scholarly journals Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization

2021 ◽  
Vol 12 ◽  
Author(s):  
Ashley Y. Choi ◽  
Miriam Manook ◽  
Danae Olaso ◽  
Brian Ezekian ◽  
Jaeberm Park ◽  
...  
Keyword(s):  
Plasma Cells ◽  
De Novo ◽  
Humoral Response ◽  
Therapeutic Interventions ◽  
Humoral Immune ◽  
Antibody Mediated Rejection ◽  
Multiple Components ◽  
Improved Outcomes ◽  
Allograft Loss

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.

scholarly journals Preceding T-Cell-Mediated Rejection Is Associated with the Development of Chronic Active Antibody-Mediated Rejection by de Novo Donor-Specific Antibody

Nephron ◽  
2020 ◽  
pp. 1-5
Author(s):  
Takahiro Tsuji ◽  
Sari Iwasaki ◽  
Keishi Makita ◽  
Teppei Imamoto ◽  
Naomichi Ishidate ◽  
...  
Keyword(s):  
T Cell ◽  
Specific Antibody ◽  
De Novo ◽  
Control Group ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries ◽  
The Mean ◽  
Microvascular Inflammation ◽  
Renal Allograft Loss ◽  
Allograft Loss

<b><i>Aim:</i></b> Chronic active antibody-mediated rejection (CAABMR) is an important cause of late-stage renal allograft loss. Early inflammatory events such as acute rejection and infection after transplantation are considered to be the risk factors of de novo donor-specific antibody (dnDSA) production. In this study, we investigated the relationship between pre­disposing T-cell-mediated rejection and dnDSA-positive CAABMR. <b><i>Methods:</i></b> We recruited 365 patients who underwent ABO-compatible renal transplantation at our hospital. Among them, 16 patients diagnosed as having dnDSA-positive CAABMR were designated as a CAABMR group, and 38 randomly selected patients were designated as a control group. All biopsies from 1 month after transplantation were included in the study. The presence or absence of borderline changes (BLCs), acute T-cell-mediated rejection (ATMR), microvascular inflammation (MVI), and C4d positive on peritubular capillaries (C4d-P) was examined. <b><i>Results:</i></b> In the CAABMR group, BLC/ATMR was found in 12 cases (75%), and the mean duration until appearance of BLC/ATMR was 282.7 ± 328.7 days. C4d-P was found in 11 cases (68.8%), and the mean duration until its appearance was 1,432 ± 1,307 days. MVI was found in all cases, and the mean duration until its appearance was 1,333 ± 1,126 days. The mean duration until diagnosis of CAABMR was 2,268 ± 1,191 days. In the control group, BLC/ATMR was found in 13 cases (34.2%), and the mean duration until the appearance of BLC/ATMR was 173.1 ± 170.4 days. C4d-P was found in 2 cases (5.3%), and the durations until its appearance were 748 and 1,881 days. No cases of MVI were found in the control group. The frequency of BLC/ATMR was significantly higher in the CAABMR group (<i>p</i> &#x3c; 0.01). <b><i>Conclusion:</i></b> Preceding BLC/ATMR is associated with the development of CAABMR with dnDSA.

scholarly journals Intensity of de novo DSA detected by Immucor Lifecodes assay and C3d fixing antibodies are not predictive of subclinical ABMR after Kidney Transplantation

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249934
Author(s):  
Dominique Bertrand ◽  
Rangolie Kaveri ◽  
Charlotte Laurent ◽  
Philippe Gatault ◽  
Maïté Jauréguy ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Prognostic Value ◽  
De Novo ◽  
Added Value ◽  
Multicentric Study ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Single Antigen ◽  
Donor Specific Antibodies ◽  
Allograft Loss

De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and allograft loss. We tested Immucor* (IM) Luminex Single-antigen beads (LSAB) assay and C3d-fixing antibodies in the setting of dnDSA and subclinical (s) ABMR. This retrospective multicentric study included 123 patients biopsied because of the presence of subclinical de novo DSA detected by One Lamda* Labscreen (MFI > 1000). In 112 patients, sera of the day of the biopsy were available and tested in a central lab with IM Lifecodes LSAB and C3d fixing antibodies assays. In 16 patients (14.3%), no DSA was detected using Immucor test. In 96 patients, at least one DSA was determined with IM. Systematic biopsies showed active sABMR in 30 patients (31.2%), chronic active sABMR in 17 patients (17.7%) and no lesions of sABMR in 49 KT recipients (51%). Intensitity criteria (BCM, BCR and AD-BCR) of DSA were not statistically different between these 3 histological groups. The proportion of patients with C3d-fixing DSA was not statistically different between the 3 groups and did not offer any prognostic value regarding graft survival. Performing biopsy for dnDSA could not be guided by the intensity criteria of IM LSAB assay. C3d-fixing DSA do not offer added value.

scholarly journals Dynamics of the Humoral Immune Response to a Prime-Boost Ebola Vaccine: Quantification and Sources of Variation

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Chloé Pasin ◽  
Irene Balelli ◽  
Thierry Van Effelterre ◽  
Viki Bockstal ◽  
Laura Solforosi ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Humoral Immune Response ◽  
Phase 1 ◽  
Humoral Response ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phase 1 Trials ◽  
Humoral Immune ◽  
Boost Immunization

ABSTRACT The Ebola vaccine based on Ad26.ZEBOV/MVA-BN-Filo prime-boost regimens is being evaluated in multiple clinical trials. The long-term immune response to the vaccine is unknown, including factors associated with the response and variability around the response. We analyzed data from three phase 1 trials performed by the EBOVAC1 Consortium in four countries: the United Kingdom, Kenya, Tanzania, and Uganda. Participants were randomized into four groups based on the interval between prime and boost immunizations (28 or 56 days) and the sequence in which Ad26.ZEBOV and MVA-BN-Filo were administered. Consecutive enzyme-linked immunosorbent assay (ELISA) measurements of the IgG binding antibody concentrations against the Kikwit glycoprotein (GP) were available for 177 participants to assess the humoral immune response up to 1 year postprime. Using a mathematical model for the dynamics of the humoral response, from 7 days after the boost immunization up to 1 year after the prime immunization, we estimated the durability of the antibody response and the influence of different factors on the dynamics of the humoral response. Ordinary differential equations (ODEs) described the dynamics of antibody response and two populations of antibody-secreting cells (ASCs), short-lived (SL) and long-lived (LL). Parameters of the ODEs were estimated using a population approach. We estimated that half of the LL ASCs could persist for at least 5 years. The vaccine regimen significantly affected the SL ASCs and the antibody peak but not the long-term response. The LL ASC compartment dynamics differed significantly by geographic regions analyzed, with a higher long-term antibody persistence in European subjects. These differences could not be explained by the observed differences in cellular immune response. IMPORTANCE With no available licensed vaccines or therapies, the West African Ebola virus disease epidemic of 2014 to 2016 caused 11,310 deaths. Following this outbreak, the development of vaccines has been accelerated. Combining different vector-based vaccines as heterologous regimens could induce a durable immune response, assessed through antibody concentrations. Based on data from phase 1 trials in East Africa and Europe, the dynamics of the humoral immune response from 7 days after the boost immunization onwards were modeled to estimate the durability of the response and understand its variability. Antibody production is maintained by a population of long-lived cells. Estimation suggests that half of these cells can persist for at least 5 years in humans. Differences in prime-boost vaccine regimens affect only the short-term immune response. Geographical differences in long-lived cell dynamics were inferred, with higher long-term antibody concentrations induced in European participants.

scholarly journals Antitestmediált rejekció: kihívás a veseátültetett betegek kezelésében

2018 ◽  
Vol 159 (46) ◽  
pp. 1913-1929 ◽  
Author(s):  
Balázs Nemes ◽  
Réka P. Szabó ◽  
László Bidiga ◽  
Károly Kalmár Nagy ◽  
Lóránt Illésy ◽  
...  
Keyword(s):  
Gold Standard ◽  
Mean Fluorescence Intensity ◽  
De Novo ◽  
Graft Loss ◽  
Exposed Group ◽  
New Drugs ◽  
Factors Affecting ◽  
Antibody Mediated Rejection ◽  
Kinetics Of

Abstract: Antibody-mediated rejection (ABMR) is one of the factors affecting the long-term graft survival after kidney transplantation (KT). Two kidney transplant centres (University of Debrecen and University of Pécs) followed up their data of cadaveric KTs that had been performed between 2013 and 2017, and reviewed the literature. There were 454 KTs in the mentioned period, 18 cases (4%) were recognised as ABMRs. Biopsy has been performed in all cases. 22% were primary, and 78% retransplanted patients. The average age was 51.2 ± 6 years. ABMR occurred 15.4 ± 22.1 months after KT. Histology showed C4d positivity in 39% of the cases. The treatment was steroid bolus + intravenous immunoglobulin (IVIG) + plasma exchange (PE) in 16 cases, rituximab was additionally given in 5 cases. 47.4% of the patients are alive with a functioning graft, four (21%) died, and 31% of the patients had a graft loss due to ABMR. ABMR is a dangerous complication after KT. Diagnostic criteria has been unclear for years. Gold standard is the histology, however, accelerated ABMR may occur even in C4d negative cases. The exposed group includes young, retransplanted patients, having a preformed donor-specific antibody (DSA), and receiving a graft from an EC donor. The occurrence of de novo DSA and the kinetics of mean fluorescence intensity (MFI) of existing ones can be a signal for the risk of an ABMR. The effectiveness of rituximab is not proven, there is a lack of long-term controlled trials for new drugs. Our results of over 40% recovery is an extensively good result. Orv Hetil. 2018; 159(46): 1913–1929.

scholarly journals Therapies for Chronic Allograft Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Young Kim ◽  
Daniel C. Brennan
Keyword(s):  
Progressive Disease ◽  
De Novo ◽  
Treatment Strategies ◽  
Ongoing Research ◽  
Chronic Allograft Rejection ◽  
Antibody Mediated Rejection ◽  
Non Invasive ◽  
Donor Specific Antibodies ◽  
Made In

Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.

scholarly journals Antibody-Mediated Rejection: Pathogenesis, Prevention, Treatment, and Outcomes

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Olivia R. Blume ◽  
Sarah E. Yost ◽  
Bruce Kaplan
Keyword(s):  
Plasma Cells ◽  
Graft Function ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Antibody Detection ◽  
Peritubular Capillary ◽  
Leukocyte Antigen ◽  
Antibody Mediated Rejection ◽  
Transplant Failure

Antibody-mediated rejection (AMR) is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA) typing including well-designed studies to determine anti-MHC-class-I-related chain A (MICA) and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP) is effective in removing alloantibodies (DSAs) from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively.

scholarly journals Disruption of Tfh:B Cell Interactions Prevents Antibody-Mediated Rejection in a Kidney Transplant Model in Rats: Impact of Calcineurin Inhibitor Dose

2021 ◽  
Vol 12 ◽  
Author(s):  
Louisa Steines ◽  
Helen Poth ◽  
Antonia Schuster ◽  
Kerstin Amann ◽  
Bernhard Banas ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Cyclosporine A ◽  
Plasma Cells ◽  
Rat Kidney ◽  
Cell Interactions ◽  
High Dose ◽  
Humoral Immune ◽  
Antibody Mediated Rejection ◽  
Follicular Helper ◽  
Transplant Model

We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.

scholarly journals Longitudinal analysis of the humoral response to SARS-CoV-2 spike RBD in convalescent plasma donors

2020 ◽  
Author(s):  
Josée Perreault ◽  
Tony Tremblay ◽  
Marie-Josée Fournier ◽  
Mathieu Drouin ◽  
Guillaume Beaudoin-Bussières ◽  
...  
Keyword(s):  
Longitudinal Analysis ◽  
Plasma Cells ◽  
De Novo ◽  
Disease Onset ◽  
Humoral Response ◽  
Spike Protein ◽  
Strongly Correlated ◽  
Receptor Binding Domain ◽  
Specific Antibodies ◽  
Plasma Collection

ABSTRACTHéma-Québec, the blood supplier in the Province of Quebec, Canada, collects and tests convalescent plasma used in a clinical trial to determine the clinical efficacy of this product for the treatment of hospitalized COVID-19 patients. So far, we have collected 1159 plasma units from 282 COVID-19 convalescent donors. The presence of antibodies to the receptor binding domain (RBD) of SARS-CoV-2 spike protein in convalescent donors was established at the first donation. Seropositive donors were asked to donate additional plasma units every six days. Until now, 15 donors have donated at least four times and, in some cases, up to nine times. This allowed us to perform a longitudinal analysis of the persistence of SARS-CoV-2 RBD-specific antibodies in these repeat donors, with the first donation occurring 33-77 days after symptoms onset and donations up to 71-114 days after symptoms onset thereafter. In all donors, the level of antibodies remained relatively stable up to about 76 days after symptoms onset but then started to decrease more rapidly to reach, in some convalescent donors, a seronegative status within 100-110 days after symptoms onset. The decline in anti-RBD antibodies was not related to the number of donations but strongly correlated with the numbers of days after symptoms onset (r = 0.821). This suggests that de novo secretion of SARS-CoV-2 RBD antibodies by short-lived plasma cells stopped about 2-3 months after disease onset, an observation that has important implications for convalescent plasma collection and seroprevalence studies undertaken several months after the peak of infection.

Association of humoral antitumor response with clinical benefit in catumaxomab-treated malignant ascites patients: Results from a phase IIIb study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2584-2584
Author(s):  
Peter Ruf ◽  
Ivonne Suckstorff ◽  
Michael Jäger ◽  
Christine Ernst ◽  
Diane Seimetz ◽  
...  
Keyword(s):  
Treatment Cycle ◽  
De Novo ◽  
Humoral Response ◽  
Fold Increase ◽  
Malignant Ascites ◽  
Humoral Immune ◽  
Kaplan Meier ◽  
Phase Iiib ◽  
The Eu

2584 Background: The bispecific antibody catumaxomab (anti-EpCAM x anti-CD3) which is approved for the treatment of malignant ascites (MA) patients (pts) in the EU elicits a humoral immune response against tumor-associated antigens. Here we present follow up data analyzing the influence of this antibody response on puncture free (PFS) and overall survival (OS). Methods: In the course of the phase IIIb study CASIMAS, MA pts with EpCAM positive tumors were treated with/without prednisolone premedication by 4 infusions of 10, 20, 50 and 150 µg of catumaxomab over 11 days (d). EpCAM and HER2-specific antibody responses in plasma samples of 23 pts were measured by ELISA. Additionally, samples of 5 pts receiving a second treatment cycle were analyzed. Pts with significant increase (≥ 2) or de novo development of anti-tumor antibodies within 38 d after treatment start were defined as responders (R). Non responders (NR) showed no humoral response by d 38 or died before. PFS and OS of R and NR were compared by Kaplan Meier analysis. Results: 11 of 23 pts (48%) showed an anti-EpCAM response and 14 of 23 pts (61%) developed HER2-specific antibodies. 6 pts (26%) reacted positive against both antigens, 4 pts (17%) had neither response. In contrast to the EpCAM R group where 73% of pts displayed detectable antibodies prior to therapy, antibodies against HER2 developed de novo. Of note, 4 of 5 individuals who received a second treatment cycle after recurring MA demonstrated an anti-HER2 Ig booster reaction which was stronger and faster in comparison to pts who received only one treatment cycle (median values at d 18: 65 vs. 11 ng/ml). Most important, there was an almost 6 fold increase in median PFS between the HER2 R and NR group (68 vs 12 d, p = 0.044 (log-rank). There was also a trend towards improved OS for pts showing either anti-HER2 and/or anti-EpCAM responses (n=19) in comparison to pts with no response at all (n=4; 143 vs. 67 d, median, p = 0.054). Conclusions: The results indicate that active anti-tumor immunization triggered by catumaxomab treatment in MA pts is associated with improved clinical outcome. Further investigations of these vaccine-like effects with higher pts numbers are warranted.

scholarly journals Case Report: Splenic Irradiation for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Allograft Recipients With De Novo Donor-Specific Antibodies

2021 ◽  
Vol 12 ◽  
Author(s):  
Lan Zhu ◽  
Zhiliang Guo ◽  
Rula Sa ◽  
Hui Guo ◽  
Junhua Li ◽  
...  
Keyword(s):  
Conventional Treatment ◽  
De Novo ◽  
Treatment Options ◽  
Intravenous Immunoglobulins ◽  
Kidney Transplant Recipients ◽  
Antibody Mediated Rejection ◽  
Splenic Irradiation ◽  
Living Related

Chronic active antibody-mediated rejection (AMR) in renal transplantation is usually refractory to current conventional treatment with rituximab, plasmapheresis (PP), and intravenous immunoglobulins (IVIG). Splenic irradiation has been reported to be effective in the rescue of early severe acute AMR after kidney transplantation; however, its effect in chronic active AMR has not been reported to date. In order to reduce donor-specific antibody (DSA) and prevent the progression of chronic AMR, we used repetitive low-dose splenic irradiation, together with rituximab and PP/IVIG, in two living-related kidney transplant recipients with pathologically diagnosed chronic active AMR and the presence of long-term class II-de novo DSA. DSA monitoring and repeated renal biopsy revealed significantly reduced DSA levels as well as alleviated glomerulitis and peritubular capillaritis in both patients after treatment, and these therapies may have played a role in delaying the progression of chronic AMR. Although DSA levels in both patients eventually rebounded to some extent after treatment, serum creatinine increased slowly in one patient during the 16-month follow-up period and remained stable in the other during the 12-month follow-up period. Given the poor efficacy of conventional treatment at present, splenic irradiation may still be one of the treatment options for chronic active AMR.

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