Background: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. Methods: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli of 250 cases of PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence microscopy (IF) studies to localize the novel antigen. Western blot analyses were performed using serum and IgG eluted from frozen biopsy tissue to demonstrate IgG binding to the antigen. Results: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in 9 cases of PLA2R-negative MN. All 9 MN cases developed following allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in 5 known cases of allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all 5 cases by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean 20.9 ± 10.1). All 14 cases were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy showed IgG (2-3+) with mild C3 (0-1+) along the GBM; IgG4 was the dominant IgG subclass. IHC following protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of FAT1-asssociated MN, but not from PLA2R-associated MN. Conclusions: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.
BackgroundTreatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX).MethodsA retrospective cohort study of MPO- or PR3-ANCA–positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m2). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared.ResultsOf 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330).ConclusionsThe apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
Background: Our understanding of the interaction between the host immune system and cancer has evolved rapidly over the previous 10 years due to the clinical success induced by checkpoint inhibition. Previous immunologic work can now be realized in combination strategies. Modified Vaccinia Ankara (MVA) offers significant opportunities due to its natural induction of innate and adaptive immunity, large payload, and excellent safety profile. Methods: MVA vectors were administered subcutaneously (SC), intravenously (IV) or intratumorally (IT) into tumor-bearing mice. Cytokine secretion profile in serum was assessed by Luminex analysis. NK and T cell infiltration and activation in various organs and cytolytic activity against target cells were determined by flow cytometrybased assays. PD-1 immune checkpoint blockade (ICB), low dose cyclophosphamide, tumor-targeting Abs or 15 Gy radiotherapy were administered along with IV MVA. Results: Recombinant MVA (rMVA) in which tumor antigens and costimulatory molecules are encoded can be customized for maximal effect by route of administration. rMVA administered intravenously (IV) causes superior induction of antigen specific T cells, cytokines and NK cells than previously seen with subcutaneous or intramuscular routes. Encoding CD40L in addition amplifies the effects and efficacy improves in relevant models. This is dependent on T cells and NK cells, indicating a potential solution to one tumor-resistance mechanism, MHC loss and/or mutation. Furthermore, the combination of rMVA with tumor targeting antibodies, checkpoint inhibition, radiotherapy or chemotherapy often showed additional synergistic therapeutic effects. Administration of MVA alone intratumorally (IT) causes innate immune activation through toll like receptors (TLRs) as well as the cGAS / STING pathway. Recombinant antigen encoding rMVA improves systemic and local antigen-specific T cell responses. These effects can be bolstered by encoding certain costimulatory molecules. Conclusions: IV and IT recombinant MVA may offer off the shelf solutions to resolve many of the host -tumor immunity interactions that result in lack of efficacy of checkpoint inhibition alone in most patients. Bavarian Nordic plans to initiate clinical trials with existing agents in 2019 applied IV and IT and will create novel constructs to maximize clinical effect, planned to initiate in 2020 and beyond. Legal entity responsible for the study: Bavarian Nordic, Inc.
Core tip: With our review we pretend to describe the non-standard pharmacologic treatments available for autoimmune hepatitis, the indications for its use and the main applications. Also, we pretend to enhance that those alternatives are only available guided by the experience in liver transplant patients and should be only used by experienced centers. The difficult-totreat patients lead to the application of those therapies mainly as salvage treatments.Casal Moura M, Liberal R, Cardoso H, Horta e Vale AM, Macedo G. Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids.
Objective Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches.
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