DSAs in early acute AMR (6), and results in differential responses in early and late-phase AMR (7). In addition, the clinical efficacy of bortezomib has been documented in cases of biopsy-proven AMR in paediatric heart transplant recipients, with complete resolution in all cases together with improvement in systolic function, and rapid reduction in DSAs (8). In terms of tolerability, bortezomib has exhibited an overall reasonable side effect profile, with reports of transient thrombocytopenia and diarrhoea during the early case series (4,6). A recent prospective evaluation of toxicities associated with bortezomib and desensitisation showed that the incidence of toxicity amongst 51 kidney transplant recipients receiving bortezomib was low and manageable, with no malignancies reported (9).

 

Professor Woodle is optimistic for the future of proteasome inhibition, as new and more selective agents are being developed and the underlying mechanisms of proteasome inhibition are being characterised in detail. He concluded that the opportunity for combination therapy to realise synergistic effects is considerable.

 

 

1.  Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-13. Epub 2009/05/23.

2.  Everly MJ, Everly JJ, Arend LJ, Brailey P, Susskind B, Govil A, et al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(5):1063-71. Epub 2009/04/07.

3.  Walsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney international. 2012;81(11):1067-74. Epub 2012/02/18.

4.  Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation. 2008;86(12):1754-61. Epub 2008/12/24.

5.  Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(1):201-9. Epub 2008/11/04.

6.  Walsh RC, Everly JJ, Brailey P, Rike AH, Arend LJ, Mogilishetty G, et al. Proteasome inhibitor-based primary therapy for antibody-mediated renal allograft rejection. Transplantation. 2010;89(3):277-84. Epub 2010/02/11.

7.  Walsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, et al. Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition. Transplantation. 2011;91(11):1218-26. Epub 2011/05/28.

8.  Morrow WR, Frazier EA, Mahle WT, Harville TO, Pye SE, Knecht KR, et al. Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients. Transplantation. 2012;93(3):319-24. Epub 2011/12/20.

9.  Schmidt N, Alloway RR, Walsh RC, Sadaka B, Shields AR, Girnita AL, et al. Prospective evaluation of the toxicity profile of proteasome inhibitor-based therapy in renal transplant candidates and recipients. Transplantation. 2012;94(4):352-61. Epub 2012/07/28.