IgM-Enriched Human Intravenous Immunoglobulin-Based Treatment of Patients With Early Donor Specific Anti-HLA Antibodies After Lung Transplantation.

BACKGROUND: At our institution, until April 2013, patients who showed early donor specific anti-HLA antibodies (DSA) after lung transplantation were preemptively treated with therapeutic plasma exchange (tPE) and a single dose of Rituximab. In April 2013, we moved to a therapy based on IgM-enriched human immunoglobulins (IVIG), repeated every 4 weeks, and a single dose of Rituximab. METHODS: This observational study was designed to evaluate the short-term patient and graft survival in patients who underwent IVIG-based DSA treatment (group A, n = 57) versus contemporary patients transplanted between April 2013 and January 2015 without DSA (group C, n = 180), as well as to evaluate DSA clearance in IVIG-treated patients versus historic patients who had undergone tPE-based treatment (group B, n = 56). Patient records were retrospectively reviewed. Follow-up ended on April 1, 2015. RESULTS: At 6 months and 1 year of follow-up, group A had a survival similar to group C (P = 0.81) but better than group B (P = 0.008). Group A showed statistically nonsignificant trends toward improved freedom from pulsed-steroid therapy and biopsy-confirmed rejection over groups B and C. The DSA clearance was better in group A than group B at treatment end (92% vs 64%; P = 0.002) and last DSA control (90% vs 75%; P = 0.04). CONCLUSIONS: Patients with new early DSA but without graft dysfunction that are treated with IVIG and Rituximab have similarly good early survival as contemporary lung transplant recipients without early DSA. The IVIG yielded increased DSA clearance compared with historic tPE-based treatment, yet spontaneous clearance of new DSA also remains common.

Long-term kidney allograft survival in patients with transplant glomerulitis.

BACKGROUND: Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell-mediated rejection (TCMR) remains unexplored. METHODS: Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G+TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m. The median follow-up was 37 (14; 77) months from biopsy. RESULTS: Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G+TCMR, and ABMR groups. Graft survival was lower in the G+TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P<0.001). CONCLUSIONS: Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.

Preemptive treatment with therapeutic plasma exchange and rituximab for early donor-specific antibodies after lung transplantation.

OBJECTIVE: De novo donor-specific anti-human leukocyte antigen antibodies develop in a high proportion of lung transplant recipients early after lung transplantation. We recently showed that de novo donor-specific antibodies (DSA) occurrence is associated with significantly increased mortality. Here, we studied the efficacy of a preemptive treatment protocol. METHODS: A retrospective observational study was conducted on all lung transplantations at Hanover Medical School between January 2009 and May 2013. RESULTS: Among the 500 transplant recipients, early DSA developed in 86 (17%). Of these, 56 patients (65%; Group A) received therapeutic plasma exchange, and 30 patients (35%; Group B) did not. Among Group A patients, 51 also received rituximab. Between groups, there was no statistically significant difference in mortality, incidence of pulsed steroid therapies, rejections diagnosed by biopsy specimen, incidence of bronchitis obliterans syndrome (BOS), or infections requiring hospitalization at 1 year and 3 years. Also, there were no statistically significant differences after matching 21 Group A with 21 Group B patients through propensity score analysis. Significantly more Group A patients (65%) than Group B patients (34%) cleared DSA at hospital discharge (p = 0.01). At the last control after transplantation (median, 14 months; interquartile range, 5-24 months), 11 Group A (22%) and 9 Group B patients (33%) still showed DSA (p = 0.28). CONCLUSIONS: Preemptive treatment with therapeutic plasma exchange and rituximab led to improved elimination of DSA early after lung transplantation (p = 0.01). However, spontaneous elimination in untreated Group B patients also occurred frequently. This treatment protocol was not associated with significantly improved outcome.

Early donor-specific antibodies in lung transplantation: risk factors and impact on survival.

BACKGROUND: The impact of early donor-specific anti-HLA antibodies (DSA) on patient and graft survival after lung transplantation remains controversial. In this study we analyzed risk factors for DSA that developed before initial hospital discharge after lung transplantation (early DSA) and compared mid-term outcomes in patients with or without DSA. METHODS: Between January 2009 and August 2013, 546 patients underwent lung transplantation at our institution. One hundred (18%) patients developed early DSA (Group A) and 446 (82%) patients (Group B) did not. Patient records were retrospectively reviewed. RESULTS: Retransplantation (odds ratio [OR] = 2.7, 95% confidence interval [CI] 1.1 to 6.5, p = 0.03), pre-operative HLA antibodies (OR = 2.1, 95% CI 1.2 to 3.4, p = 0.003) and primary graft dysfunction (PGD) score Grade 2 or 3 at 48 hours (OR = 2.6, 95% CI 1.5 to 4.6, p = 0.001) were associated with early DSA development. Overall, 1- and 3-year survival in Group A and B patients was 79 ± 4% vs 88 ± 2% and 57 ± 8% vs 74 ± 3%, respectively (p = 0.019). Eleven Group A (11%) and 32 Group B (7%) patients died before hospital discharge (p = 0.34). Among patients surviving beyond discharge, 1- and 3-year survival in Group A and B patients was 89 ± 4% vs 95 ± 1% and 65 ± 8% vs 80 ± 3% in Group A and B patients, respectively (p = 0.04). Multivariate analysis identified early anti-HLA Class II DSA (OR = 1.9, 95% CI 1.0 to 3.4, p = 0.04) as an independent risk factor for post-discharge mortality but not for in-hospital mortality. CONCLUSIONS: Pre-operative HLA antibodies, retransplantation or post-operative PGD increase the risk of developing early DSA, which were independently associated with an increased risk for mortality.

Plus- and minus-end directed microtubule motors bind simultaneously to herpes simplex virus capsids using different inner tegument structures.

Many viruses depend on host microtubule motors to reach their destined intracellular location. Viral particles of neurotropic alphaherpesviruses such as herpes simplex virus 1 (HSV1) show bidirectional transport towards the cell center as well as the periphery, indicating that they utilize microtubule motors of opposing directionality. To understand the mechanisms of specific motor recruitment, it is necessary to characterize the molecular composition of such motile viral structures. We have generated HSV1 capsids with different surface features without impairing their overall architecture, and show that in a mammalian cell-free system the microtubule motors dynein and kinesin-1 and the dynein cofactor dynactin could interact directly with capsids independent of other host factors. The capsid composition and surface was analyzed with respect to 23 structural proteins that are potentially exposed to the cytosol during virus assembly or cell entry. Many of these proteins belong to the tegument, the hallmark of all herpesviruses located between the capsid and the viral envelope. Using immunoblots, quantitative mass spectrometry and quantitative immunoelectron microscopy, we show that capsids exposing inner tegument proteins such as pUS3, pUL36, pUL37, ICP0, pUL14, pUL16, and pUL21 recruited dynein, dynactin, kinesin-1 and kinesin-2. In contrast, neither untegumented capsids exposing VP5, VP26, pUL17 and pUL25 nor capsids covered by outer tegument proteins such as vhs, pUL11, ICP4, ICP34.5, VP11/12, VP13/14, VP16, VP22 or pUS11 bound microtubule motors. Our data suggest that HSV1 uses different structural features of the inner tegument to recruit dynein or kinesin-1. Individual capsids simultaneously accommodated motors of opposing directionality as well as several copies of the same motor. Thus, these associated motors either engage in a tug-of-war or their activities are coordinately regulated to achieve net transport either to the nucleus during cell entry or to cytoplasmic membranes for envelopment during assembly.