ライフサイエンスコーパス: AAT

20 pression from resistant codon-optimized AAT (AAT-opt) transgene cassette using adeno-associated virus

21 AAT levels were tested, including using AAV AAT-opt transgene cassettes targeted to muscle and liver

22 re consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation h

23 evels of AAT and both soluble and aggregated AAT protein in the liver.

24 and hepatocyte-specific markers (i.e., ALB, AAT, TO, and G6P), and by 28 days represented more than

25 After implantation of skin allografts, AAT-treated mice had greater numbers of foxp3-positive c

26 hich exhibits an aspartate aminotransferase (AAT) fold.

27 In aspartate aminotransferase (AAT), an extended hydrogen bond network is coupled to th

28 We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and

29 ce of the inverse correlations of MMP-26 and AAT in cells/tissues.

30 of EFV monotherapy, 103N mutations (AAC and AAT) rapidly emerged and increased in the population to

31 splantation course of patients with AATD and AAT-replete COPD.

32 of overall rates of FEV1 decline in AATD and AAT-replete patients with COPD showed no significant dif

33 e interactions among DC, CD4(+) T cells, and AAT in vitro and in vivo.

34 d islet function was analyzed in control and AAT treated hosts.

35 in resolving exudates identified HX, GSN and AAT as potential leads for new drug discovery programs.

36 balance between lipoproteins, proteases, and AAT in atherosclerosis.

37 combination vectors carrying piZZ shRNA and AAT-opt transgenes separately, or a single bicistronic A

38 ealing that motifs (AT)n, (AG)n, (AC)n, and (AAT)n exhibit the highest allelic diversity.

39 alpha-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction o

40 Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by neutrophil-dr

41 Alpha-1 antitrypsin (AAT) deficiency is a common single-gene disorder among N

42 Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gen

43 In this study we used alpha-1 antitrypsin (AAT) deficiency with the piZZ mutant phenotype as a mode

44 ines from patients with alpha-1 antitrypsin (AAT) deficiency, for which there is currently no drug or

45 s from mutations in the alpha-1 antitrypsin (AAT) gene.

46 alpha-1 antitrypsin (AAT) has been shown to reduce inflammatory markers, prom

47 rine protease inhibitor alpha-1 antitrypsin (AAT) on IL-32 levels and showed suppression of IL-32 and

48 s, we demonstrated that alpha-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for

49 alpha(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition

50 Because alpha-1-antitrypsin (AAT) decreases HIV replication in PBMCs and monocytic ce

51 Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disease, caused by m

52 the monogenic disorder alpha-1-antitrypsin (AAT) deficiency.

53 fects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model.

54 Alpha-1-antitrypsin (AAT) is synthesized and secreted mainly by hepatocytes,

55 relation between plasma alpha-1-antitrypsin (AAT) levels in human donors and the development of acute

56 ease relevant inhibitor alpha-1-antitrypsin (AAT) Z-variant with catalytically inactive elastase.

57 tions of the biomarkers alpha-1-antitrypsin (AAT), myeloperoxidase, and neopterin.

58 alpha1 -Antitrypsin (AAT) deficiency is one of the most common genetic disord

59 The rationale of alpha1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema

60 Mutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained

61 alpha1-Antitrypsin (AAT) is a potent protease inhibitor, deficiency of which

62 alpha1-Antitrypsin (AAT) is a serpin, the primary function of which is to re

63 serum protease inhibitor alpha1-antitrypsin (AAT) possesses antiinflammatory properties and reduces c

64 ine proteinase inhibitor alpha1-antitrypsin (AAT) prevents type 1 diabetes development in NOD mice an

65 ibution of two misfolded alpha1-antitrypsin (AAT) variants responsible for AAT deficiency disease: nu

66 rate that treatment with alpha1-antitrypsin (AAT), an agent that dampens inflammation, does not direc

67 the proteomic analysis, alpha1-antitrypsin (AAT), hemopexin (HX), and gelsolin (GSN), and tested aga

68 For newly synthesized alpha1-antitrypsin (AAT), the modification of its asparagine-linked oligosac

69 A sulfated alpha1-antitrypsin (AAT), thought to be a default secretory pathway marker,

70 r 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and c

71 erine protease inhibitor alpha-1 antitrysin (AAT).(2)

72 s that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular dis

73 Because AAT is naturally occurring and available clinically, exa

74 Because AAT therapy exerts antiinflammatory and immune modulator

75 Because AAT treatment in humans is safe, its use during human is

76 individuals suggesting that affinity between AAT and elastase is strongly modulated by so-far overloo

77 results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the g

78 ly prevent liver pathology and restore blood AAT concentration in AAT deficiencies.

79 To restore blood AAT levels in AAV8/shRNA-treated mice, several strategie

80 e been employed for the gene therapy of both AAT-deficient lung disease and liver disease.

81 of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial c

82 ilitate automated quantification of cellular AAT accumulation using a 96-well immunofluorescence read

83 ility to efficiently develop tools to combat AAT.

84 pulation in muscle biopsy samples containing AAT-expressing myofibers.

85 In contrast, AAT suppressed LPS-induced in vitro secretion of proinfl

86 portantly, these OVA-specific CTLs decreased AAT expression in mice treated with AAV2-OVA/AAT vector

87 The Delta AAT mutation is predicted to result in the loss of one o

88 to 100-fold lower than native plasma-derived AAT.

89 This trafficking occurs without detectable AAT polymerization or binding to lipid rafts.

90 er of CD3 transcripts decreased in the DLNs, AAT did not affect IL-2 activity in vitro.

91 ducible functional CCR7 is maintained during AAT-mediated anti-inflammatory conditions.

92 ower (80%, P < 0.001) when exposed to either AAT or rAAT.

93 decreased by 60-80% (P < 0.001) with either AAT or rAAT.

94 In this review, we examine AAT resistance in GBMs, with an emphasis on six potentia

95 ction of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this

96 fically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulin

97 1-antitrypsin (AAT) variants responsible for AAT deficiency disease: null Hong Kong (NHK) and Z allel

98 er were highly statistically significant for AAT (28.71; P < 0.0001) and myeloperoxidase (62.79; P <

99 he hepatocyte, which is the primary site for AAT production.

100 ocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to pr

101 n therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protect

102 Thus, gene therapy for AAT lung disease is conceived of as augmentation of seru

103 hypoxia plays a key role in GBM escape from AAT.

104 udied, 2 that related to intestinal function-AAT and myeloperoxidase-were associated with small but h

105 ce, several strategies to restore functional AAT levels were tested, including using AAV AAT-opt tran

106 Furthermore, AAT-ASO administration in these animals stopped liver di

107 Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinan

108 sense oligonucleotide targeted against hAAT (AAT-ASO) and found reductions in circulating levels of A

109 However, AAT demonstrates transient effects because many patients

110 iZ transgenic mouse strain expresses a human AAT (hAAT) transgene that contains the AATD-associated G

111 nt were examined using OT-II cells and human AAT (0.5 mg/ml).

112 ined and donor-derived cells expressed human AAT protein.

113 ytes, using transgenic mice expressing human AAT-Z.

114 s, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger

115 tributes to the intracellular retention of I AAT.

116 ed by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (3

117 t strategies, may therefore be beneficial in AAT deficiency-associated liver disease.

118 es directly enhance the rate of catalysis in AAT.

119 ology and restore blood AAT concentration in AAT deficiencies.

120 Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)Fox

121 e achieved high gene-targeting efficiency in AAT-deficiency patient iPSCs with 25%-33% of the clones

122 on therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrop

123 rotein replacement for treating emphysema in AAT-ZZ individuals.

124 the functional mass of beta cells expands in AAT-treated diabetic NOD mice.

125 es with the enhancement in catalytic rate in AAT.

126 egulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its

127 ,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation.

128 Z mice exhibit many AATD symptoms, including AAT protein aggregates, increased hepatocyte death, and

129 An integrated AAT-AMS program was effective in both de-labeling of AAL

130 pon exposure of CD4(+) T cells to OVA-loaded AAT-treated DC, 2.7-fold more Foxp3(+) Treg cells were o

131 ung destruction and early emphysema in a low AAT, and high neutrophil elastase environment in the lun

132 and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways o

133 r is abnormal, but not in those expressing M AAT.

134 ed virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.

135 essing normal, M-type alpha-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multi

136 Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL

137 We demonstrate that in AATD, misfolded AAT protein accumulates in the endoplasmic reticulum of

138 the preferential selection of the misfolded AAT monomer for proteasomal degradation.

139 utcomes when initiated after starting modern AAT.

140 a distinct secretory pathways, although most AAT is secreted within a few hours and virtually none is

141 g shRNA in piZZ transgenic mice, both mutant AAT mRNA in the liver and defected serum protein level w

142 mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not inc

143 es, we observed over 90% knockdown of mutant AAT with a 13- to 30-fold increase of circulating wild-t

144 ted iPSCs were functional without the mutant AAT accumulation.

145 The mutant AAT protein aggregates and accumulates in the liver lead

146 Accumulation of mutated AAT protein aggregates in hepatocytes leads to endoplasm

147 se-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltra

148 Nine AAT-deficient subjects were enrolled sequentially in coh

149 0% reduction in levels of circulating normal AAT, demonstrating potential for this approach in higher

150 ctions enhance intracellular accumulation of AAT mutants and implicate the oxidative ER state as a pa

151 er, the mechanism behind these activities of AAT is poorly understood.

152 hind the favorable tolerogenic activities of AAT.

153 ence of FDC supernatant, but the addition of AAT at concentrations >0.5 mg/ml inhibited virus replica

154 data suggest that systemic administration of AAT can be a promising therapy to treat acute liver fail

155 Administration of AAT early after BMT decreased mortality in three models

156 e aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute

157 hese findings suggest that administration of AAT represents a novel unique and viable strategy to mit

158 Administration of AAT-ASO in nonhuman primates led to an approximately 80%

159 nsufficient antiprotease activity because of AAT deficiency in the lungs is a contributing factor to

160 hepatocellular carcinoma, whereas decline of AAT levels in sera is responsible for pulmonary emphysem

161 The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-termi

162 s, suggesting a cell type-specific effect of AAT.

163 odels of BMT, we have studied the effects of AAT on GvHD severity.

164 Therapeutic effects of AAT were evaluated by monitoring animal survival, histop

165 hibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung i

166 cking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver inj

167 e primarily owing to the loss of function of AAT in neutralizing neutrophil elastase and other pro-in

168 likely to contribute to the inactivation of AAT, to the follow-up liberation of the Ser protease act

169 ess, supporting the routine incorporation of AAT into AMS programs.

170 ated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging.

171 Intra-articular injection of AAT or GSN protected cartilage integrity in mice with in

172 ally 48 h after intra-articular injection of AAT or GSN.

173 nd found reductions in circulating levels of AAT and both soluble and aggregated AAT protein in the l

174 The expression levels of AAT homeologs showed unequal contributions in response t

175 a gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared

176 and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due

177 record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as ad

178 48-linked Ub-IkappaBalpha in the presence of AAT, correlating altered ubiquitination with a prolonged

179 In the presence of AAT, degradation of cytoplasmic IkappaBalpha was dramati

180 In the presence of AAT, islets displayed enhanced viability and inducible i

181 lammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.

182 d novel mechanism and highlights the role of AAT augmentation therapy in ameliorating inflammation in

183 pical corticosteroid use before the start of AAT (OR, 3.85; 95% CI, 1.35-11.03), a corneal ring infil

184 -29.67), and age >/=33 years at the start of AAT (OR, 4.02; 95% CI, 1.46-11.06).

185 other feature of AK) present at the start of AAT (OR, 5.89; 95% CI, 1.17-29.67), and age >/=33 years

186 findings were collected both at the start of AAT and subsequently at the time that topical corticoste

187 ee of scleritis and hypopyon at the start of AAT, topical corticosteroids were not associated with wo

188 ent of corticosteroid use after the start of AAT, was used to estimate the odds ratios (ORs) of a sub

189 costeroids had been used before the start of AAT.

190 ong patients with AATD is similar to that of AAT-replete patients with COPD, patients with AATD with

191 protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced infl

192 mice expressing human AATZ (the Z variant of AAT) confers any competitive advantages compared to host

193 AT expression from resistant codon-optimized AAT (AAT-opt) transgene cassette using adeno-associated

194 Exogenous administration of HX, GSN, or AAT abrogated the effects of IL-1beta and osteoarthritic

195 ole for Arg-434 similar to its role in other AAT alpha-family members.

196 AAT expression in mice treated with AAV2-OVA/AAT vector that followed a time course mimicking uncoati

197 pressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal,

198 Post-AAT, prescribing of narrow-spectrum penicillins was more

199 spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard

200 AT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant.

201 ic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) w

202 to antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread.

203 tion of a mutant alpha1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes an

204 eatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation the

205 d mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AA

206 that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing

207 Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 d

208 ive clinical drugs were identified to reduce AAT accumulation in diverse patient iPSC-derived hepatoc

209 rs/templates containing nucleotide repeats [(AAT)(3)/(ATT)(5), (ATT)(3)/(AAT)(5), (CAG)(3)/(CTG)(5),

210 ld-type AAT protein from the shRNA-resistant AAT-opt cassette.

211 Golgi complex, kinetics alone cannot resolve AAT release via distinct secretory pathways, although mo

212 Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammatio

213 -rich DNA with a preference for the sequence AAT.

214 A serum AAT level of 11 muM represents the protective threshold

215 cretion into the blood and causing low serum AAT levels ( approximately 3-7 muM with normal serum lev

216 isease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils.

217 Seven mutations from set AAT-TAT were combined by site-directed mutagenesis to gi

218 few mutations occur in the intersection (set AAT intersection TAT) of amino acid residues that are co

219 tations occurs in a subset of positions (set AAT-TAT) that is conserved (>or=75% identical) in AATase

220 Severe AAT deficiency (plasma levels below 11 mum) is most comm

221 gnal differentiates between healthy and sick AAT-deficient individuals suggesting that affinity betwe

222 We found that endogenous SO2/AAT pathway existed in adipose tissues including perivas

223 e most consistent with the idea that soluble AAT abundantly enters ISGs and then is efficiently reloc

224 M-specific AAT expression was observed in all subjects in a dose-de

225 M-specific AAT was expressed above background in all subjects in co

226 Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells com

227 Because newly synthesized AAT arrives very rapidly in the Golgi complex, kinetics

228 ed ISG exocytosis reroutes newly synthesized AAT directly into the medium and prevents its arrival in

229 The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intra

230 These data suggest that short-term AAT treatment of human islet transplant recipients may b

231 mes were dramatically improved by short-term AAT treatment.

232 incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-

233 demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and

234 It is now apparent that AAT has important immune-regulatory roles that would be

235 We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation mo

236 eal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-kil

237 In summary, this study demonstrates that AAT can regulate neutrophil apoptosis by a previously un

238 We recently discovered that AAT is efficiently cleaved by a novel metalloproteinase,

239 n we describe novel findings indicating that AAT significantly reduces cytokine- and streptozotocin (

240 eases NF-kappaB activity, we postulated that AAT might also block FDC-mediated HIV replication.

241 ic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients

242 These findings suggest that AAT modulates immune and inflammatory functions and may

243 l models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore

244 typic and phenotypic differences between the AAT-relevant species of parasite or host and their model

245 upports the functional role of MMP-26 in the AAT cleavage and inflammation.

246 racellular DC IL-10 was 2-fold higher in the AAT group.

247 n with engrafted hepatocytes occurred in the AAT-Z-expressing mice even in the absence of severe live

248 hat MMP-26, by cleaving and inactivating the AAT serpin, operates as a unique functional link that re

249 a genetic disease, caused by mutation of the AAT gene.

250 uble LT declined faster (P < 0.002) than the AAT-replete patients.

251 We learned that the AAT-specific T cells in this patient were cytolytic in p

252 Antiangiogenic therapy (AAT) is a treatment option that targets GBM-associated v

253 These AATs are also necessary to maintain intracellular ornith

254 Thus, AAT monotherapy provides allografts with antiinflammator

255 ormal, M-type alpha-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m.

256 ght have a competitive advantage relative to AAT-Z-expressing hepatocytes, using transgenic mice expr

257 cular and biochemical basis of resistance to AAT in GBM patients.

258 h shares considerable sequence similarity to AAT-1, a protein originally identified in testis as an A

259 Taken together, AAT significantly improves islet graft survival after in

260 We describe these amino acid transporters (AATs).

261 Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and Trypanosoma v

262 immunity after AAV2-OVA/alpha1 anti-trypsin (AAT) administration.

263 an serum-derived alphaalpha-1- anti-trypsin (AAT) reduces production of proinflammatory cytokines, in

264 ent increases in transgene-derived wild-type AAT after local intramuscular vector administration.

265 g., shRNA) and restore circulating wild-type AAT expression from resistant codon-optimized AAT (AAT-o

266 ransplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z

267 to 30-fold increase of circulating wild-type AAT protein from the shRNA-resistant AAT-opt cassette.

268 uced INS-1 cells stably expressing wild-type AAT.

269 Z-type AAT molecules polymerize within the hepatocyte, precludi

270 Under AAT treatment (60 mg/kg), DLN contained twice more fluor

271 However, despite altering the ratio in vivo, AAT had no direct effects on either the donor T effector

272 Here, 283 full length wheat AAT genes representing 100 distinct groups of homeologs

273 However, no systematic analysis of wheat AAT genes has been reported to date.

274 treatment is liver transplantation, whereas AAT replacement therapy is therapeutic for emphysema.

275 , these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vi

276 dates for amino acid uptake from soil whilst AATs highly expressed in senescing leaves and stems may

277 cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular

278 cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded popu

279 addition, treatment of AATD individuals with AAT augmentation therapy decreased neutrophil ADAM-17 ac

280 nally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentra

281 ties in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement wit

282 Further analysis of patients with AAT (<1 year duration, n=4) and AAP (>1 year duration, n

283 Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturba

284 ed for augmentation therapy in patients with AAT deficiency.

285 of hepatocellular carcinoma in patients with AAT deficiency.

286 between patients with AATD and patients with AAT-replete COPD (P > 0.09).

287 d January 2008, a total of 231 patients with AAT-replete COPD and 45 with AATD underwent LT at Clevel

288 transplantation when they were treated with AAT compared with mice treated with saline.

289 fted with allogeneic islets and treated with AAT monotherapy (n = 24).

290 Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor nec

291 lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients.

292 e reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well

293 antly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity.

294 itioning and postconditioning treatment with AAT resulted in attenuation or prevention of GVHD and su

295 Systemic treatment with AAT significantly decreased Jo2-induced liver cell apopt

296 th FDCs or their supernatant with or without AAT, and ensuing viral RNA and p24 production were monit

297 nt of cells with reducing agents increases Z AAT secretion.

298 requency for the common missense mutation (Z-AAT) ranges from 4% in the US to nearly 25% in the Repub

299 o having to downregulate the production of Z-AAT protein.

300 s thought to be owing to toxicity from the Z-AAT mutant protein that folds poorly and forms insoluble