Sustained reduction of alloantibody secreting plasma cells and donor specific antibody with proteasome inhibition in mice

Redfield, Robert; Lou, Yahuan; Rodríguez, Eduardo; Rostami, Susan; Parsons, Ronald F.; Noorchashm, Hooman; Naji, Ali; Abt, Peter L.

doi:10.1016/j.trim.2013.09.010

Cited by 9 publications

(3 citation statements)

References 36 publications

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“…Bortezomib is already applied to treat AMR [28][29][30]. In a murine study, bortezomib could eliminate alloantibody-secreting plasma cells and reduce alloantibodies [31]. It was also proposed as a possible agent in a desensitization protocol for highly sensitized patients in kidney transplantation [32,33].…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of Isoagglutinin Rebound in Adult ABO-Incompatible Living Donor Liver Transplantation

Lee

et al. 2021

JPM

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ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) can be performed successfully. However, anti-ABO isoagglutinin rebound may cause antibody-mediated rejection (AMR) and graft loss. The risk threshold of isoagglutinin rebound is still not defined. 76 ABO-I LDLT recipients were divided into group A (n = 56) with low isoagglutinin titers (<1:256), and group B (n = 20) with high isoagglutinin titers (≥1:256), at initial assessment for liver transplantation. The last 12 patients in group B received a modified desensitization regimen by adding bortezomib to deplete plasma cells. Six (10.7%) patients in group A and 10 (50.0%) patients in group B had postoperative isoagglutinin rebound (p < 0.001). Three patients (5.54%) in group A and two patients (10%) in group B developed clinical AMR (p = 0.602). The cutoff value of postoperative isoagglutinin rebound to cause clinical AMR was ≥1:1024. Among the 12 patients in group B with bortezomib administration, isoagglutinin rebounded up to 1:128 only, and no clinical AMR occurred. In conclusion, the patients with high isoagglutinin titers had a higher rate of postoperative isoagglutinin rebound. Isoagglutinin rebound ≥1:1024 is risky for developing clinical AMR. Adding bortezomib into the desensitization regimen may mitigate isoagglutinin rebound, and avoid clinical AMR.

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Section: Discussionmentioning

confidence: 99%

Clinical Relevance of Isoagglutinin Rebound in Adult ABO-Incompatible Living Donor Liver Transplantation

Lee

et al. 2021

JPM

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“…Plasma cells can be protected in the niche of bone marrow environment, and drug efficacy against plasma cells can be decreased during the inactive stage of antibody production. 23 , 24 To bypass rebound problems or extend the immediate benefit for antibody reduction, it is possible to repeat the current desensitization regimen or apply desensitization to patients when allocation can be offered within a brief period (eg, patients with a long waiting period and a recent history of offer).…”

Section: Discussionmentioning

confidence: 99%

Desensitization Using Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation

Jeong

Jambaldorj

Kwon³

et al. 2016

Medicine

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Combination therapy of intravenous immunoglobulin (IVIG) and rituximab showed a good transplant rate in highly sensitized wait-listed patients for deceased donor kidney transplantation (DDKT), but carried the risk of antibody-mediated rejection. The authors investigated the impact of a new combination therapy of bortezomib, IVIG, and rituximab on transplantation rate.This study was a prospective, open-labeled clinical trial. The desensitization regimen consisted of 2 doses of IVIG (2 g/kg), a single dose of rituximab (375 mg/m2), and 4 doses of bortezomib (1.3 mg/m2). The transplant rate was analyzed. Anti-Human leukocyte antigen (HLA) DRB antibodies were determined by a Luminex solid-phase bead assay at baseline and after 2, 3, and 6 months in the desensitized patients.There were 19 highly sensitized patients who received desensitization and 17 patients in the control group. Baseline values of class I and II panel reactive antibody (%, peak mean fluorescence intensity) were 83 ± 16.0 (14952 ± 5820) and 63 ± 36.0 (10321 ± 7421), respectively. Deceased donor kidney transplantation was successfully performed in 8 patients (42.1%) in the desensitization group versus 4 (23.5%) in the control group. Multivariate time-varying covariate Cox regression analysis showed that desensitization increased the probability of DDKT (hazard ratio, 46.895; 95% confidence interval, 3.468–634.132; P = .004). Desensitization decreased mean fluorescence intensity values of class I panel reactive antibody by 15.5% (20.8%) at 2 months. In addition, a liberal mismatch strategy in post hoc analysis increased the benefit of desensitization in donor-specific antibody reduction. Desensitization was well tolerated, and acute rejection occurred only in the control group.In conclusion, a desensitization protocol using bortezomib, high-dose IVIG, and rituximab increased the DDKT rate in highly sensitized, wait-listed patients.

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“…Mice were given bortezomib (Millennium Pharmaceuticals or Santa Cruz Biotechnology) or phosphate‐buffered saline (PBS) injection via the intravenous (IV) route (unless mentioned otherwise) 0.75 mg/kg body weight twice with a 36‐hour interval. Mice were then either euthanized 36 to 48 hours after the second injection for analysis or were transfused (IV injection) with the equivalent of 1 human unit of transgenic KEL RBCs (75 µL of RBCs) that had been collected in the anticoagulant preservative solution CPDA‐1 and filter leukoreduced over a syringe filter (Pall).…”

Section: Methodsmentioning

confidence: 99%

Bortezomib decreases the magnitude of a primary humoral immune response to transfused red blood cells in a murine model

et al. 2016

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Background Few therapeutic options currently exist to prevent or to mitigate transfusion associated RBC alloimmunization. We hypothesized that bortezomib, a proteasome inhibitor currently being utilized for HLA alloantibody and ADAMTS13 autoantibody reduction, may be beneficial in a transfusion setting. Herein, we utilized a reductionist murine model to test our hypothesis that bortezomib would decrease RBC alloimmune responses. Study designs and methods Wild type mice were treated with bortezomib or saline and transfused with murine RBCs expressing the human KEL glycoprotein. Levels of anti-KEL immunoglobulins in transfusion recipients were measured by flow cytometry. The impact of bortezomib treatment on recipient plasma cells and other immune cells was also assessed by flow cytometry and immunofluorescence. Results Following bortezomib treatment, mice had a 50% reduction in splenic leukocytes and a targeted reduction in bone marrow plasma cells. Mice treated with bortezomib prior to the transfusion of KEL RBCs became allommunized in 3/3 experiments, although their serum anti-KEL IgG levels were 2.6-fold lower than those in untreated mice. Once a primary antibody response was established, bortezomib treatment did not prevent an anamnestic response from occurring. Conclusion To the extent that these findings are generalizable to other RBC antigens and to humans, bortezomib monotherapy is unlikely to be of significant clinical benefit in a transfusion setting where complete prevention of alloimmunization is desirable. Given the impact on plasma cells, however, it remains plausible that bortezomib therapy may be beneficial for RBC alloimmunization prevention or mitigation if used in combination with other immunomodulatory therapies.

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Sustained reduction of alloantibody secreting plasma cells and donor specific antibody with proteasome inhibition in mice

Cited by 9 publications

References 36 publications

Clinical Relevance of Isoagglutinin Rebound in Adult ABO-Incompatible Living Donor Liver Transplantation

Clinical Relevance of Isoagglutinin Rebound in Adult ABO-Incompatible Living Donor Liver Transplantation

Desensitization Using Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation

Bortezomib decreases the magnitude of a primary humoral immune response to transfused red blood cells in a murine model

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