Bortezomib and sirolimus inhibit the chronic active antibody-mediated rejection in experimental renal transplantation in the rat

Vogelbacher, Regina; Meister, Silke; Gückel, Eva; Starke, Charlotte; Wittmann, Sandra K.; Stief, Andrea; Voll, Reinhard; Daniel, Christoph; Hugo, Christian

doi:10.1093/ndt/gfq230

Cited by 53 publications

(31 citation statements)

References 27 publications

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“…As expected, advanced chronic lesions (severe transplant glomerulopathy) in this patient remained unchanged [32]. Such promising results as well a recent experimental model [31] provided a valuable basis for the design of a systematic intervention trial.…”

Section: Introductionsupporting

confidence: 70%

Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial

Eskandary

Bond

Schwaiger

et al. 2014

Trials

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BackgroundDespite major advances in transplant medicine, improvements in long-term kidney allograft survival have not been commensurate with those observed shortly after transplantation. The formation of donor-specific antibodies (DSA) and ongoing antibody-mediated rejection (AMR) processes may critically contribute to late graft loss. However, appropriate treatment for late AMR has not yet been defined. There is accumulating evidence that the proteasome inhibitor bortezomib may substantially affect the function and integrity of alloantibody-secreting plasma cells. The impact of this agent on the course of late AMR has not so far been systematically investigated.Methods/designThe BORTEJECT Study is a randomized controlled trial designed to clarify the impact of intravenous bortezomib on the course of late AMR. In this single-center study (nephrological outpatient service, Medical University Vienna) we plan an initial cross-sectional DSA screening of 1,000 kidney transplant recipients (functioning graft at ≥180 days; estimated glomerular filtration rate (eGFR) >20 ml/minute/1.73 m2). DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR. Forty-four patients with biopsy-proven AMR will then be included in a double-blind placebo-controlled intervention trial (1:1 randomization stratified for eGFR and the presence of T-cell-mediated rejection). Patients in the active group will receive two cycles of bortezomib (4 × 1.3 mg/m2 over 2 weeks; 3-month interval between cycles). The primary end point will be the course of eGFR over 24 months (intention-to-treat analysis). The sample size was calculated according to the assumption of a 5 ml/minute/1.73 m2 difference in eGFR slope (per year) between the two groups (alpha: 0.05; power: 0.8). Secondary endpoints will be DSA levels, protein excretion, measured glomerular filtration rate, transplant and patient survival, and the development of acute and chronic morphological lesions in 24-month protocol biopsies.DiscussionThe impact of anti-humoral treatment on the course of late AMR has not yet been systematically investigated. Based on the hypothesis that proteasome inhibition improves the outcome of DSA-positive late AMR, we suggest that our trial has the potential to provide solid evidence towards the treatment of this type of rejection.Trial registrationClinicaltrials.gov: NCT01873157.

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Section: Introductionsupporting

confidence: 70%

Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial

Eskandary

Bond

Schwaiger

et al. 2014

Trials

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“…Inhibitors of mammalian target of rapamycin (mTOR) are potent immunosuppressants with antiproliferative and antimigratory capacities. Sirolimus as a representative of this group displayed potency in controlling an already established humoral alloimmune response as indicated by decreased circulating alloantibodies as well as peritubular C4d in the kidney in a renal allotransplantation rat model [52]. Its administration also led to a reduction in anti‐equine antibody formation after renal transplantation in man treated with equine antithymocyte globulin [53] and strong inhibition of B‐cell responses in vitro [50].…”

Section: Discussionmentioning

confidence: 99%

Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation

Matz¹,

Lehnert²,

Lorkowski³

et al. 2012

Transplant International

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Summary Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B‐cell‐specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B‐cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B‐lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL‐10 production in primary stimulated B cells. In addition, B‐cell co‐cultures with pre‐activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T‐cell‐dependent immunoglobulin production. Sotrastaurin did not inhibit B‐cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B‐cell functions in a dose‐dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T‐cell‐dependent B‐cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B‐lymphocyte function and activation.

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“…Glomerulosclerosis was determined using PAS stained sections as described [20]. Glomerular hypertrophy was determined by measuring the glomerular tuft area of 50 glomerular cross-sections with computer-assisted morphometry using Metavue software (Visitron GmbH, Puchheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

Long-Term Gene Therapy with Thrombospondin 2 Inhibits TGF-β Activation, Inflammation and Angiogenesis in Chronic Allograft Nephropathy

et al. 2013

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We recently identified Thrombospondin-2 (TSP-2) as a regulator of matrix remodelling and inflammation in experimental kidney disease by using TSP-2 null mice and successfully proved TSP-2 overexpression as a therapeutic concept in a short term glomerulonephritis model in the rat. In this current study, we investigated if long-term TSP-2 overexpression is also capable to ameliorate the progression of chronic kidney disease in the setting of the chronic allograft nephropathy F344-Lewis model in the rat. Two weeks after renal transplantation, two rat thigh muscles were transfected once only with either a TSP-2 overexpressing plasmid (n = 8) or a luciferase-expressing plasmid as control (n = 8). Rats were monitored for renal function, histological changes and gene expression in the graft for up to 30 weeks after transplantation. Unexpectedly, only in the TSP-2 treated group 2 rats died before the end of the experiment and renal function tended to be worsened in the TSP-2 group compared to the luciferase-treated controls. In addition, glomerular sclerosis and tubular interstitial injury as well as cortical fibronectin deposition was significantly increased in the TSP-2 treated kidneys despite reduced TGF-β activation and marked anti-inflammatory (macrophages, T-cells and B-cells) effects in this group. Long-term TSP-2 therapy impaired repair of renal endothelium, as demonstrated by significant higher glomerular and peritubular endothelial rarefaction and reduced endothelial cell proliferation in the transplanted kidneys from TSP-2 treated rats compared to controls. This TSP-2 effect was associated with decreased levels of renal VEGF but not VEGF1 receptor. In conclusion, despite its anti-inflammatory and TGF-β activation blocking effects, TSP-2 gene therapy did not ameliorate but rather worsened experimental chronic allograft nephropathy most likely via its anti-angiogenic properties on the renal microvasculature.

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Bortezomib and sirolimus inhibit the chronic active antibody-mediated rejection in experimental renal transplantation in the rat

Abstract: BZ and SRL represent promising drugs with anti-humoral activity in the situation of an already established chronic humoral or mixed alloimmune response after renal transplantation.

Cited by 53 publications

References 27 publications

Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial

Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial

Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation

Long-Term Gene Therapy with Thrombospondin 2 Inhibits TGF-β Activation, Inflammation and Angiogenesis in Chronic Allograft Nephropathy

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