Search

The introduction of reverse genetic technology to generate recombinant VHSVs (rVHSVs) has contributed to the uncovering of functional roles of viral genes and to the development of attenuated prophylactic vaccines. In this study, to assess the possible use of rVHSVs as a tool of combined vaccines, we newly rescued rVHSVs that harbor viral envelop-studded eGFP (rVHSV-A-SGT) or nucleoprotein-fused eGFP (rVHSV-A-NLG), and the ability of these rVHSVs to induce adaptive humoral immunity in olive flounder (Paralichthys olivaceus) was compared with that of rVHSV-A-eGFP that expresses eGFP as a soluble form in the cytoplasm of infected cells. The results showed that antibodies against eGFP were efficiently induced by the immunization of olive flounder with rVHSV-A-SGT and rVHSV-A-NLG, while rVHSV-A-eGFP was poor in the ability to induce antibody response against eGFP. These results suggest that the display of heterologous antigens on VHSV envelop is a good way to develop efficient combined vaccines and the fusion of foreign antigen with N protein can also be a way to enhance immunogenicity of a foreign antigen. The present recombinant VHSVs - rVHSV-A-SGT and rVHSV-A-NLG – not only express foreign antigens in host cell cytoplasm but also display antigens in or on the virus particles. Further researches on the availability of recombinant VHSVs as combined vaccines against multiple fish pathogens are needed. • The possible use of rVHSVs expressing antigen on or in viral particles was assessed. • rVHSV expressing viral envelop-studded eGFP (rVHSV-A-SGT) was rescued. • Another rVHSV expressing nucleoprotein-fused eGFP (rVHSV-A-NLG) was rescued. • Antibodies against eGFP were efficiently induced by rVHSV-A-SGT and rVHSV-A-NLG. • Display of antigens on VHSV envelop would be a good way to develop combined vaccines. [ABSTRACT FROM AUTHOR]

This study aims to compare 2 common induction strategies, basiliximab and ATG. Analysis of the ISHLT transplant registry was performed. The database was queried for pediatric heart transplants from January 1, 2000, to June 30, 2015, who had received induction with basiliximab or ATG. Primary end-point was graft survival. Secondary end-points included 1-year survival and 1-year conditional survival. There were 3158 heart transplants who received induction with basiliximab or ATG. The ATG cohort was younger, more likely to have congenital heart disease or be a retransplant, have a higher PRA, longer ischemic time, and been transplanted earlier in the study period (all P<.01). There was no difference in graft loss in the basiliximab cohort compared to the ATG cohort (HR 1.18 P=.06). On conditional 1-year survival analysis, basiliximab induction was associated with graft loss (HR=1.35 95% CI 1.1-1.7, P<.01), and in the propensity-matched cohort, the basiliximab cohort was more likely to experience rejection prior to discharge (P=.04). Infection prior to discharge was more common in the antithymocyte cohort. Induction with ATG is associated with improved late graft survival compared to basiliximab. [ABSTRACT FROM AUTHOR]

To improve the pharmacological properties of maize ribosome-inactivating protein (maize RIP) for targeting HIV-infected cells, the previously engineered TAT-fused active form of maize RIP (MOD) was further engineered for cysteine-directed PEGylation. In this work, two potential antigenic sites, namely Lys-78 and Lys-264, were identified. They were mutated to cysteine residue and conjugated with PEG5k or PEG20k. The resultant PEG derivatives of MOD variants were examined for ribosome-inactivating activity, circulating half-life and immunogenicity. Our results showed that MOD-PEG conjugates had two- to five-fold lower biological activity compared to the wild-type. Mutation of the two sites respectively did not decrease the anti-MOD IgG and IgE level in mice, but the conjugation of PEG did dramatically reduce the antigenicity. Furthermore, pharmacokinetics studies demonstrated that attachment of PEG20k prolonged the plasma half-life by five-fold for MOD-K78C and 17-fold for MOD-K264C, respectively. The site-specific mutation together with PEGylation therefore generated MOD derivatives with improved pharmacological properties. [ABSTRACT FROM AUTHOR]

Background. Antibody induction with polyclonal rabbitantithymocyte globulin (rATG) or an interleukin-2 receptor antagonist (IL-2RA) is widely used in kidney transplantation. Methods. Collaborative Transplant Study data from 38 311 first deceased-donor kidney transplants (2004-13) were analysed. Transplants were classified as 'normal risk' or 'increased risk' according to current guidelines. Cox regression analysis was applied to subpopulations of propensity score-matched recipients. Results. rATG or IL-2RA induction was given to 64% of increased-risk and 53% of normal-risk patients, respectively. rATG and IL-2RA induction were each associated with reduced risk for graft loss versus no induction in increased-risk patients [hazard ratio (HR) 0.85, P = 0.046 and HR 0.89, P = 0.011, respectively]. The HR values for incidence of treated rejection in increased-risk patients for rATG and IL-2RA versus no induction were 0.75 (P = 0.037) and 0.77 (P < 0.001), respectively. In the normal risk subpopulation, neither induction therapy significantly affected the risk of graft loss or treated rejection. Hospitalization for infection was increased by rATG (P < 0.001) and IL-2RA (P < 0.001) induction. In contrast to patients transplanted during 1994-2003, among patients transplanted during 2004-13, rATG did not significantly affect the risk of non-Hodgkin's lymphoma versus no induction (P = 0.68). Conclusion. Induction therapy following kidney transplantation should be targeted to increased-risk transplants. In this analysis, a beneficial effect of antibody induction in normalrisk transplants could not be demonstrated. [ABSTRACT FROM AUTHOR]

Our center has offered thymoglobulin induction with steroid minimization to our pediatric renal transplant patients for the last 10 yr. Steroid minimization or avoidance has shown favorable results in survival, kidney function, and growth in previous studies of pediatric patients. We report our experience with this protocol over the past 10 yr with respect to patient/graft survival, acute rejection episodes, renal function, linear growth, bone density, cardiovascular risk factors, and opportunistic infections. A retrospective chart review was performed for pediatric renal transplant patients on the steroid-minimized protocol between January 2002 and December 2011 on an intention to treat basis. Patient demographics, height, weight, serum creatinine, i GFR, biopsies, and survival data were collected. Height and weight z-scores were calculated with Epi Info 7, using the CDC 2000 growth charts. Survival was calculated using Kaplan- Meier analysis. e GFR was calculated using the original and modified Schwartz equations. Forty-four pediatric patients were identified, aged 13 months to 19 yr. Five-yr survival was 95.5% for males and 94.4% for females. Only five patients had biopsy-proven ACR, two of which were at more than 12 months post-transplantation. Height delta z-scores from transplant to one, three, and five yr were 0.34, 0.38, and 0.79, respectively. Weight delta z-scores from transplant to one, three, and five yr were 0.87, 0.79, and 0.84, respectively. Mean original Schwartz e GFR was 84.3 ± 15.8 mL/min/1.73 m2, modified Schwartz e GFR was 59.3 ± 11.5 mL/min/1.73 m2, and i GFR was 64.2 ± 8.5 mL/min/1.73 m2 at three yr. Of 18 subjects who had a bone density exam, none had a z-score less than −2 on DEXA exam at one-yr post-transplantation. Fifty-one percent of patients were on antihypertensives at the time of transplant compared with 43% at one-yr post-transplantation. Three yr post-transplantation, the average LDL was <100 mg/dL, and average total cholesterol was <200 mg/dL. There were no clinical episodes of EBV or CMV infection. A steroid-minimized protocol with thymoglobulin induction is safe and provides favorable improvement in linear growth, stable graft function, stable or improved cardiovascular risk factors, and normal bone density in pediatric renal transplant patients. [ABSTRACT FROM AUTHOR]

Rabbit antithymocyte globulin ( ATG-F) is an extensively used induction agent. To our knowledge, no study to date has assessed reduced ATG-F dosage in children undergoing renal transplantation. This was a retrospective analysis of pediatric renal recipients in the Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, from May 2007 to February 2013. Thirty-nine children underwent renal transplantation including 25 living related and 14 cardiac deceased donor transplantation. Each recipient received ATG-F 1.5 mg/kg/d once daily for 4 days. Of the 39 recipients, five (12.8%) showed delayed graft function, including one of 25 recipients (4%) of living donor and four of 14 recipients (28.6%) of deceased donor transplantation (p < 0.05). Six of the 39 recipients (15.4%) showed acute rejection on renal biopsy. Follow-up in these children ranged from 6 to 87 months. The one-, three-, and five-yr recipients and grafts survival rates postoperation were each 94.9% and 97.3%, 97.3%, and 94.6%, respectively. The incidence of postoperative infection was 35.9% (14/39), and did not differ significantly in the living related and deceased donor groups (p > 0.05). Low-dose ATG-F can be safely used as an immune induction agent in pediatric renal transplantation. [ABSTRACT FROM AUTHOR]

Half an hour after reperfusion, the kidney, transplanted to the infant from an adult brain dead standard criteria donor, became flabby and acquired blue color. Hyperacute rejection was suspected as a consequence of false negative cross match, and eculizumab was administered with the purpose to treat antibody-mediated injury, with fast and clear effect. The patient's blood was tested for donor-specific antibodies on the next day, and results were negative. We attribute graft damage to reperfusion injury and explain eculizumab's effectiveness to its ability to prevent progression of reperfusion injury. [ABSTRACT FROM AUTHOR]

Emami S, Huang E, Kuo H-T, Kamgar M, Bunnapradist S. Multivariate analysis of antibody induction therapy and their associated outcomes in live donor kidney transplantation in the recent era. Clin Transplant 2011 DOI: 10.1111/j.1399-0012.2011.01517.x. © 2011 John Wiley & Sons A/S. Abstract: The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n = 21 919) and a later era (2003-2008, n = 26 837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era. [ABSTRACT FROM AUTHOR]

Ojogho O, Sahney S, Cutler D, Baron PW, Abdelhalim FM, James S, Zuppan C, Franco E, Concepcion W. Mycophenolate mofetil in pediatric renal transplantation: Non-induction vs. induction with basiliximab.Pediatr Transplantation 2005: 9: 80–83.© 2005 Blackwell MunksgaardNorth American Pediatric Renal Transplant Cooperative Study (NAPRTCS) reports have shown anti-T cell antibody, OKT3, to be deleterious in pediatric renal transplant recipients treated with mycophenolate mofetil (MMF). Unlike OKT3, basiliximab is a chimeric monoclonal antibody to the alpha subunit of the interleukin-2 receptor on activated T-lymphocytes. We sought to examine the outcome of MMF with or without basiliximab induction therapy in pediatric renal transplantation. Between January 1998, and June 2001, 49 pediatric renal transplants were performed at our center and 41 met the criteria for this study. We retrospectively analyzed the records of 25 patients who received MMF, Prednisone, CSA or TAC, alone (group I) and 16 patients who received MMF, CSA or TAC, and Prednisone in combination with basiliximab (group II). The two groups were similar with respect to recipient or donor age, gender, ethnicity, donor source (LD vs. CAD), cold ischemia time, and primary diagnosis. The basiliximab group had a shorter follow up period because of its more recent addition to our pediatric immunosuppression protocol, 12.9 ± 5.9 months vs. 35.5 ± 7.2 months for group I (p < 0.0001). At 6 months, the acute rejection rate was 16% (group I) compared with 25% (group II) (p = 0.689). The patient and graft survival at 6 and 12 months were 100% respectively for both groups. Basiliximab was well tolerated without significant adverse events. At 6 months, there was no significant difference between the groups in the incidence of urinary tract infection or cytomegalovirus infection. These data suggest that in the short-term, MMF with or without basiliximab induction therapy appears to yield excellent and statistically similar outcomes. However, further controlled studies are necessary to verify these findings as well as to define the role of basiliximab in MMF-treated pediatric renal transplant recipients. [ABSTRACT FROM AUTHOR]

Avian H5N1 influenza A viruses are considered to be of high pandemic potential as they are able to cross the avian-human species barrier and cause disease in humans. In the present study we assessed the impact of amino acid substitutions in the hemagglutinin (HA) of antigenic escape mutants of influenza A/Mallard/Pennsylvania/10218/84 (H5N2) (Mld/PA/84-MA) virus on the level of neutralizing antibodies and the ability to protect mice against challenge with the wild type H5 influenza virus. β-Propiolactone-inactivated vaccines prepared from eight different H5 escape mutants could be separated into two groups based on levels of protection. One group of escape mutants [m46(7), m46(7)-24B9, m46(7)-55, and m46(7)-55-24B9] was characterized by providing high levels of protection (90.0–95.4% survival) to mice against subsequent challenge with 5 LD50 of wild type Mld/PA/84-MA virus. The other group of escape mutants [m176/26, m55(2), m55(2)-24B9, and m24B9-176/26] provided moderate level of protection (57.1–66.6% survival) in mice. Analysis of the amino acid substitutions in the HA revealed that two amino acid changes in antigenic site B of the HA molecule (D126→N and K152→N) were associated for decreases in the levels of antibody and the immune protection afforded by vaccination with these H5 virus escape mutants. The phenotypic effects of mutations in HA gene of H5 virus may be of importance to appraise the extent and direction of H5 influenza viruses antigenic evolution. [Copyright &y& Elsevier]

Abstract: Mycophenolate mofetil (MMF) is a new immunosuppressive agent that blocks de novo purine synthesis in T and B lymphocytes via a potent selective inhibition of inosine monophosphate dehydrogenase. MMF has been shown to significantly reduce the incidence of acute rejection in both adult and pediatric renal transplantation. The impact of MMF on routine antibody induction therapy in pediatric renal transplantation has not been defined. Remarkably, a recent North American Pediatric Transplant Cooperative Study concluded that T-cell antibody induction therapy was deleterious for patients who received MMF. Our study examines the use of MMF in an evolving immunosuppressive strategy to avoid antibody induction in both living (LD) and cadaver (CAD) donor pediatric renal transplantation. We retrospectively analyzed the records of 43 pediatric renal transplants that received MMF-based triple therapy without antibody induction therapy between November 1996 and April 2000. We compared CAD (n = 17) with LD (n = 26). The two groups were similar demographically except that CAD had significantly younger donors than LD, 26.1 ± 13.7 vs. 36.2 ± 9.2 yr (p = 0.006). All the patients received MMF at 600 mg/m2 /b.i.d. (maximum dose of 2 g/d) and prednisone with cyclosporine (86%) or tacrolimus (14%). Mean follow-up was >36 months for each group. Acute rejection rate at 6 months was 11.8% (CAD) vs. 15.4% (LD) (p = 0.999) and at 1 yr was 23.5% (CAD) vs. 26.9% (LD) (p = 0.999). Mean estimated glomerular filtration rate (ml/min/1.73 m2 ) at 6 months was 73.3 ± 15.3 (CAD) vs. 87.6 ± 24.2 (LD) (p = 0.068). Patient survival at 1, 2, and 3 yr was 100, 100, and 100% for CAD vs. 100, 96, and 96% for LD, respectively. Graft survival at 1, 2, and 3 yr was 100, 100, and 94% for CAD vs. 96, 88, and 71% for LD, respectively. Graft loss in CAD was because of chronic rejection (n = 2) while in LD it was because of non-compliance (n = 6), post-transplant... [ABSTRACT FROM AUTHOR]

PURPOSE: Risk factors, sites, and mortality of hospitalized cytomegalovirus (CMV) disease in renal transplant recipients have not been studied in a national population.METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System from 1 July 1, 1994 to June 30, 1997 were analyzed in an historical cohort study of patients with a primary discharge diagnosis of CMV disease (ICD9 Code 078.5x).RESULTS: Renal transplant recipients had an incidence density of hospitalized CMV disease of 1.26/100 person years, and 79% of hospitalizations for CMV disease occurred in the first six months post transplant. The leading manifestation of hospitalized infection was pneumonia (17%). In logistic regression analysis controlling for transplant era, pre-transplant dialysis &ges; 6 months, maintenance mycophenolate mofetil (MMF) therapy, and allograft rejection, but not induction antibody therapy, were significantly associated with hospitalized CMV disease. Compared with recipients with negative CMV serology (R-) who had donor kidneys with negative CMV serology (D−), D+/R− had the highest risk of hospitalization for CMV disease [adjusted odds ratio (AOR) 5.19, 95% confidence interval (CI) 3.89–6.93] followed by D+/R+ recipients, whereas D−/R+ were not at significantly increased risk. In Cox Regression analysis the relative risk of death associated with hospitalized CMV disease was 1.32 (95% CI 1.02–1.71).CONCLUSIONS: Even in modern era, renal transplant recipients were at high risk for hospitalizations for CMV disease, which were associated with decreased patient survival. Current prophylactic measures have apparently not reduced the high risk of D+/R− recipients. Prolonged pre-transplant dialysis and maintenance MMF should also be considered risk factors for hospitalized CMV infection, and prospective trials of prophylactic antiviral therapy should be performed in these subgroups. [Copyright &y& Elsevier]

Introduction: The safety and efficacy of daclizumab (1 mg/kg/dose every 14 d for five doses) has been established in kidney and heart transplant recipients. Alternative dosing regimens based on pharmacokinetic simulation and limited clinical trials are being investigated. The purpose of this ongoing multicenter study is to determine the safety and efficacy of two dosing regimens of daclizumab as an adjunctive immunosuppressive agent compared with no antibody induction in simultaneous kidney–pancreas transplant (SKPT) recipients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids as primary immunosuppression. Methods: This is an interim report of a multicenter, prospective, open-label, randomized study with a target enrolment of 290 patients. Eligible SKPT patients were randomized to one of three groups: daclizumab 1 mg/kg/dose every 14 d for five doses (Group I), daclizumab 2 mg/kg/dose every 14 d for two doses (Group II), and no antibody induction (Group III). The primary endpoint of the study is a composite of the incidence of presumed or biopsy-proven kidney or pancreas rejection, graft loss, or death within the first 6 months post-transplantation. Results: A total of 166 patients were randomized into the three groups [Group I (n=70), Group II (n=74), Group III (n=22)]. Demographic and transplant characteristics were similar among the groups. At a minimum follow-up of 3 months, patient, kidney and pancreas graft survival rates were similar among the three groups. However, the rates of acute renal allograft rejection were 18% (Group I), 8% (Group II), and 36% (Group III), p < 0.05. The probabilities of either kidney or pancreas allograft rejection were 22% (Group I), 8% (Group II), and 38% (Group III). At 3 months, the actuarial event-free survival (no acute rejection, allograft loss, or death) rates were 67, 81 and 50% in Groups I, II, and III, respectively. There were no differences in the incidence of infectious complications among... [ABSTRACT FROM AUTHOR]

Applying computer-assisted epitope prediction to the amino-acid sequence of the epidermal growth factor receptor (EGFR), the extracytoplasmic domain HGFR(516-529) was selected as a putative antigenic region. EGFR(516-529) was synthesized on a solid-phase matrix and N-terminally linked to the low mol. wt adjuvant tripalmitoyl-S-glyceryl-cysteinyl-serine (Pam3 Cys-Ser). The conjugation to this B cell and macrophage-activating lipopeptide considerably enhanced the immunogenicity of the EGFR peptide. Using the conjugate Pam3 Cys-Ser-EGFR(516-529), a peptide-specific monoclonal antibody was produced. By flow cytometry and immunoprecipitation the antibody was demonstrated to recognize EGFR on A431 cells, expressing large numbers of EGFR. With this novel approach synthetic immunogens can be prepared which could serve as thermostable synthetic vaccines with great potential in countries where a functional cold chain cannot be maintained. [ABSTRACT FROM AUTHOR]

Botulinum toxin type B (BoNT/B) has been recommended as an alternative for patients who have become resistant to botulinum toxin type A (BoNT/A). This study aimed to compare the clinical effect, within a patient, of four injections with low doses of rimabotulinumtoxinB with the effect of the preceding abobotulinumtoxinA (aboBoNT/A) injections. In 17 patients with cervical dystonia (CD) who had become resistant to aboBoNT/A, the clinical effect of the first four rimabotulinumtoxinB (rimaBoNT/B) injections was compared to the effect of the first four aboBoNT/A injections using a global assessment scale and the TSUI score. After the first two BoNT/B injections, all 17 patients responded well and to a similar extent as to the first two BoNT/A injections, but with more side effects such as dry mouth and constipation. After the next BoNT/B injection, the improvement started to decline. The response to the fourth BoNT/B injection was significant (p < 0.048) lower than the fourth BoNT/A injection. Only three patients developed a complete secondary treatment failure (CSTF) and five patients a partial secondary treatment failure (PSTF) after four BoNT/B injections. In nine patients, the usual response persisted. With the use of low rimaBoNT/B doses, the induction of CSTF and PSTF to BoNT/B could not be avoided but was delayed in comparison to the use of higher doses. In contrast to aboBoNT/A injections, PSTF and CSTF occurred much earlier, although low doses of rimaBoNT/B had been applied. [ABSTRACT FROM AUTHOR]