Antibody-mediated Rejection In Lung Transplantation Research Articles

Successful use of therapeutic plasma exchange for the management of acute lung transplant rejection secondary to immune checkpoint inhibitor therapy

The use of immune checkpoint inhibitors (ICIs) in individuals with a history of solid organ transplantation is fraught with the emergence of solid organ transplantation rejection (SOTR). The current recommendations for the management of SOTRs secondary to ICI include the use of high-dose steroids along with the escalation of immunosuppressive therapy. Therapeutic Plasma Exchange (TPE) has been described to be effective in managing various immune-related toxicities, however, the data for using TPE in the setting of acute SOTRs induced by ICIs are limited. Herein, we describe the successful use of TPE in a patient with a history of bilateral lung transplantation who developed an episode of mixed acute cellular and antibody-mediated lung transplant rejection after a single dose of PD-1 inhibitor Pembrolizumab for the treatment of underlying melanoma.

Antibody-Mediated Rejection in Lung Transplantation: Diagnosis and Therapeutic Armamentarium in a 21st Century Perspective.

Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donor-derived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR.

Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation.

Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.

Antibody-Mediated Rejection and Lung Transplantation.

Antibody-mediated rejection (AMR) is now a widely recognized form of lung allograft rejection, with mounting evidence for AMR as an important risk factor for the development of chronic lung allograft dysfunction and markedly decreased long-term survival. Despite the recent development of the consensus diagnostic criteria, it remains a challenging diagnosis of exclusion. Furthermore, even after diagnosis, treatment directed at pulmonary AMR has been nearly exclusively derived from practices with other solid-organ transplants and other areas of medicine, such that there is a significant lack of data regarding the efficacy for these in pulmonary AMR. Lastly, outcomes after AMR remain quite poor despite aggressive treatment. In this review, we revisit the history of AMR in lung transplantation, describe our current understanding of its pathophysiology, discuss the use and limitations of the consensus diagnostic criteria, review current treatment strategies, and summarize long-term outcomes. We conclude with a synopsis of our most pressing gaps in knowledge, introduce recommendations for future directions, and highlight promising areas of active research.

Antibodies Against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Associated With an Unfavorable COVID19 Disease Course

BackgroundLung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course.Methods65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20).ResultsThe presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 – 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 – 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 – 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 – 6.0, p <0.05).ConclusionAuto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.

Single-Center Experience of Outcomes and Prescribing Patterns of IV Immunoglobulin Use in Critically Ill Patients.

Retrospective, observational study. Single, academic medical center medical ICU. Adults who received greater than or equal to 1 dose of IV immunoglobulin during their medical ICU admission from 2011 to 2018. Prescribing patterns, level of evidence supporting use, and cost. A total of 389 patients received greater than or equal to 1 dose of IV immunoglobulin for 46 discrete indications and 36.5% of indications had low-quality data supporting use of IV immunoglobulin. The primary indication for IV immunoglobulin was hypogammaglobulinemia (35.5%) followed by antibody-mediated lung transplant rejection (15.4%). Nonsurvivors received lower median dosing (g/kg) and number of doses compared with survivors (0.4 g/kg [0.4-1 g/kg] vs 0.5 g/kg [0.4-1 g/kg] [p = 0.0003] and 1.0 [1-2] vs 2 [1-3] doses [p = 0.0001], respectively). Dosing was based on ideal body weight in 258 patients (66%). High-quality data supported IV immunoglobulin use in 15 patients (4%). The median cost per dose of IV immunoglobulin in nonsurvivors was $4,893 ($4,078-$8,155) versus $5,709 ($4,078-$10,602) in survivors (p = 0.04). IV immunoglobulin is prescribed for many indications in the medical ICU with low-quality evidence supporting its use and dosing regimens are variable. Hospital survivors received a higher dose and greater number of doses of IV immunoglobulin compared with nonsurvivors. National guidelines are needed to help inform IV immunoglobulin utilization and reduce healthcare costs.

Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants.

Diagnosing lung transplant rejection currently depends on histologic assessment of transbronchial biopsies (TBB) with limited reproducibility and considerable risk of complications. Mucosal biopsies are safer but not histologically interpretable. Microarray-based diagnostic systems for TBBs and other transplants suggest such systems could assess mucosal biopsies as well. We studied 243 mucosal biopsies from the third bronchial bifurcation (3BMBs) collected from seven centers and classified them using unsupervised machine learning algorithms. Using the expression of a set of rejection-associated transcripts annotated in kidneys and validated in hearts and lung transplant TBBs, the algorithms identified and scored major rejection and injury-related phenotypes in 3BMBs without need for labeled training data. No rejection or injury, rejection, late inflammation, and recent injury phenotypes were thus scored in new 3BMBs. The rejection phenotype correlated with IFNG-inducible transcripts, the hallmarks of rejection. Progressive atrophy-related changes reflected by the late inflammation phenotype in 3BMBs suggest widespread time-dependent airway deterioration, which was especially pronounced after two years posttransplant. Thus molecular assessment of 3BMBs can detect rejection in a previously unusable biopsy format with potential utility in patients with severe lung dysfunction where TBB is not possible and provide unique insights into airway deterioration. ClinicalTrials.gov NCT02812290.

Donor-Specific Antibodies and Antibody-Mediated Rejection after Alemtuzumab Induction Therapy: A Retrospective Analysis of a High-Volume Lung Transplant Center

Purpose Within the last years increasing attention has been given to antibody-mediated rejection (AMR) due to its poor long-term outcomes. The impact of alemtuzumab on donor-specific antibodies (DSAs) and AMR in lung transplantation is currently unclear and most evidence comes from kidney transplantation. This study aimed to analyze the impact of alemtuzumab induction on the incidence of DSAs and AMR. Methods All patients transplanted between 2007 and 2017, who received alemtuzumab as induction therapy, were included in this retrospective single-center analysis. The following parameters were evaluated: donor-specific antibodies, C4d deposition, lung histology and occurrence of antibody-mediated rejection. Results Within the study period 525 patients received alemtuzumab as induction therapy. Pre-transplant DSAs were present in 64 (12.2%) recipients (53 anti-HLA class I and 40 anti-HLA class II). De novo (dn) DSAs developed in 93 (17.7%) recipients after transplantation (78 anti-HLA class I and 113 anti-HLA class II). Median time to development of dnDSA was 104 days (42-165) and incidence rates at 1 and 5-years after transplantation were 12.1% and 21.4%, respectively. In 20 (3.8%) recipients clinical AMR was diagnosed. Among them, 7 (35%) patients had a definite diagnosis, 9 (45%) a probable one and 4 (20%) a possible one as defined by the latest ISHLT AMR grading system. Deposition of C4d was only positive in 4 (20%) clinical AMR patients. Capillaritis was observed in 4 (20%) cases and neutrophilic septal margination in 3 cases (15%). Anti-HLA class I and class II were positive in 11 (55%) and 13 (65%) recipients, respectively. Long-term survival of recipients, who developed AMR, was significantly worse than other recipients, with a 5-years rate of 45% vs 75% (p Conclusion Alemtuzumab induction therapy is associated with a low incidence of dnDSAs and AMR. Long-term outcome of these patients remains poor.

Current challenges and opportunities in the management of antibody-mediated rejection in lung transplantation.

There is increasing recognition of the importance of antibody-mediated rejection (AMR) after lung transplantation. The development of donor-specific antibodies, a key feature of AMR, occurs in approximately 30% of lung transplant recipients and is associated with poor posttransplant outcomes. This review highlights recently developed AMR diagnostic criteria in lung transplantation, potential mechanisms that mediate the development of AMR, and discusses current and emerging treatment strategies for this significant, graft-limiting complication. A major advance is the development of consensus guidelines to precisely define AMR amongst lung transplant. Regimens for the treatment of AMR continue to evolve with varying success reported with regards to antibody clearance and improving clinical outcomes. A multimodality treatment approach is common, typically involving a combination of intravenous immune globulin, plasmapheresis, rituximab, and bortezomib or carfilzomib. Recent studies suggest several new agents including tocilizumab, belimumab, daratumumab, plerixafor, and C1 esterase inhibitor as potentially novel and effective therapies to employ in AMR treatment. Despite advancements in the diagnosis of AMR through well defined consensus guidelines, there is limited evidence to guide treatment. Current data suggests that conventional approaches are of suboptimal efficacy, but emerging therapeutic agents with diverse biological mechanisms offer promise for improved AMR treatment.

Acute rejection.

Despite induction immunosuppression and the use of aggressive maintenance immunosuppressive regimens, acute allograft rejection following lung transplantation is still a problem with important diagnostic and therapeutic challenges. As well as causing early graft loss and mortality, acute rejection also initiates the chronic alloimmune responses and airway-centred inflammation that predispose to bronchiolitis obliterans syndrome (BOS), also known as chronic lung allograft dysfunction (CLAD), which is a major source of morbidity and mortality after lung transplantation. Cellular responses to human leukocyte antigens (HLAs) on the allograft have traditionally been considered the main mechanism of acute rejection, but the influence of humoral immunity is increasingly recognised. As with other several other solid organ transplants, antibody-mediated rejection (AMR) is now a well-accepted and distinct clinical entity in lung transplantation. While acute cellular rejection (ACR) has defined histopathological criteria, transbronchial biopsy is less useful in AMR and its diagnosis is complicated by challenges in the measurement of antibodies directed against donor HLA, and a determination of their significance. Increasing awareness of the importance of non-HLA antigens further clouds this issue. Here, we review the pathophysiology, diagnosis, clinical presentation and treatment of ACR and AMR in lung transplantation, and discuss future potential biomarkers of both processes that may forward our understanding of these conditions.

Characteristics of Donor-Specific Antibodies Associated With Antibody-Mediated Rejection in Lung Transplantation.

Although donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) are frequently found in recipients after lung transplantation (LT), the characteristics of DSA which influence antibody-mediated rejection (AMR) in LT are not fully defined. We retrospectively analyzed 206 consecutive LT patients of our center (2010–2013). DSAs were detected by using luminex single antigen beads assay and mean fluorescence intensity was assessed. Within the study population, 105 patients had positive DSA. Patients with and without AMR (AMRPos, n = 22, and AMRNeg, n = 83, respectively) were compared. AMRPos patients had significantly greater frequencies of anti-HLA DQ DSA (DQ DSA) than AMRNeg patients (95 vs 58%, respectively, p < 0.0001). Compared to AMRNeg patients, AMRPos patients had higher DQ DSA sum MFI [7,332 (2,067–10,213) vs 681 (0–1,887), p < 0.0001]. DQ DSA when associated with AMR, had more frequent graft loss and chronic lung allograft dysfunction (CLAD). These data suggest (i) that DSA characteristics clearly differ between AMRPos and AMRNeg patients and (ii) the deleterious impact of DQ DSA on clinical outcome.

Subclinical Antibody-Mediated Rejection

Subclinical Antibody-Mediated Rejection

Antibody-Mediated Rejection in Lung Transplantation: Clinical Outcomes and Donor-Specific Antibody Characteristics.

In the context of lung transplant (LT), because of diagnostic difficulties, antibody-mediated rejection (AMR) remains a matter of debate. We retrospectively analyzed an LT cohort at Foch Hospital to demonstrate the impact of AMR on LT prognosis. AMR diagnosis requires association of clinical symptoms, donor-specific antibodies (DSAs), and C4d(+) staining and/or histological patterns consistent with AMR. Prospective categorization split patients into four groups: (i) DSA positive, AMR positive (DSA(pos) AMR(pos) ); (ii) DSA positive, AMR negative (DSA(pos) AMR(neg) ); (iii) DSA limited, AMR negative (DSA(Lim) ; equal to one specificity, with mean fluorescence intensity of 500-1000 once); and (iv) DSA negative, AMR negative (DSA(neg) ). AMR treatment consisted of a combination of plasmapheresis, intravenous immunoglobulin and rituximab. Among 206 transplanted patients, 10.7% were DSA(pos) AMR(pos) (n = 22), 40.3% were DSA(pos) AMR(neg) (n = 84), 6% were DSA(Lim) (n = 13) and 43% were DSA(neg) (n = 88). Analysis of acute cellular rejection at month 12 showed higher cumulative numbers (mean plus or minus standard deviation) in the DSA(pos) AMR(pos) group (2.1 ± 1.7) compared with DSA(pos) AMR(neg) (1 ± 1.2), DSA(Lim) (0.75 ± 1), and DSA(neg) (0.7 ± 1.23) groups. Multivariate analysis demonstrated AMR as a risk factor for chronic lung allograft dysfunction (hazard ratio [HR] 8.7) and graft loss (HR 7.56) for DSA(pos) AMR(pos) patients. Our results show a negative impact of AMR on LT clinical course and advocate for an early active diagnostic approach and evaluation of therapeutic strategies to improve prognosis.

Donor-specific antibody and antibody-mediated rejection in lung transplantation

Donor-specific antibody and antibody-mediated rejection in lung transplantation

Antibody-mediated Rejection in Lung Transplantation.

There has been increasing awareness of antibody-mediated rejection (AMR) as an important cause of graft failure after lung transplantation in recent years. However, the diagnostic criteria for pulmonary AMR are not well defined. All four tenets of AMR in kidney and heart transplantation, graft dysfunction, complement component deposition, circulating donor-specific antibodies (DSA), and histopathologic changes consistent with AMR, are infrequently present in lung transplantation. Nonetheless, the lung transplant community has made important progress recognizing cases of AMR and developing a definition. However, AMR is often refractory to therapy resulting in graft failure and death. In this review, we discuss the progress and challenges in the diagnosis and therapeutic options for pulmonary AMR. In addition, we briefly examine emerging paradigms of C4d-negative AMR and chronic AMR, and conclude that significant progress is needed to mitigate the effects of humoral immune responses after lung transplantation.

Antibody-mediated rejection in lung transplantation: fable, spin, or fact?

The lung transplant community continues to struggle with the diagnosis and management of antibody-mediated rejection. The four diagnostic tenets of donor-specific antibodies, C4d staining, histopathologic changes, and allograft dysfunction, which were largely derived from the early Banff meetings on renal transplantation, have somewhat arbitrarily been applied to lung transplantation. With the passage of time, it is increasingly apparent that merits of these diagnostic pillars are less robust in lung transplantation. In this article, we summarize some of the controversies and challenges surrounding the diagnosis of antibody-mediated rejection in lung transplantation.

Lung Transplant Recipients Suspected of Antibody Mediated Rejection Treated with Plasmapheresis Have a Poor Prognosis

Purpose No standard criteria exists for antibody mediated rejection (AMR) in lung transplant recipients and there is no consensus of treatment of suspected AMR. We report the outcome in patients suspected of AMR, based on radiological, pathological and immunological criteria, treated with plasmapheresis. Methods and Materials Retrospective single center study of lung transplant recipients who were treated with plasmapheresis from 2007 to 2011 due to the suspicion of AMR. A tentative diagnosis of AMR was based on 1) >20% decline in FEV1, 2) transbronchial biopsies showing diffuse alveolar or interstitial damage with or without acute cellular rejection, 3) No infection as a plausible cause of damage, 4) Presence of extensive ground-glass pattern on HR-CT, 5) detection of Donor specific HLA antibodies (DSA) by solid-phase HLA microbead assay (Luminex). Results Eleven patients were identified with suspicion of AMR and treatment with plasmapheresis. 7/11 patients had more than 20% decline in FEV1. All patients fulfilled criteria 2, 3, and 4 and Luminex analysis was performed in 8/11 patients with detection of Donor specific HLA antibodies and with a positive Donor specific B-cell cross-match in 4/11 patients. Biopsies demonstrated a wide spectrum of morphology: DAD (4),NSIP (3), COP (3), OB (3), AIP (1), positive C4D (1). Two patients with DAD and one with COP had grade A2/A3. All 11 transplant recipients were treated with plasmapheresis and subsequently Rituximab or Alemtuzumab. Eight patients died within 9 months from the last plasmapheresis. Conclusions Although treated aggressively with plasmapheresis and other immunmodulating therapies the outcome of suspected AMR was poor. No specific pathological pattern was found in this small study and a tentative diagnosis of AMR based solely on CT and transbronchial biopsies is probably difficult to distinguish from the recently defined Restrictive Allograft Syndrome. More specific criteria for AMR in lung transplantation are needed.

Proteasome Inhibitor Therapy for Antibody-Mediated Lung Transplant Rejection

Purpose Antibody mediated rejection (AMR) is a significant challenge after lung transplantation and no consensus exists on the optimal therapeutic approach. Bortezomib may serve as a treatment option by eradicating the antibody-producing plasma cells. We report clinical experience with bortezomib for AMR after lung transplantation. Methods and Materials Five lung transplant recipients with clinical AMR and donor-specific antibodies (DSA) (defined as MFI > 2000) were treated with bortezomib (1.3 mg/m 2 ). Serial measurements of DSA were conducted by single antigen bead on Luminex, OneLambda. The immunodominant DSA (iDSA) was assigned to the DSA with the highest MFI value at the time of diagnosis. Results In this cohort, AMR developed a median of 10.5 months after transplant; bortezomib treatment resulted in elimination of iDSA in 2 patients (1, 2), and a 50% reduction without clearance in another (3). The remaining two patients (4, 5) had persistent DSA without decline in MFI. Despite iDSA reduction in patients 1, 2, and 3, this did not translate to a meaningful clinical benefit (absence of resolution of acute AMR in patient 1). During therapy, one patient experienced grade IV thrombocytopenia; otherwise, side effects were mild and transient. Prior to AMR, all patients had normal graft function; however, all 3 patients surviving to hospital discharge developed chronic, severe graft dysfunction. Two of the 5 patients are still alive 132 (2) and 230 (5) days after treatment for AMR. Conclusions Although these preliminary results do not support a strong clinical or immunological response to bortezomib, we cannot exclude a prescribing bias for use in more severe cases of AMR. Bortezomib treatment for AMR warrants further investigation to fully elucidate its potential benefit. iDSAMFI at DiagnosisMFI at last follow-upResolution of acute AMRPatient 1DQ64516

Antibody-mediated lung transplant rejection

Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation.

Antibody-mediated rejection in lung transplantation: Myth or reality?

Whether antibody-mediated rejection after lung transplantation exists as an entity is debated by immunologists, histopathologists, and clinicians, without a strong consensus regarding diagnostic characteristics despite an increasing body of evidence that attests to a significant role in other solid organ transplant disciplines. Evidence for and against the protean manifestations of antibody-mediated rejection after lung transplantation is discussed, with special reference to hyperacute pulmonary allograft rejection as well as acute and chronic pulmonary allograft rejection, emphasizing the potential role of complement and antibodies to human leukocyte antigens and anti-endothelial antigens. A well-described clinical phenotype exists for hyperacute pulmonary allograft rejection with low-level evidence for efficacy of therapy with intravenous immunoglobulin, plasmapheresis, and anti-CD20 monoclonal antibodies plus supportive care, if instituted early in the evolution of the process. The clinical phenotype of acute antibody-mediated rejection is now better defined, if not widely diagnosed, and a similar treatment protocol appears effective. The role of antibody-mediated rejection in the development of chronic pulmonary allograft rejection remains an exciting area for further study based on some compelling preliminary work to date. Antibody-mediated rejection after lung transplantation remains a major area for research. In the clinical domain, experience suggests antibody-mediated rejection should be considered a potential cause of graft dysfunction, whether concomitant acute cellular rejection is diagnosed or not, and especially where resistance to corticosteroid therapy is encountered.