| 1. |
- Abu Hamdeh, Sami, et al.
(författare)
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Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
- 2018
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 28:4, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.
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| 2. |
- Boberg, Andreas, et al.
(författare)
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Murine models for HIV vaccination and challenge
- 2008
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1476-0584 .- 1744-8395. ; 7:1, s. 117-130
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 only infects humans and chimpanzees. SIV or SHIV are, therefore, used as models for HIV in rhesus, cynomologus and pigtail macaques. Since conducting experiments in primate models does not fully mimic infection or vaccination against HIV-1 and is expensive, there is a great need for small-animal models in which it is possible to study HIV-1 infection, immunity and vaccine efficacy. This review summarizes the available murine models for studying HIV-1 infection with an emphasis on our experience of the HIV-1-infected-cell challenge as a model for evaluating candidate HIV-1 vaccines. In the cell-based challenge model, several important factors that, hopefully, can be related to vaccine efficacy in humans were discovered: the efficiency of combining plasmid DNA representing several of the viral genes originating from multiple clades of HIV-1, the importance of adjuvants activating innate and induced immunity and the enhanced HIV eradication by drug-conjugated antibody. © 2008 Future Drugs Ltd.
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| 3. |
- Johansson, Susanne E, et al.
(författare)
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NK Cell Function and Antibodies Mediating ADCC in HIV-1-Infected Viremic and Controller Patients
- 2011
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Ingår i: Viral immunology. - : Mary Ann Liebert. - 0882-8245 .- 1557-8976. ; 24:5, s. 359-368
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the Fc gamma RIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were divided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-gamma expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.
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| 4. |
- Rollman, Erik
(författare)
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Concepts in DNA immunization overcoming viral diversity and enhancing plasmid immunogenicity
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- On April 23, 1984, the prominent scientist Robert Gallo held a historical press conference at the Department of Health and Human Services, Washington D.C., USA. He announced that his laboratory at the National Institutes of Health had over the last months isolated a retrovirus named Human T-cell Leukemia Virus type III (HTLV-III). The virus came from 48 patients in the homosexual community in San Francisco. The city had just been hit by the mysterious epidemic of acquired immunodeficiency syndrome (AIDS). HTLV-111 was later renamed human immunodeficiency virus (HIV). At the same meeting, Gallo further explained that his laboratory was able to grow large quantities of the virus in cell cultures and as a consequence it was stated that "we believe that the new process will enable us to develop a vaccine to prevent AIDS in the future ... we hope to have such a vaccine ready for testing in approximately two years." This thesis is printed on the very same day, twenty years later and the now mature field of HIV/AIDS vaccine development has still not discovered what exactly mediates protection against HIV infection, while we are still far away from a clinically useful vaccine. Why is this? What makes HIV so special when other virus diseases, like polio, can be recognized and eliminated by the immune system, and where vaccination works very well? The focal points of this thesis are two major problems in modem vaccine development. Many viruses exist in multiple subtypes or serotypes, a phenomenon that has serious implications for the choice of vaccine antigen. It is especially critical when trying to vaccinate against HIV, the surface structure (gpl20) of which presents immense antigenic variability. Moreover, modem genetic vaccines based on smaller units of the virus or consisting of multiple genes (combination genetic vaccine) are weak immunogens, this is the second problem that this thesis explores. More specifically, we have shown that removal of inhibitory elements in a DNA immunogen is of importance for efficient induction of immunity. Further, antibody responses to a DNA immunogen can be substantially enhanced if the genetic immunogen is coupled to a carrier, in our case the polyomavirus VP1 capsid. In combination with generally immunoactivating agents, for instance recombinant granulocyte macrophage colony stimulating factor (GM-CSF), the HIV envelope genes from multiple subtypes (A, B and C) can change the envelope DNA immunogen into a potent entity that induces high titers of broadly reactive antibodies as well as cellular responses. We also show that immunization with proteins followed by DNA immunogens, a strategy tentatively called "reverse prime-boost immunization" induces strong immunity. These findings will be further validated in human clinical trials within the near future. Last but not least, we have developed an HIV murine challenge model based on pseudotyped viral particles; combining the HIV genome and the murine leukemia virus (HIV/MuLV) envelope. This model resembles human acute primary HIV infection. Protection in this model can be ascribed to cellular immunity, in the complete absence of antibodies. Using this model, we have shown that primeboost immunization induces better protection against subtype homologous HIV challenge, than against heterologous exposure. The immunization strategies covered in this thesis describe the biological problems that face vaccine development in general and HIV vaccinology in particular. The problems and concepts illustrate why the statement by several scientists in the 1980s has proven to be somewhat premature.
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| 5. |
- Rollman, Erik, et al.
(författare)
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Evaluation of immunogenicity and efficacy of combined DNA and adjuvanted protein vaccination in a human immunodeficiency virus type 1/murine leukemia virus pseudotype challenge model
- 2007
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 25:11, s. 2145-2154
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Tidskriftsartikel (refereegranskat)abstract
- A DNA plasmid encoding human immunodeficiency virus type 1 (HIV-1) env, nef and tat genes was used in mice in a prime-boost immunization regimen with the corresponding recombinant proteins. The genetic immunogen was delivered with a gene gun and the proteins were injected intramuscularly together with the adjuvant AS02A. Immunizations were followed by experimental challenge with pseudotyped HIV-1 subtype A or B virus. In an initial experiment in which animals were challenged four weeks after the final immunization, all single modality and prime-boost vaccinations resulted in a significant level of protection as compared to control animals. There was a trend for DNA-alone immunization yielding the highest protection. In a subsequent study, a late challenge was performed 19 weeks after the final immunization. All groups having received the DNA vaccine, either alone or in combination with adjuvanted protein, exhibited strong protection against HIV replication. The subtype-specific protection against the experimental HIV challenge was significantly stronger than the cross-protection. Cellular and humoral immune responses were assessed during immunization and after challenge, but without clear correlation to protection against HIV replication. The data suggest that either DNA or protein antigens alone provide partial protection against an HIV-1/MuLV challenge and that DNA immunization is essential for achieving very high levels of efficacy in this murine HIV-1 challenge model. While prime-boost combinations were more immunogenic than DNA alone, they did not appear to provide any further enhancement over DNA vaccine mediated efficacy. The DNA immunogen might prime low levels of CD8+ T cells responsible for virus clearance or possibly a yet unidentified mechanism of protection. © 2006 Elsevier Ltd. All rights reserved.
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| 8. |
- Tucker, Stina, et al.
(författare)
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The Murine Version of BAN2401 (mAb158) Selectively Reduces Amyloid-beta Protofibrils in Brain and Cerebrospinal Fluid of tg-ArcSwe Mice
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 43:2, s. 575-588
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (A beta) immunotherapy for Alzheimer's disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble A beta protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for A beta protofibrils over A beta monomers. Further, we confirm the presence of the target by showing that both antibodies efficiently immunoprecipitate soluble A beta aggregates in human AD brain extracts. mAb158 reached the brain and reduced the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric A beta(42) could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble A beta protofibrils, with minimal binding to A beta monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full phase 1 development, and available data indicate a favorable safety profile in AD patients.
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