Multifocal motor neuropathy with high titers of anti‐MAG antibodies

Multifocal motor neuropathy (MMN) and anti‐myelin‐associated glycoprotein (anti‐MAG)‐associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49‐year‐old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti‐MAG immunoglobulin Mλ (IgMλ) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti‐MAG antibodies may vary.     

Dynamics of anti‐human leukocyte antigen antibodies after renal transplantation and their impact on graft outcome

The purpose of this study was to sequentially monitor anti‐HLA antibodies and correlate the results with antibody‐mediated rejection (AMR), graft survival (GS), and graft function (GF). We collected sera from 111 kidney transplant recipients on transplant days 0, 7, 14, 30, 60, 90, 180, and 360 and analyzed PRA levels by ELISA. DSAs were analyzed by single‐antigen beads in rejecting kidneys. At pre‐transplant, 79.3% of the patients were non‐sensitized (PRA = 0%) and 20.7% were sensitized (PRA > 1%). After transplant, patients were grouped by PRA profile: no anti‐HLA antibodies pre‐ or post‐transplant (group HLApre?/post?; n = 80); de novo anti‐HLA antibodies post‐transplant (group HLApre?/post+; n = 8); sensitized pre‐transplant/increased PRA post‐transplant (group HLApre+/post↑; n = 9); and sensitized pre‐transplant/decreased PRA post‐transplant (group HLApre+/post↓; n = 14). De novo anti‐HLA antibodies were detected at 7–180 d. In sensitized patients, PRA levels changed within the first 30 d post‐transplant. Incidence of AMR was higher in HLApre?/post+ and HLApre+/post↑ than in HLApre?/post?, and HLApre+/post↓ (p < 0.001) groups. One‐yr death‐censored GS was 36% in group HLApre+/post↑, compared with 98%, 88% and 100% in groups HLApre?/post?, HLApre?/post+, and HLApre+/post↓, respectively (p < 0.001). Excluding first‐year graft losses, GF and GS were similar among the groups. In conclusion, post‐transplant antibody monitoring can identify recipients at higher risk of AMR.     

Factors influencing long‐term outcome after kidney transplantation

Many factors influence the long‐term outcome of kidney transplantation, which is defined very schematically by patient death or renal dysfunction leading to graft loss. The most important of these factors is most likely the quality of the transplant itself, with kidneys from living donors showing a positive impact, while kidneys from expanded criteria donors show deleterious impacts. Various clinicopathological scores exist to predict mid‐ to long‐term outcomes and avoid the transplantation of kidneys displaying inferior results. The key factors related to the recipient include their age as well as disease recurrence, HLA matching, HLA immunization, ethnic background, time on dialysis, and cardiovascular comorbidities. Renal function, defined based on estimated GFR and/or proteinuria values, is a result of all these factors. Delayed graft function has a detrimental long‐term impact, as does the level of renal function impairment either in stable condition or in case of progressing dysfunction. Finally, although current immunosuppression regimes are highly efficient in preventing acute rejection, the burden of specific (diabetes, nephrotoxicity) and nonspecific (infection and cancer) side effects has significant negative long‐term consequences that may well be worse in the future because of the increasing ages of both donors and recipients. The development of safer immunosuppression strategies is therefore crucial to improve long‐term outcomes.     

Redo living‐donor lobar lung transplantation for bronchiolitis obliterans associated with antibody‐mediated rejection

Living‐donor lobar lung transplantation (LDLLT) is an established therapy for patients with end‐stage lung disease, but living‐donor lobar lung retransplantation (re‐LDLLT) is rarely reported. We previously reported a case of unilateral antibody‐mediated rejection after LDLLT in the presence of newly formed donor‐specific antibodies against a right‐lobe donor. The same patient developed contralateral bronchiolitis obliterans, resulting in bilateral bronchiolitis obliterans, but re‐LDLLT was successful. Pathological findings of the explanted lungs were consistent with the clinical course of the patient. One year after re‐LDLLT, the patient is doing well without any anti‐human leukocyte antigen antibodies. Four lobes from four different donors were transplanted in this patient. The first two lobes were rejected eventually, but the two lobes implanted later presented no signs of rejection at least for 1 year after the transplant. Herein, we report this rare case and compare the clinical course and pathological findings.     

The influence of non‐HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes

Non‐HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti‐angiotensin II type 1‐receptor‐activating antibodies (anti‐AT1R) have been mentioned to stimulate a severe vascular rejection, but the pretransplant screening has not been introduced yet. The aim of our study was to assess the incidence and importance of anti‐AT1R antibodies and their influence on renal transplant in the 1st year of observation. We prospectively evaluated the presence of anti‐AT1R antibodies in 117 consecutive renal transplant recipients in pre‐ and post‐transplant screening. Anti‐AT1R antibodies were observed in 27/117 (23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti‐AT1R(+) group. The patients with anti‐AT1R Abs >9 U/ml lost their graft more often. Biopsy‐proven AR was described in 4/27 (15%) pts in the anti‐AT1R(+) group and 13/90 (14.4%) in the anti‐AT1R(?) group, but more severe cases of Banff IIB or antibody‐mediated rejection (AMR) were more often observed in anti‐AT1R (+) 4/27 (15%) vs. 1/90 (1.1%) in anti‐AT1R(+) (P = 0.009). Patients with anti‐AT1R Abs level >9 U/ml run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti‐AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti‐AT1R‐positive ones lost the graft. Our study suggests monitoring of anti‐AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure, and graft loss.     

Vaccination with a piggyBac plasmid with transgene integration potential leads to sustained antigen expression and CD8 T cell responses

DNA vaccination with plasmid has conventionally involved vectors designed for transient expression of antigens in injected tissues. Next generation plasmids are being developed for site-directed integration of transgenes into safe sites in host genomes and may provide an innovative approach for stable and sustained expression of antigens for vaccination. The goal of this study was to evaluate in vivo antigen expression and the generation of cell mediated immunity in mice injected with a non-integrating plasmid compared to a plasmid with integrating potential. Hyperactive piggyBac transposase-based integrating vectors (pmhyGENIE-3) contained a transgene encoding either eGFP (pmhyGENIE-3-eGFP) or luciferase (pmhyGENIE-3-GL3), and were compared to transposase-deficient plasmids with the same transgene and DNA backbone. Both non-integrating and integrating plasmids were equivalent at day 1 for protein expression at the site of injection. While protein expression from the non-integrating plasmid was lost by day 14, the pmhyGENIE-3 was found to exhibit sustained protein expression up to 28 days post-injection. Vaccination with pmhyGENIE-3-eGFP resulted in a robust CD8⁺ T cell response that was three-fold higher than that of non-integrating plasmid vaccinations. Additionally we observed in splenocyte restimulation experiments that only the vaccination with pmhyGENIE-3-eGFP was characterized by IFNγ producing CD8⁺ T cells. Overall, these findings suggest that plasmids designed to direct integration of transgenes into the host genome are a promising approach for designing DNA vaccines. Robust cell mediated CD8⁺ T cell responses generated using integrating plasmids may provide effective, sustained protection against intracellular pathogens or tumor antigens.     

Summary of knowledge gaps related to quality and efficacy of current influenza vaccines

Influenza viruses are a public health threat, as they are pathogenic, highly transmissible and prone to genetic changes. For decades vaccination strategies have been based on trivalent inactivated vaccines, which are regulated by specific guidelines. The progress in scientific knowledge and the lessons learned from the A(H1N1)2009 pandemic have highlighted further the need to improve current guidelines, including the immunogenicity criteria set by the CHMP in 1997, and to promote the discussion on the shortcomings encountered, e.g. the evaluation of vaccine efficacy in the paediatric and elderly populations, the measurement of the naivety of a population, the impact of prior immunity on subsequent vaccinations, and the technical issues with the serological assays for detection of immunity and immunogenicity.     

Efficacy of bortezomib for reducing donor‐specific antibodies in children and adolescents on a steroid minimization regimen

AMR is increasingly being recognized as an important cause of renal allograft injury, contributing to significant morbidity and graft loss. There are few controlled trials and no well‐established treatment guidelines for AMR in renal transplant recipients. We retrospectively reviewed the outcome of four pediatric renal transplant recipients on a steroid minimization immunosuppression protocol treated with bortezomib for elevated DSA and acute AMR from 2012 to 2013. All patients received four doses of bortezomib 1.3 mg/m² given on days one, four, eight, and 11. All patients also received other treatments prior to bortezomib, which may have included rituximab, methylprednisolone, plasmapheresis, and/or IVIg. While bortezomib in addition to other therapies significantly decreased DSA titers, DSA remained very elevated months after treatment. All four patients had immediate improvement or stabilization of renal function but one eventually lost her graft. There were no adverse events related to bortezomib six months after treatment.