Proteasome inhibition for antibody-mediated rejection

Everly, J; Walsh, R. C.; Alloway, Rita R.; Woodle, E. Steve

doi:10.1097/mot.0b013e328330f304

Cited by 86 publications

(73 citation statements)

References 28 publications

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“…A similar rationale has driven the use of bortezomib to deplete the alloreactive HLA-matched antibodies encountered during solid-organ transplant rejection. 69 The few case reports describing the use of this therapy in patients with refractory TTP have used a dosing regimen that is typical for the treatment of multiple myeloma, in which bortezomib is given at 1.3 mg/m 2 on days 1, 4, 8, 11, and repeated every 21 days. Further studies to establish the role of bortezomib in the management of refractory and/or relapsing TTP are needed.…”

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confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

145

143

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Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy. (Blood. 2015;125(25):3860-3867) Case A 25-year-old previously healthy woman presented with a 3-day history of fatigue, nausea, abdominal pain, and easy bruising. She was alert, oriented, afebrile, had mild abdominal tenderness, and purpura on her extremities. Her hemoglobin was 8.4 g/dL; platelets, 15 3 10 9 /L; creatinine, 1.1 mg/dL; and her lactate dehydrogenase and reticulocytes were increased. Schistocytes and nucleated red blood cells were easily seen on her peripheral blood smear. In the absence of other obvious precipitators of thrombocytopenia and microangiopathic hemolytic anemia (MAHA), she was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP). Blood samples were sent for ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13) activity and inhibitor levels, and the patient was immediately started on plasma exchange (PEX) and prednisone 1 mg/kg per day. She responded well initially, and her platelets rose to 105 000/mL on day 4. However, on day 5, she was febrile and her platelets dropped to 40 000/mL. BackgroundAcquired TTP was initially characterized by thrombocytopenia, MAHA, renal failure, neurologic deficits, and fever. However, it is now well accepted that neither renal failure nor high fevers are key diagnostic features. Thrombocytopenia and MAHA are required for diagnosis when TTP is suspected. TTP is a hematologic emergency, with a mortality of 90% if untreated. Treatment with PEX and cortico...

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confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

145

143

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“…Our observations in the current study, that alloantibody detection, complement deposition, and CAV severity correlate closely with each other, add further compelling support for the generally accepted hypothesis that alloantibody contributes to the pathogenesis of CAV. Based on the large body of data suggesting that anti-donor antibody is pathogenic, depletion of B cells with rituximab (35,36) and of plasma cells with bortezomib (37,38) are being evaluated in kidney transplant patients. These studies will determine whether late posttransplant depletion of B cells or plasma cells will attenuate alloantibody production or modulate the progression of incipient chronic antibodymediated renal allograft rejection.…”

Section: Discussionmentioning

confidence: 99%

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Kelishadi¹,

Azimzadeh²,

Zhang³

et al. 2010

J. Clin. Invest.

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Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (αCD20) rituximab depleted CD20 + B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20 + B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with αCD20 or CsA alone. In animals treated with both αCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20 + B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic. IntroductionThe majority of human allograft recipients develop clinically significant chronic rejection, with incidence and severity increasing steadily over time after transplant. For example, over 50% of human cardiac allograft recipients and 80% of lung recipients exhibit chronic rejection within 10 years. Recent additions to the clinical immunosuppressive armamentarium, such as blocking (1) or depleting antibodies (2) and pharmacologic inhibitors (3), have had little appreciable impact on this phenomenon (4-6).The causes of chronic rejection remain incompletely understood. The classic chronic rejection lesions found in heart (cardiac allograft vasculopathy [CAV]), lung (obliterative bronchiolitis), liver (vanishing bile duct syndrome), and renal (chronic allograft nephropathy) allografts are often temporally associated with detection of anti-donor antibodies, implicating alloantibody as an effector mechanism. Animal models (7-10) and clinical data (11-13) consistently implicate T cell-mediated immunity in the elicited alloantibody response. Thus the current consensus paradigm for chronic rejection holds that T cell-mediated adaptive immunity to alloantigens amplifies innate immune activation initiated by donor brain death and organ ischemia/reperfusion. Influenced in part by the intensity of innate immune activation, T cells propagate pathogenic vascular remodeling and sustain alloantigen-specific chronic inflammation in the transplanted organ. Under the influence

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“…The use of Bortezomib in clinical transplantation is advantageous for the specific targeting of long-living CD38+/CD138+/CD20-PCs in the bone marrow and secondary lymphoid tissue. Subsequent studies have shown that Bortezomib alone had little or no impact on DSA levels (Sberro-Soussan et al, 2010); however, when used in combination with PP, IVIG or Rituximab, a prominent reduction in class I and class II DSA concentrations were demonstrated (Diwan et al, 2011;Everly et al, 2009;Perry et al, 2009). In summary, removing DSAs or anti-A/B blood group antibodies expands the donor pool for highly sensitiz ed or ABOi k idney TCs; however, these methods introduce several concerning issues.…”

Section: The Removal Of Anti-ab Blood Group Antibodiesmentioning

confidence: 99%

“…An analysis of graft outcomes in six ABOi donor/recipient combinations did not demonstrate any differences in either creatinine levels or the rate of humoral rejection . More recently, several groups have reported successful implementations of the drug Bortezomib (C 19 H 25 BN 4 O 4 ) (Velcade) for DS and AMR treatment in kidney transplantation (Everly et al, 2009;Raghavan et al, 2010;Walsh et al, 2010). Originally, Bortezomib was used for the treatment of multiple myeloma, which is a tumor consisting of plasma cells (PCs) (Cavo 2006;Mitchell 2003).…”

Section: The Removal Of Anti-ab Blood Group Antibodiesmentioning

confidence: 99%

Characteristics, Detection, and Clinical Relevance of Alloantibodies in Kidney Transplantation

Lobashevsky¹

2011

Kidney Transplantation - New Perspectives

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Proteasome inhibition for antibody-mediated rejection

Cited by 86 publications

References 28 publications

How I treat refractory thrombotic thrombocytopenic purpura

How I treat refractory thrombotic thrombocytopenic purpura

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Characteristics, Detection, and Clinical Relevance of Alloantibodies in Kidney Transplantation

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