FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2885193934> ?p ?o ?g. }

• W2885193934 endingPage "736" @default.
• W2885193934 startingPage "724" @default.
• W2885193934 abstract "Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy–mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns. Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy–mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns. Sensitization to human leukocyte antigens (HLAs) affects 30% of patients currently on the kidney waiting list.1Hart A Smith JM Skeans MA et al.OPTN/SRTR 2015 annual data report: kidney.Am J Transplant. 2017; 17: 21-116Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar Desensitization treatments have proven effective at lowering the risk of hyperacute rejection.2Gloor JM DeGoey SR Pineda AA et al.Overcoming a positive crossmatch in living-donor kidney transplantation.Am J Transplant. 2003; 3: 1017-1023Crossref PubMed Scopus (237) Google Scholar, 3Riella LV Safa K Yagan J et al.Long-term outcomes of kidney transplantation across a positive complement-dependent cytotoxicity crossmatch.Transplantation. 2014; 97: 1247-1252Crossref PubMed Scopus (39) Google Scholar, 4Bartel G Wahrmann M Regele H et al.Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation.Am J Transplant. 2010; 10: 2033-2042Crossref PubMed Scopus (63) Google Scholar Early results also suggest acceptable 1-year graft survival despite high rejection rates.5Gloor JM Winters JL Cornell LD et al.Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.Am J Transplant. 2010; 10: 582-589Crossref PubMed Scopus (0) Google Scholar, 6Haririan A Nogueira J Kukuruga D et al.Positive cross-match living donor kidney transplantation: longer-term outcomes.Am J Transplant. 2009; 9: 536-542Crossref PubMed Scopus (0) Google Scholar, 7Jordan SC Tyan D Stablein D et al.Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial.J Am Soc Nephrol. 2004; 15: 3256-3262Crossref PubMed Scopus (357) Google Scholar Desensitized patients increase their chance of transplantation compared to remaining on the waiting list until a compatible match is found.8Montgomery RA Lonze BE King KE et al.Desensitization in HLA-incompatible kidney recipients and survival.N Engl J Med. 2011; 365: 318-326Crossref PubMed Scopus (498) Google Scholar However, current desensitization strategies have known limitations. First, long-term graft survival of desensitized recipients remains inferior to nonsensitized counterparts6Haririan A Nogueira J Kukuruga D et al.Positive cross-match living donor kidney transplantation: longer-term outcomes.Am J Transplant. 2009; 9: 536-542Crossref PubMed Scopus (0) Google Scholar,9Bentall A Cornell LD Gloor JM et al.Five-year outcomes in living donor kidney transplants with a positive crossmatch.Am J Transplant. 2013; 13: 76-85Crossref PubMed Scopus (150) Google Scholar,10Marfo K Lu A Ling M Akalin E Desensitization protocols and their outcome.Clin J Am Soc Nephrol. 2011; 6: 922-936Crossref PubMed Scopus (187) Google Scholar due to an increased rate of anti-HLA and donor-specific antibodies (DSAs) that correlate with chronic transplant glomerulopathy and allograft vasculopathy. Additionally, the current methods of desensitization are prone to antibody rebound. The incomplete durability of these therapies may be due to the failure to address the relevant sources of antibody in sensitized patients, such as long-lived plasma cells (PCs) in the secondary lymphoid organs and bone marrow (BM). A new class of drugs called proteasome inhibitors has demonstrated the capability of preferentially eliminating PCs. The first drug of this class, bortezomib, was approved for the treatment of refractory multiple myeloma and induces apoptosis in PCs through the inhibition of the 26S proteasome.11Naujokat C Berges C Höh A et al.Proteasomal chymotrypsin-like peptidase activity is required for essential functions of human monocyte-derived dendritic cells.Immunology. 2007; 120: 120-132Crossref PubMed Scopus (35) Google Scholar The disruption of proteasome function inhibits both malignant cells and conventional PCs.12Perry DK Burns JM Pollinger HS et al.Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production.Am J Transplant. 2009; 9: 201-209Crossref PubMed Scopus (0) Google Scholar,13Diwan TS Raghavaiah S Burns JM Kremers WK Gloor JM Stegall MD The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo.Transplantation. 2011; 91: 536-541Crossref PubMed Scopus (59) Google Scholar Bortezomib has shown promise in treatment of acute antibody-mediated rejection (AMR) following kidney transplantation14Everly MJ Everly JJ Susskind B et al.Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection.Transplantation. 2008; 86: 1754-1761Crossref PubMed Scopus (330) Google Scholar,15Walsh RC Everly JJ Brailey P et al.Proteasome inhibitor-based primary therapy for antibody-mediated renal allograft rejection.Transplantation. 2010; 89: 277-284Crossref PubMed Scopus (0) Google Scholar and has recently been tested for desensitization .4Bartel G Wahrmann M Regele H et al.Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation.Am J Transplant. 2010; 10: 2033-2042Crossref PubMed Scopus (63) Google Scholar,16Woodle ES Shields AR Ejaz NS et al.Prospective iterative trial of proteasome inhibitor-based desensitization.Am J Transplant. 2015; 15: 101-118Crossref PubMed Scopus (98) Google Scholar Although initially promising results were reported,17May LJ Yeh J Maeda K et al.HLA desensitization with bortezomib in a highly sensitized pediatric patient.Pediatr Transplant. 2014; 18: E280-E282Crossref PubMed Scopus (15) Google Scholar,18Jeong JC Jambaldorj E Kwon HY et al.Desensitization using bortezomib and high-dose immunoglobulin increases rate of deceased donor kidney transplantation.Medicine (Baltimore). 2016; 95: e2635Crossref PubMed Scopus (32) Google Scholar recent clinical studies have indicated lack of efficacy in late AMR and in desensitization for lung transplantation candidates.19Eskandary F Regele H Baumann L et al.A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection.J Am Soc Nephrol. 2018; 29: 591-605Crossref PubMed Scopus (0) Google Scholar,20Snyder LD Gray AL Reynolds JM et al.Antibody desensitization therapy in highly sensitized lung transplant candidates.Am J Transplant. 2014; 14: 849-856Crossref PubMed Scopus (63) Google Scholar We have previously established a rigorous model of sensitized non-human primate (NHP) kidney transplantation that closely mimics the human situation.21Burghuber CK Kwun J Page EJ et al.Antibody-mediated rejection in sensitized nonhuman primates: modeling human biology.Am J Transplant. 2016; 16: 1726-1738Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar We demonstrated that bortezomib monotherapy was able to reduce PCs, but DSA levels did not decrease, potentially due to induced germinal center (GC) B cell and Tfh expansion in the lymph nodes (LNs), suggesting humoral compensation.22Kwun J Burghuber C Manook M et al.Humoral compensation after bortezomib treatment of allosensitized recipients.J Am Soc Nephrol. 2017; 28: 1991-1996Crossref PubMed Scopus (50) Google Scholar We therefore hypothesized that combining bortezomib with costimulation blockade (CoB) to inhibit upstream GC responses would lead to efficient and durable desensitization and promote long-term graft survival after kidney transplantation. Thirteen rhesus macaques were sensitized via two skin grafts separated by >6 weeks from maximally MHC-mismatched donors (Figure 1A). Skin transplants were uniformly rejected. Retrospectively, serum DSA (Table 1) showed a peak median MFI ratio of 36.6 ± 22.3 in the control group versus 45.2 ± 19.8 in the treatment group for T cell and 23.0 ± 12.5 versus 27.1 ± 15.9 for B cell crossmatches, respectively. There was no difference in sensitization between the two groups (P = .5 and .6). The comparison of antibody load prior to transplantation was equivalent (9.6 ± 6.6 versus 9.9 ± 9.5 for T cell and 6.6 ± 3.0 versus 6.2 ± 5.4 for B cell crossmatches, P = .9 and .9). Thus, animals were uniformly sensitized.TABLE 1Flow-crossmatch results after sensitization with two skin grafts (sensitization parameters of sensitized nonhuman primate)AnimalDSA T cell XM (MFI ratio)DSA B cell XM (MFI ratio)Control grouphighestat transplanthighestat transplantMonkey 552.75.919.86.4Monkey 675.121.445.58.6Monkey 726.38.215.95.1Monkey 828.96.234.47.8Monkey 918.62.99.42.2Monkey 1044.316.118.74.5Monkey 1110.26.817.311.4Therapy groupPrePostPrePostMonkey 2037.63.52.215.72.12.9Monkey 2153.216.26.242.422.915.8Monkey 2247.942.722.310.35.73.7Monkey 2333.510.04.628.13.63.7Monkey 2420.86.43.416.52.71.8Monkey 2578.360.022.449.620.79.4MFI ratio, MFI fold increase to baseline level; DSA, donor-specific antibodies; XM, Crossmatch; pre/post, before/after desensitization. Open table in a new tab MFI ratio, MFI fold increase to baseline level; DSA, donor-specific antibodies; XM, Crossmatch; pre/post, before/after desensitization. There were no adverse events during desensitization therapy with bortezomib (1.3 mg/m2) and CoB (20 mg/kg belatacept and 20 mg/kg 2C10.R4) for one month, but some monkeys had a loss of appetite, a consistent observation with bortezomib monotherapy reported previously.22Kwun J Burghuber C Manook M et al.Humoral compensation after bortezomib treatment of allosensitized recipients.J Am Soc Nephrol. 2017; 28: 1991-1996Crossref PubMed Scopus (50) Google Scholar We evaluated the reduction of MFI ratio in T and B cell FXMs and found that after 4 weeks of therapy, the DSA MFI ratio had decreased by a mean of 52% ± 10% and 24% ± 32% in T and B cell crossmatches (P = .07 and .12; Figure 1B,C). We also analyzed immune cells related to the humoral response before and after desensitization. We found that circulating naïve (CD27−IgD+CD20+) and memory (CD27+IgD− CD20+) B cells did not change in frequency during treatment (Figure S1). However, proliferating B cells measured by Ki67 staining were decreased in the blood (P = .005) and LNs (P = .016; Figure 2A). Since this may indicate suppression of GC-driven B cell expansion, we evaluated Tfh cell population in LNs. Specifically, we evaluated the change of frequency of CD4+PD1hi and CD4+CXCR5+ Tfh cells, as well as CD4+PD1hiCXCR5+ICOS+GC–related Tfh cells in the LNs. Following desensitization, CD4+PD1hi and CD4+CXCR5+ cells were significantly reduced (Figure S2), and CD4+PD1hiCXCR5+ICOS+Tfh decreased by 88.5% (P = .074; Figure 2B). Surprisingly, the combination of belatacept and 2C10R4 was able to suppress Tfh cells, even in allosensitized animals. In addition, CD19+CD20-CD38+IgG+PCs in BM were reduced by 45% (P = .015; Figure 2C). The combination of CoB with a PC-targeting agent, such as bortezomib, is able to suppress PC depletion-mediated GC activation. All animals underwent life-sustaining kidney transplantation using a kidney from their previous completely HLA-mismatched skin donor. As previously reported, basiliximab induction was not capable of controlling the immediate posttransplant memory T cell response.21Burghuber CK Kwun J Page EJ et al.Antibody-mediated rejection in sensitized nonhuman primates: modeling human biology.Am J Transplant. 2016; 16: 1726-1738Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Therefore, anti-CD4 and -CD8 monoclonal antibodies were used for induction followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and a steroid taper (Figure 3A). Whereas all monkeys in the control group showed early humoral rejection, as reported previously,21Burghuber CK Kwun J Page EJ et al.Antibody-mediated rejection in sensitized nonhuman primates: modeling human biology.Am J Transplant. 2016; 16: 1726-1738Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar in the dual therapy (CoB +bortezomib) group only one rejection occurred (monkey 23), showing features of AMR and thrombotic microangiopathy (TMA) on postoperative day (POD) 8. All other animals maintained excellent kidney function with a mean serum creatinine (sCr) at sacrifice of 0.97 ± 0.33 mg/dL (normal range 0.8-2.3 mg/dL) and a mean peak sCr of 2.70 ± 0.18 mg/dL and maintained low level of sCr over time. Contrarily, the control group demonstrated markedly elevated mean peak sCr of 6.38 ± 1.22 (P = .0004; Figure 3B). Mean graft survival was prolonged over 40 ± 44 days in the dual therapy group compared to 22 ± 19 days in the control (P = .073) with less antibody-mediated injuries including TMA (Figure 3C,E). However, noncensored recipient survival was not different (Figure 3D). As shown in Table 2, despite excellent graft function, animals in the dual therapy group accrued non-rejection complications limiting their survival. One animal (monkey 21), developed an atonic bladder, resulting in urosepsis and bladder empyema with Enterococcus faecium and Escherichia coli. Nevertheless, kidney function remained stable. Another animal (monkey 22) experienced BM suppression, resulting in refractory anemia and neutropenia. This myelosuppression was temporally associated with cytomegalovirus (CMV) viremia, ganciclovir therapy, and graft CMV infection. The animal was sacrificed after three blood transfusions per protocol requirements. Again, kidney function was not compromised. A third animal (monkey 25) lost weight and exhibited sepsis. At necropsy, a mesenteric abscess was present and Klebsiella pneumoniae was cultured. The last animal (monkey 24) survived until the end of the study period (>100 days) without evidence of kidney dysfunction. All monkeys reactivated CMV to varying degrees and were treated with ganciclovir. Monkeys receiving desensitization therapy pretransplant had a trend toward higher CMV copies posttransplant (mean peak CMV copies/mL 85 × 103 ± 54 × 103 control vs. 550 × 103 ±531 × 103 therapy; P = 0.18; Figure 4A). Although rare CMV+ cells were seen in the graft of one control monkey, three of five desensitized monkeys showed CMV nephritis (Figure 4B).TABLE 2Treatment, outcomes, and reason for sacrifice in controls and desensitized animalsAnimalDesensitizationImmunosuppressionSurvival (days)Complication/reason for sacrificeSerum creatinine at sacrificeBortezomib (n = 2)BTZ (3.5 mg/kg)NANACardiopulmonary complications (death <48 h)NABortezomib (n = 4)BTZ (1.3 mg/m2)NANALost appetiteNAControl (n = 6)Monkey 7aMonkey 7 and monkey 20 were excluded from posttransplant analysis.noneInd/TAC/MMF/Ster1Unknown, kidney failure10.2Monkey 6noneInd/TAC/MMF/Ster1Kidney failure, hyperacute rejection5.28Monkey 8noneInd/TAC/MMF/Ster7Kidney failure, rejection4.85Monkey 11noneInd/TAC/MMF/Ster8Kidney failure, rejection7.64Monkey 9noneInd/TAC/MMF/Ster27Kidney failure, rejection6.0Monkey 10noneInd/TAC/MMF/Ster43Kidney failure, rejection7.81Monkey 5noneInd/TAC/MMF/Ster44Kidney failure, rejection6.65Therapy (n = 5)Monkey 20aMonkey 7 and monkey 20 were excluded from posttransplant analysis.Bela/2C10/BTZInd/TAC/MMF/Ster1Kidney failure, graft thrombosisMonkey 23Bela/2C10/BTZInd/TAC/MMF/Ster8Kidney failure, rejection8.6Monkey 21Bela/2C10/BTZInd/TAC/MMF/Ster16Urosepsis, monkey condition1.1Monkey 25Bela/2C10/BTZInd/TAC/MMF/Ster21Anemia, bone marrow depletionbMonkey 25 received three blood transfusions posttransplant for anemia.0.9Monkey 22Bela/2C10/BTZInd/TAC/MMF/Ster41Retroperitoneal abscess0.55Monkey 24Bela/2C10/BTZInd/TAC/MMF/Ster>120No complication, end of study1.33Ind, induction; TAC, tacrolimus; MMF, mycophenolate mofetil; Ster, steroids.a Monkey 7 and monkey 20 were excluded from posttransplant analysis.b Monkey 25 received three blood transfusions posttransplant for anemia. Open table in a new tab FIGURE 4Animals with dual targeting desensitization show increased level of CMV reactivation, CMV nephritis but antibody against CMV or tetanus were not compromised. (A) Increased risk of CMV infection with desensitization. CMV copies at the time of peak showed a strong trend of increase after desensitization compared to untreated animals. (B) Hematoxylin and eosin shows characteristic cytomegalovirus intranuclear inclusions (arrows) in peritubular capillary endothelial cells from desensitized animals. No changes in the level of anti-gB IgG (C) and the level of anti-TT (tetanus) IgG (D) compared to pretreatment or before sensitizationView Large Image Figure ViewerDownload Hi-res image Download (PPT) Ind, induction; TAC, tacrolimus; MMF, mycophenolate mofetil; Ster, steroids. In addition to renal allograft function assessed by sCr, grafts were evaluated by biopsy for indication and at necropsy. Results were scored in blinded fashion using Banff criteria.23Haas M Sis B Racusen LC et al.Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14: 272-283Crossref PubMed Scopus (1058) Google Scholar,24Loupy A Haas M Solez K et al.The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology.Am J Transplant. 2017; 17: 28-41Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar Complete Banff grading for individual monkey biopsies is shown in Table 3. Control samples showed various degrees of rejection featuring signs of microvascular inflammation, namely glomerulitis (Banff g-score) and peritubular capillaritis (Banff ptc-score). The threshold for microvascular inflammation suspicious of AMR per Banff criteria (g + ptc ≥2) was surpassed in all control animals (median 4; IQR 3-4.25), but not desensitized animals (median 2; IQR 0.5-2.5). C4d staining was positive in all control animals. However, only one specimen stained convincingly after desensitization (Figure 5A). We calculated an AMR score from the ordinal numeric variables of g + ptc +C4d resulting in a median of 6 (IQR 5.75-7) in control animals (Table 4). Desensitized monkeys showed a lower median score of 2 (IQR 1-5; P = .02; Figure 5B). In treated animals, posttransplant DSA remained low (less than twofold increase compared to pretransplant nadir) whereas in some control monkeys, strong rebounds were seen (Figure 5C). In accordance with this, calculated AMR score shows a strong positive correlation to circulating DSA level at sacrifice (r = 0.68 and P = .02 for T cell FXM; r = 0.59 and P = .058 for B cell FXM, Figure 5D) from both untreated control and desensitized animals. This suggests an impact of the desensitization on AMR via lowering the DSA level. Notably, both animals showed a similar pattern of GC contraction (decreased Ki67+ area within CD20 B cell follicles) after T cell depletion or kidney transplantation. As shown in Figure 4E, GC staining appeared earlier in control animals compared to desensitized recipients. Interestingly, a recipient with no DSA showed hyperplastic germinal center staining at POD 120 after desensitization. This suggests the desensitization strategy suppressed GC reconstitution after T cell depletion, but allowed GC responses later with a lack of antidonor antibody response.TABLE 3BANFF gradings of graft at the time of sacrificeAnimalNves%i%ci%cttvigcictcgmmcvahPtcTubular injuryInterstitial plasma cellsInterstitial neutrophilsInterstitial eosinophilsEdemaInclusionsPTC fibrinGlomerular fibrinArteriole fibrinControl (n = 7)Monkey 520405110210101002111010000Monkey 61050000020000002201000111Monkey 7aMonkey 7 and monkey 20 were excluded from posttransplant analysis.1500000000000001100000001Monkey 910207210131111101101011000Monkey 81522200030100000100010111Monkey 10103020522231111212111110111Monkey 111555100030111001100000010Therapy (n = 6)Monkey 20aMonkey 7 and monkey 20 were excluded from posttransplant analysis.10000000000000001000001Monkey 211521000000000001000000000Monkey 231015000020001001100000010Monkey 222555010020000100000001000Monkey 251053000030000001101001000Monkey 2415407230211100000100000000a Monkey 7 and monkey 20 were excluded from posttransplant analysis. Open table in a new tab TABLE 4Outcome in control and therapy group of sensitized monkeys after kidney transplantation. (Posttransplant histology; comparison treatment group/control group; in order of survival time)AnimalSurvival (d)ACRAMR score (Banff)Other indicationsControl (n = 6)aMonkey 7 (POD3) is excluded from control.gptcC4dtotalMonkey 544borderline1236AMR, borderline ARMonkey 61none2226AMR, TMA, hyperacute rejectionMonkey 87none3025AMR, TMAMonkey 927borderline3126AMR, borderline ARMonkey 1043Banff IIB3227AMR + ACRMonkey 118none3126AMR, TMAAMR score median 6 (IQR 5.75−7)Therapy (n = 5)bMonkey 20 (POD0) is excluded from therapy group for technical complications.Monkey 238none2136AMR, TMAMonkey 2116none0112CMV + nephritisMonkey 2521none3104AMR, CMV + nephritisMonkey 2241none2002CMV + nephritisMonkey 24>120Banff IB1001ACR1BAMR score median 2 (IQR 1−5)AR, acute rejection; AMR, antibody-mediated rejection; g, glomerulitis; ptc, peritubular capillary inflammation; C4d, C4d deposition in walls of peritubular capillaries (immunohistochemistry); TMA, thrombotic microangiopathy; CMV, cytomegalovirus.a Monkey 7 (POD3) is excluded from control.b Monkey 20 (POD0) is excluded from therapy group for technical complications. Open table in a new tab AR, acute rejection; AMR, antibody-mediated rejection; g, glomerulitis; ptc, peritubular capillary inflammation; C4d, C4d deposition in walls of peritubular capillaries (immunohistochemistry); TMA, thrombotic microangiopathy; CMV, cytomegalovirus. In this study we tested the effect of dual targeting of germinal centers with CoB and plasma cells (or antibody-secreting cells) with bortezomib as a desensitization strategy in a highly sensitized model of kidney transplantation. The monkeys were sensitized by repeated (two sequential) skin grafts from a maximally MHC-mismatched donor. Following stabilization of DSA levels, we desensitized six rhesus macaques with a four-week course of bortezomib, belatacept, and anti-CD40 mAb (2C10.R4). In order to confirm the durability of desensitization, we performed kidney transplantation using a graft from the previous skin donor. Such direct potent sensitization of non-human primate recipients using two skin grafts from the future kidney donor creates a far higher immunological barrier than human patients would be expected to encounter from a donor kidney to which they are sensitized. In an effort to develop a model that is relevant to the human situation, we intentionally tested desensitization in a highly MHC-immunized host to assess efficacy of treatment strategies. Desensitization with CoB and bortezomib showed a trend toward reduction of DSA by T cell crossmatch, but no statistical significance was achieved (Figure 1). The results of B cell crossmatch were more variable, with one monkey actually showing an increase in DSA. Similarly, human data show different effects of bortezomib on MHC class I and II antibodies, including a greater resistance to desensitization of some MHC class II DSAs.25Philogene MC Sikorski P Montgomery RA Leffell MS Zachary AA Differential effect of bortezomib on HLA class I and class II antibody.Transplantation. 2014; 98: 660-665Crossref PubMed Scopus (30) Google Scholar Another explanation is a potential assay-related underestimation of the DSA decline, as background luminescence is stronger in B cell FXM than in T cell FXM,26Karpinski M Rush D Jeffery J et al.Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch.J Am Soc Nephrol. 2001; 12: 2807-2814Crossref PubMed Google Scholar,27Le Bas-Bernardet S Hourmant M Valentin N et al.Identification of the antibodies involved in B-cell crossmatch positivity in renal transplantation.Transplantation. 2003; 75: 477-482Crossref PubMed Scopus (84) Google Scholar resulting in higher baseline MFI and therefore a smaller change. Furthermore, we alloimmunized animals twice with two skin transplantations prior to receiving a kidney from the same donor. This repeated immunization produces high levels of donor-specific sensitization and makes reducing the level of DSA a significant challenge. In our parallel study with single allo-skin sensitization, the same regimen reduced the DSA level significantly.28Kwun J Burghuber C Manook M et al.Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates.Blood Adv. 2017; 1: 2115-2119Crossref PubMed Scopus (27) Google Scholar Nevertheless, the DSA reduction contrasted with data using bortezomib monotherapy (Table S1), which showed profound BM PC reduction but no DSA decrease.22Kwun J Burghuber C Manook M et al.Humoral compensation after bortezomib treatment of allosensitized recipients.J Am Soc Nephrol. 2017; 28: 1991-1996Crossref PubMed Scopus (50) Google Scholar In addition, treatment with bortezomib alone resulted in rebound GC response including increased class-switched B cell proliferation and Tfh cells.22Kwun J Burghuber C Manook M et al.Humoral compensation after bortezomib treatment of allosensitized recipients.J Am Soc Nephrol. 2017; 28: 1991-1996Crossref PubMed Scopus (50) Google Scholar Belatacept and anti-CD40mAb have been shown to prevent antigen-specific antibody formation in small animals29Kim I Wu G Chai N-N Klein AS Jordan SC Immunological characterization of de novo and recall alloantibody suppression by CTLA4Ig in a mouse model of allosensitization.Transplant Immunol. 2016; 38: 84-92Crossref PubMed Scopus (0) Google Scholar,30Upadhyay M Priya GK Ramesh P et al.CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naïve and plasma cells.J Cell Physiol. 2014; 229: 1387-1396Crossref PubMed Scopus (10) Google Scholar and in nonsensitized transplant recipients.31Vincenti F Rostaing L Grinyo J et al.Belatacept and long-term outcomes in kidney transplantation.N Engl J Med. 2016; 374: 333-343Crossref PubMed Scopus (412) Google Scholar We have seen similar effects from belatacept/2C10.R4 on de novo DSA production and GC responses in a NHP model of de novo AMR.32Kim EJ Kwun J Gibby AC et al.Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.Am J Transplant. 2014; 14: 59-69Crossref PubMed Scopus (138) Google Scholar Furthermore, belatacept also showed its unique ability of controlling humoral response in transplant patients.33Leibler C Thiolat A Henique C et al.Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk.J Am Soc Nephrol. 2018; 29: 1049-1062Crossref PubMed Scopus (61) Google Scholar However, the expected impact of CoB was minimal in the sensitized setting since activated or memory T cells are not costimul" @default.
• W2885193934 created "2018-08-22" @default.
• W2885193934 creator A5003099842 @default.
• W2885193934 creator A5007319566 @default.
• W2885193934 creator A5012052292 @default.
• W2885193934 creator A5029981005 @default.
• W2885193934 creator A5031418109 @default.
• W2885193934 creator A5049766839 @default.
• W2885193934 creator A5055271145 @default.
• W2885193934 creator A5056778092 @default.
• W2885193934 creator A5068677230 @default.
• W2885193934 creator A5070055950 @default.
• W2885193934 creator A5073283527 @default.
• W2885193934 creator A5078530019 @default.
• W2885193934 creator A5090680688 @default.
• W2885193934 date "2019-03-01" @default.
• W2885193934 modified "2023-10-13" @default.
• W2885193934 title "Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients" @default.
• W2885193934 cites W1506151781 @default.
• W2885193934 cites W1506252195 @default.
• W2885193934 cites W1541245237 @default.
• W2885193934 cites W1554670304 @default.
• W2885193934 cites W1582072552 @default.
• W2885193934 cites W1737600104 @default.
• W2885193934 cites W1779151064 @default.
• W2885193934 cites W1989569525 @default.
• W2885193934 cites W1996635899 @default.
• W2885193934 cites W1998323660 @default.
• W2885193934 cites W1999123359 @default.
• W2885193934 cites W2011919289 @default.
• W2885193934 cites W2014021133 @default.
• W2885193934 cites W2029688404 @default.
• W2885193934 cites W2030088102 @default.
• W2885193934 cites W2040492897 @default.
• W2885193934 cites W2059192187 @default.
• W2885193934 cites W2061425310 @default.
• W2885193934 cites W2062191855 @default.
• W2885193934 cites W2067655048 @default.
• W2885193934 cites W2076344904 @default.
• W2885193934 cites W2087246785 @default.
• W2885193934 cites W2106831081 @default.
• W2885193934 cites W2109532971 @default.
• W2885193934 cites W2116180543 @default.
• W2885193934 cites W2122262316 @default.
• W2885193934 cites W2131535623 @default.
• W2885193934 cites W2142141375 @default.
• W2885193934 cites W2149086605 @default.
• W2885193934 cites W2157116205 @default.
• W2885193934 cites W2162186379 @default.
• W2885193934 cites W2166277046 @default.
• W2885193934 cites W2170256066 @default.
• W2885193934 cites W2172173946 @default.
• W2885193934 cites W2219468584 @default.
• W2885193934 cites W2221834647 @default.
• W2885193934 cites W2315014922 @default.
• W2885193934 cites W2317185835 @default.
• W2885193934 cites W2328127288 @default.
• W2885193934 cites W2330241326 @default.
• W2885193934 cites W2515648410 @default.
• W2885193934 cites W2552263672 @default.
• W2885193934 cites W2589207177 @default.
• W2885193934 cites W2740266422 @default.
• W2885193934 cites W2767115738 @default.
• W2885193934 cites W2773812249 @default.
• W2885193934 cites W2783160856 @default.
• W2885193934 cites W2917257812 @default.
• W2885193934 doi "https://doi.org/10.1111/ajt.15067" @default.
• W2885193934 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7185755" @default.
• W2885193934 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30102844" @default.
• W2885193934 hasPublicationYear "2019" @default.
• W2885193934 type Work @default.
• W2885193934 sameAs 2885193934 @default.
• W2885193934 citedByCount "56" @default.
• W2885193934 countsByYear W28851939342019 @default.
• W2885193934 countsByYear W28851939342020 @default.
• W2885193934 countsByYear W28851939342021 @default.
• W2885193934 countsByYear W28851939342022 @default.
• W2885193934 countsByYear W28851939342023 @default.
• W2885193934 crossrefType "journal-article" @default.
• W2885193934 hasAuthorship W2885193934A5003099842 @default.
• W2885193934 hasAuthorship W2885193934A5007319566 @default.
• W2885193934 hasAuthorship W2885193934A5012052292 @default.
• W2885193934 hasAuthorship W2885193934A5029981005 @default.
• W2885193934 hasAuthorship W2885193934A5031418109 @default.
• W2885193934 hasAuthorship W2885193934A5049766839 @default.
• W2885193934 hasAuthorship W2885193934A5055271145 @default.
• W2885193934 hasAuthorship W2885193934A5056778092 @default.
• W2885193934 hasAuthorship W2885193934A5068677230 @default.
• W2885193934 hasAuthorship W2885193934A5070055950 @default.
• W2885193934 hasAuthorship W2885193934A5073283527 @default.
• W2885193934 hasAuthorship W2885193934A5078530019 @default.
• W2885193934 hasAuthorship W2885193934A5090680688 @default.
• W2885193934 hasBestOaLocation W28851939341 @default.
• W2885193934 hasConcept C126322002 @default.
• W2885193934 hasConcept C170493617 @default.
• W2885193934 hasConcept C203014093 @default.
• W2885193934 hasConcept C2776364478 @default.
• W2885193934 hasConcept C2777478702 @default.

• next