Treatment Of Antibody-mediated Rejection Research Articles

Neutrophil depletion attenuates antibody-mediated rejection in a renal transplantation mouse model.

Antibody-mediated rejection (AMR) can cause graft failure following renal transplantation. Neutrophils play a key role in AMR progression, but the exact mechanism remains unclear. We investigated the effect of neutrophils on AMR in a mouse kidney transplantation model. The mice were divided into five groups: syngeneic transplantation (Syn), allograft transplantation (Allo), and three differently treated AMR groups. The AMR mouse model was established using skin grafts to pre-sensitize recipient mice. Based on the AMR model, Ly6G-specific monoclonal antibodies were administered to deplete neutrophils (NEUT-/- + AMR) and TACI-Fc was used to block B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) signaling (TACI-Fc + AMR). Pathological changes were assessed using hematoxylin-eosin and immunohistochemical staining. Banff values were evaluated using the Banff 2015 criteria. Donor-specific antibody (DSA) levels were assessed using flow cytometry, and BAFF and APRIL concentrations were measured using ELISA. Compared to the Syn and Allo groups, a significantly increased number of neutrophils and increased C4d and IgG deposition were observed in AMR mice, accompanied by elevated DSA levels. Neutrophil depletion inhibited inflammatory cell infiltration and reduced C4d and IgG deposition. Neutrophil depletion significantly decreased DSA levels after transplantation and suppressed BAFF and APRIL concentrations, suggesting a mechanism for attenuating AMR-induced graft damage. Similar results were obtained after blockading BAFF/APRIL using a TACI-Fc fusion protein. In summary, neutrophil infiltration increased in the AMR mouse renal transplantation model. Neutrophil depletion or blockading the BAFF/APRIL signaling pathway significantly alleviated AMR and may provide better options for the clinical treatment of AMR.

Efficacy and safety of eculizumab for treatment of antibody-mediated rejection following renal transplantation

Efficacy and safety of eculizumab for treatment of antibody-mediated rejection following renal transplantation

Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection.

In this project, we describe proteasome inhibitor (PI) treatment of antibody-mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n=8; bortezomib (BTZ) n=2. Patients received 1-3 cycles of PI. All patients had ≥1 strong donor-specific antibody (DSA) (mean fluorescence intensity [MFI]>8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR=13%-89%) in undiluted serum and 92% (IQR=53%-95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced>50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI>8000 at 1:16 dilution was less responsive totreatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction>40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1year after treatment. 9/10 (90%) patients survived to 1year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model.

One-third of HLA-incompatible kidney transplant recipients experience antibody mediated rejection (AMR) with limited treatment options. This study describes a novel treatment strategy for AMR consisting of proteasome inhibition and costimulation blockade with or without complement inhibition in a nonhuman primate model of kidney transplantation. All rhesus macaques in the present study were sensitized to maximally MHC-mismatched donors by two sequential skin transplants prior to kidney transplant from the same donor. All primates received induction therapy with rhesus-specific ATG (rhATG) and were maintained on various immunosuppressive regimens. Primates were monitored postoperatively for signs of acute AMR, which was defined as worsening kidney function resistant to high dose steroid rescue therapy, and a rise in serum donor-specific antibody (DSA) levels. Kidney biopsies were performed to confirm AMR using Banff criteria. AMR treatment consisted of carfilzomib and belatacept for a maximum of four weeks with or without complement inhibitor. Treatment with carfilzomib and belatacept was well tolerated and no treatment-specific side effects were observed. After initiation of treatment, we observed a reduction of class I and class II DSA in all primates. Most importantly, primates had improved kidney function evident by reduced serum creatinine and BUN as well as increased urine output. A four-week treatment was able to extend graft survival by up to two months. In summary, combined carfilzomib and belatacept effectively treated AMR in our highly sensitized nonhuman primate model, resulting in normalization of renal function and prolonged allograft survival. This regimen may translate into clinical practice to improve outcomes of patients experiencing AMR.

Feasibility of Interleukin-6 Receptor Blockade in Cardiac Antibody-mediated Rejection.

Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies.

Cardiac Allograft Rejection: Strategies for Success in the Face of Immune Challenges.

Heart transplantation for patients with end-stage heart failure refractory to medical therapy has remained definitive treatment with significant advances in posttransplant care. Despite improvement in postoperative morbidity and mortality, acute cellular rejection (ACR) and antibody-mediated rejection (AMR) remain substantial challenges that can lead to allograft failure and patient mortality. Immunosuppressive agents have been the mainstay of both prevention and treatment for ACR and AMR; however, many challenges exist with traditional therapies. There are a multitude of molecular pathways involved in mediating the humoral and cellular response to rejection, offering various targets for treatment. This review summarizes therapies used in the management of ACR and AMR as extrapolated from use in induction therapy and treatment of other solid-organ transplant rejection. Future studies focused on cardiac transplant recipients are needed to expand therapeutic options.

Current Therapies in Kidney Transplant Rejection.

Despite significant advancements in immunosuppressive therapies, kidney transplant rejection continues to pose a substantial challenge, impacting the long-term survival of grafts. This article provides an overview of the diagnosis, current therapies, and management strategies for acute T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). TCMR is diagnosed through histological examination of kidney biopsy samples, which reveal the infiltration of mononuclear cells into the allograft tissue. Corticosteroids serve as the primary treatment for TCMR, while severe or steroid-resistant cases may require T-cell-depleting agents, like Thymoglobulin. ABMR occurs due to the binding of antibodies to graft endothelial cells. The most common treatment for ABMR is plasmapheresis, although its efficacy is still a subject of debate. Other current therapies, such as intravenous immunoglobulins, anti-CD20 antibodies, complement inhibitors, and proteasome inhibitors, are also utilized to varying degrees, but their efficacy remains questionable. Management decisions for ABMR depend on the timing of the rejection episode and the presence of chronic changes. In managing both TCMR and ABMR, it is crucial to optimize immunosuppression and address adherence. However, further research is needed to explore newer therapeutics and evaluate their efficacy.

Dual Antibody Treatment for Simultaneous Acute Cellular Rejection and Antibody-Mediated Rejection After Liver Transplantation: A Case Report

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but sometimes has a grave prognosis. We herein describe a 40-year-old man who developed simultaneous acute cellular rejection and acute AMR due to de novo donor-specific anti-human leukocyte antigen antibodies after living donor liver transplantation. He underwent living donor liver transplantation with his brother-in-law as the donor. Hepatic function deteriorated on postoperative day 6, and a liver biopsy revealed histologic findings of typical acute cellular rejection. However, steroid pulse therapy and thymoglobulin did not produce a clinical response, and his liver function dramatically deteriorated on postoperative day 13 (aspartate aminotransferase, 2787 IU/L; total bilirubin, 14.1 mg/dL). We diagnosed acute AMR based on positive immunohistochemical staining for C4d in portal areas and added plasma exchange and high-dose intravenous immunoglobulin after rituximab. The patient's clinical state improved and ultimately resolved. To our knowledge, this is the first report of dual antibody treatment for simultaneous acute cellular rejection and acute AMR induced by de novo donor-specific anti-human leukocyte antigen antibodies. Despite his fulminant clinical course, we successfully rescued the recipient with immediate anti-humoral therapy. The rapid treatment decision and adequate understanding of the mechanisms of anti-humoral therapy were crucial to overcoming acute AMR in this case.

Early Versus Late Acute AMR in Kidney Transplant Recipients-A Comparison of Treatment Approaches and Outcomes From the ANZDATA Registry.

Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure and demonstrates different properties depending on whether it occurs early (<6 mo) or late (>6 mo) posttransplantation. We aimed to compare graft survival and treatment approaches for early and late AMR in Australia and New Zealand. Transplant characteristics were obtained for patients with an AMR episode reported to the Australia and New Zealand Dialysis and Transplant Registry from January 2003 to December 2019. The primary outcome of time to graft loss from AMR diagnosis, with death considered a competing risk, was compared between early and late AMR using flexible parametric survival models. Secondary outcomes included treatments used, response to treatment, and time from AMR diagnosis to death. After adjustment for other explanatory factors, late AMR was associated with twice the risk of graft loss relative to early AMR. The risk was nonproportional over time, with early AMR having an increased early risk. Late AMR was also associated with an increased risk of death. Early AMR was treated more aggressively than late with more frequent use of plasma exchange and monoclonal/polyclonal antibodies. There was substantial variation in treatments used by transplant centers. Early AMR was reported to be more responsive to treatment than late. Late AMR is associated with an increased risk of graft loss and death compared with early AMR. The marked heterogeneity in the treatment of AMR highlights the need for effective, new therapeutic options for these conditions.

#6369 RESULTS OF KIDNEY TRANSPLANTATION IN PATIENTS WITH LOW MFI PREFORMED DONOR SPECIFIC ANTIBODIES

Abstract Background and Aims Preformed DSA at transplantation, significantly increase risk of antibody-mediated rejection (ABMR). While pre-existing positive DSA with concomitant positive cross-match is a general contra-indication to kidney transplantation, DSA presence with negative crossmatch is still a controversial topic. The presence of DSA with Mean Fluorescence Index (MFI) up to 3.000 and a negative cross-match is not valued as a contraindication to transplantation and is widely accepted. In some transplant centers the chance of transplantation is also offered to DSA positive patients, with MFI up to 5.000. Aim of this study was to analyze graft and patient survival, acute cellular rejection, humoral rejection, renal function and side effects in kidney transplant recipients (KTR) with positive DSA (MFI up to 3.000) and negative cross-match. Method Nineteen pts (age 53+/-11) with chronic renal failure on chronic hemodialysis treatment (8+/-6 years) received a kidney transplant between May 2017 and December 2020. Median PRA was 66%; 100% pts had DSA with average MFI 2122 (min 1039, max 3779). As immunosuppressive therapies all pts received induction with Thymoglobuline plus Rituximab, followed by maintenance immunosuppression with Tacrolimus, MofetilMycoFenolate and Steroids. All patients were on periodic follow up in our Transplant Clinic. Mean follow up was 26.5+/-14.4 months. Results were compared to a concomitant KTR group DSA and crossmatch negative. Results After 2y follow-up, 17/19 pts are alive (89.5%), one patient died (1/19, 5.2%) after treatment for ABMR. Three patients returned to dialysis treatment (15.8%) during the first year post-tx, because of: PNF 1pt; irreversible ABMR rejection 2 pts. One other patient had reversible ABMR. Cumulative one year graft survival was 79% and the cumulative incidence of ABMR was 15.8%. Average 2 years follow-up creatinine was 1.46+/-0.88 mg/dl, median 2 year GFR was 51+/-25 ml/min. Comparing the matched control group (19 pts DSA and cross-match negative) 2 years patient survival, graft survival, GFR, acute rejection were not significantly different. Incidence of acute rejection was higher in the DSA positive group (16% vs 0%), as well as graft loss (21% vs 12%). Conclusion Our data suggest that low dose Thymoglobuline plus Rituximab induction allow kidney transplantation in recipient with high PRA (69%) and positive DSA with low MFI (&amp;lt; 3.000), with higher risk of acute rejection, and graft loss.

#4610 LACK OF EFFICACY AND SAFETY OF ECULIZUMAB FOR TREATMENT OF ANTIBODY-MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Method This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Cases of AMR were diagnosed in the early post-transplantation period in 2 patients (eculizumab arm: 1 patient, SOC arm: 1 patient) and in the late period in 9 patients. Most of the reports show that eculizumab, in combination with other therapeutic measures such as PP and/or IVIG, effectively reversed rejection. However, eculizumab alone could not treat AMR effectively. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Tocilizumab for antibody-mediated rejection treatment in lung transplantation

Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.

The Trend of Serum Creatinine Does Not Predict Follow-Up Biopsy Findings Among Kidney Transplant Recipients With Antibody-Mediated Rejection.

We included all cases of AMR at our program between March 2016 and July 2020 who had a follow-up biopsy after the index biopsy, with initial diagnosis of AMR. We trended the Scr and change in Scr (delta Scr) and its association with being a responder (microvascular inflammation, MVI ≤1) or nonresponder (MVI >1), as well as graft failure. A total of 183 kidney transplant recipients were included, 66 in the responder group and 177 in the nonresponder group. The MVI scores and sum chronicity scores, along with transplant glomerulopathy scores, were higher in the nonresponder group. However, Scr at index biopsy was similar in responders (1.74 ± 0.70) versus nonresponders (1.83 ± 0.65; P = 0.39), as were the delta Scr at various time points. After adjustment for multiple variables, delta Scr was not associated with being a nonresponder. Also, delta Scr value at follow-up biopsy compared with index biopsy among responders was 0 ± 0.67 (P = 0.99) and among nonresponders was -0.01 ± 0.61 (P = 0.89). Being a nonresponder was significantly associated with an increased risk of graft failure at the last follow-up in univariate analysis but was not in multivariate analysis (hazard ratio 1.35; 95% confidence interval, 0.58-3.17; P = 0.49). We found that Scr is not a good predictor of the resolution of MVI, supporting the utility of follow-up biopsies after treatment of AMR.

Preventative effect of TSPO ligands on mixed antibody-mediated rejection through a Mitochondria-mediated metabolic disorder

BackgroundImmune-mediated rejection was the major cause of graft dysfunction. Although the advances in immunosuppressive agents have markedly reduced the incidence of T-cell-mediated rejection after transplantation. However, the incidence of antibody-mediated rejection (AMR) remains high. Donor-specific antibodies (DSAs) were considered the major mediators of allograft loss. Previously, we showed that treatment with 18-kDa translocator protein (TSPO) ligands inhibited the differentiation and effector functions of T cells and reduced the rejection observed after allogeneic skin transplantation in mice. This study we further investigate the effect of TSPO ligands on B cells and DSAs production in the recipients of mixed-AMR model.MethodsIn vitro, we explored the effect of treatment with TSPO ligands on the activation, proliferation, and antibody production of B cells. Further, we established a heart-transplantation mixed-AMR model in rats. This model was treated with the TSPO ligands, FGIN1-27 or Ro5-4864, to investigate the role of ligands in preventing transplant rejection and DSAs production in vivo. As TSPO was the mitochondrial membrane transporters, we then investigated the TSPO ligands effect on mitochondrial-related metabolic ability of B cells as well as expression of downstream proteins.ResultsIn vitro studies, treatment with TSPO ligands inhibited the differentiation of B cells into CD138+CD27+ plasma cells; reduced antibodies, IgG and IgM, secretion of B cells; and suppressed the B cell activation and proliferation. In the mixed-AMR rat model, treatment with FGIN1-27 or Ro5-4864 attenuated DSA-mediated cardiac-allograft injury, prolonged graft survival, and reduced the numbers of B cells, including IgG+ secreting B cells, T cells and macrophages infiltrating in grafts. For the further mechanism exploration, treatment with TSPO ligands inhibited the metabolic ability of B cells by downregulating expression of pyruvate dehydrogenase kinase 1 and proteins in complexes I, II, and IV of the electron transport chain.ConclusionsWe clarified the mechanism of action of TSPO ligands on B-cell functions and provided new ideas and drug targets for the clinical treatment of postoperative AMR.

Translation of therapeutic strategies to modulate B cell reponses from non-human primate models to human kidney transplantation.

Using novel drugs targeting lymphocyte costimulation, cytokines, antibody, complement, and plasma cells, we have developed strategies in a non-human primate model to modulate the B cell response to incompatible kidney transplants. After more than two decades of research supported by mechanistic studies, this has resulted in clinically relevant approaches that are currently enrolling in clinical trials or preparing for such. In this manner, we aim to address the problems of HLA sensitization for very highly sensitized patients awaiting transplantation and the unmet need of effective treatment for antibody-mediated rejection.

(1110) Treatment of Antibody-Mediated Rejection in Adolescent Heart Transplant Recipients with Daratumumab

(1110) Treatment of Antibody-Mediated Rejection in Adolescent Heart Transplant Recipients with Daratumumab

HLA class II antibody activation of endothelial cells induces M2 macrophage differentiation in peripheral blood.

Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. The stimulation of ECs by F(ab')2 fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68+ and CD163+ (M2-type) macrophages, respectively, but not CD86+ macrophages. These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation.

De novo Donor-specific Anti-human Leukocyte Antigen Antibody and Its Outcome in Pediatric Renal Transplant Recipients: A Single-center Experience in India

Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR.

636. Meningococcal Vaccination and Antibiotic Prophylaxis Practices in Solid Organ Transplant Recipients undergoing Eculizumab Therapy

Abstract Background Eculizumab, an inhibitor of terminal complement activation, has been utilized in pre-transplant desensitization, treatment of antibody-mediated rejection and thrombotic microangiopathy in solid organ transplant recipients (SOTR). Eculizumab is associated with meningococcal disease, leading to guidelines for vaccination against serogroups ACWY (menACWY) and B (menB) at least 2 weeks prior to eculizumab therapy. In persons requiring emergent use of eculizumab, prophylaxis for at least 2 weeks is recommended. SOTRs respond suboptimally to vaccination, raising consideration for pre-transplant vaccination and prolonged prophylaxis in those undergoing eculizumab therapy. We sought to describe meningococcal vaccination and prophylaxis practices among SOTRs receiving eculizumab. Methods We performed a retrospective chart review of meningococcal vaccination, including number and timing pre- or post-transplant, along with prophylaxis prescribing and duration in SOTRs receiving eculizumab across 3 distinct Mayo Clinic Enterprise sites (Rochester, Arizona, and Florida). Results 200 SOTRs receiving at least one dose of eculizumab between 1/1/2008 and 9/16/2021 were reviewed. Eculizumab indications included antibody mediated rejection (38%), desensitization (26%), and thrombotic microangiopathy (19%). 83% (166/200) of SOTRs received eculizumab for an unanticipated post-transplant complication. Vaccination rates were 82% (164/200) and 35.5% (71/200) for menACWY dose 1 and 2, respectively, and 54% (108/200) and 28.5% (57/200) for menB dose 1 and 2, respectively. The majority received their first vaccination post-transplant: menACWY 66.5% (133/200) and menB 2.5% (185/200). Among those without vaccination pre-eculizumab, 22.3% (41/184) were not prescribed prophylaxis. The median duration of prophylaxis was 62 (range 4-2651) days. Conclusion Most SOTRs underwent meningococcal vaccinations near the time of eculizumab administration post-transplant for an unanticipated complication. One-fifth of those meeting criteria were not provided meningococcal prophylaxis. These findings may support pre-transplant administration of meningococcal vaccinations and heightened awareness for meningococcal prophylaxis in SOTRs receiving eculizumab. Disclosures All Authors: No reported disclosures.

Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts

Interleukin-6 (IL-6) is a cytokine critical for innate and adaptive immune responses. However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome. Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.