Liste der Referenzen

Referenzen

[Kelly2004]: Kelly, K.M., et.al.: Induction of Autoimmunity by Adjuvant Hydrocarbons
in: Yehuda Shoenfeld and Noel R. Rose (Ed): Infection and Autoimmunity. , Elsevier 2005, ISBN: 978-0-444-51271-0 pp.87-104
... More recently, it has become clear that other hydrocarbons, notably the mineral oil Bayol F and the endogenous hydrocarbon squalene, also can induce lupus-like disease in mice [6]. These substances share the capacity to serve as immunological adjuvants, defined as "substances used in combination with a specific antigen that produce more immunity than the antigen alone" [7]. The induction of murine lupus by immunological adjuvants is significant for two reasons. First, it provides a model for the interaction of environmental triggers with the genetic background in systemic autoimmunity and secondly, it raises the possibility that adjuvant hydrocarbons might trigger autoimmune disease in susceptible humans...
... steigert die Möglichkeit, dass Kohlenwasserstoff-Adjuvantien Autoimmunkrankheiten in anfälligen Menschen auslösen können...
[Carlson2000]: Carlson, B.C. et al.: The endogenous adjuvant squalene can induce a chronic T-cell mediated arthritis in rats. American Journal of Pathology 2000, 156: 2057- 2065
Squalene is a cholesterol precursor, which stimulates the immune system nonspecifically. We demonstrate that one intradermal injection of this adjuvant lipid can induce joint-specific inflammation in arthritis-prone DA rats. Histopathological and immunohistochemical analyses revealed erosion of bone and cartilage, and that development of polyarthritis coincided with infiltration of alphabeta(+) T cells. Depletion of these cells with anti-alphabeta TcR monoclonal antibody (R73) resulted in complete recovery, whereas anti-CD8 and anti-gammadelta TcR injections were ineffective. The apparent dependence on CD4(+) T cells suggested a role for genes within the major histocompatibility complex (MHC), and this was concluded from comparative studies of MHC congenic rat strains, in which DA.1H rats were less susceptible than DA rats. Furthermore, LEW.1AV1 and PVG.1AV1 rats with MHC identical to DA rats were arthritis-resistant, demonstrating that non-MHC genes also determine susceptibility. Some of these genetic influences could be linked to previously described arthritis susceptibility loci in an F2 intercross between DA and LEW.1AV1 rats (ie, Cia3, Oia2 and Cia5). Interestingly, some F2 hybrid rats developed chronic arthritis, a phenotype not apparent in the parental inbred strains. Our demonstration that an autoadjuvant can trigger chronic, immune-mediated joint-specific inflammation may give clues to the pathogenesis of rheumatoid arthritis, and it raises new questions concerning the role of endogenous molecules with adjuvant properties in chronic inflammatory diseases.
Squalen ist eine Vorstufe des Cholesterins und stimuliert das Immunsystem unspezifisch. Wir demonstrieren, dass eine intradermale Injektion dieses Lipid-Adjuvans eine Gelenkentzündung in Arthritis-anfälligen Ratten induzieren kann.
Furthermore, it has recently been suggested that anti-squalen antibodies (Abs) can develop as a consequence of vaccination with vaccines containing squalene, and that these Abs are associcated with pathology in the Gulf War syndrome (Dr. Pam Asa, personal communication)
Kürzlich wurde festgestellt, dass Anti-Squalen-Antikörper (Abs) sich als Folge einer Impfung mit Squalen-haltigen Impfstoffen entwickeln können und das diese Abs mit der Pathologie des Golf-Krieg-Syndroms assoziiert sind (Dr. Pam Asa, persönliche Mitteilung).
[Asa2000]: Asa, P.B. et al.: Antibodies to squalene in Gulf War syndrome. Exp. Mol. Pathol. 2000 Feb 68(1): 55-64
Gulf War Syndrome (GWS) is a multisystemic illness afflicting many Gulf War-era veterans. The molecular pathological basis for GWS has not been established. We sought to determine whether the presence of antibodies to squalene correlates with the presence of signs and symptoms of GWS. Participants in this blinded cohort study were individuals immunized for service in Desert Shield/Desert Storm during 1990-1991. They included 144 Gulf War-era veterans or military employees (58 in the blinded study), 48 blood donors, 40 systemic lupus erythematosus patients, 34 silicone breast implant recipients, and 30 chronic fatigue syndrome patients. Serum antibodies to squalene were measured. In our small cohort, the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene. All (100%) GWS patients immunized for service in Desert Shield/Desert Storm who did not deploy, but had the same signs and symptoms as those who did deploy, had antibodies to squalene. In contrast, none (0%) of the deployed Persian Gulf veterans not showing signs and symptoms of GWS have antibodies to squalene. Neither patients with idiopathic autoimmune disease nor healthy controls had detectable serum antibodies to squalene. The majority of symptomatic GWS patients had serum antibodies to squalene.
Die Mehrzahl der Patienten mit Symptomen des Golfkrieg-Syndroms hatte Antikörper gegen Squalen im Serum.
[Asa2002]: Asa, P.B. et al.: Antibodies to squalene in recipients of anthrax vaccine. Exp.Mol. Pathol. 2002 Aug; 73 (1): 19-27 )
We previously reported that antibodies to squalene, an experimental vaccine adjuvant, are present in persons with symptoms consistent with Gulf War Syndrome (GWS) (P. B. Asa et al., Exp. Mol. Pathol 68, 196-197, 2000). The United States Department of Defense initiated the Anthrax Vaccine Immunization Program (AVIP) in 1997 to immunize 2.4 million military personnel. Because adverse reactions in vaccinated personnel were similar to symptoms of GWS, we tested AVIP participants for anti-squalene antibodies (ASA). In a pilot study, 6 of 6 vaccine recipients with GWS-like symptoms were positive for ASA. In a larger blinded study, only 32% (8/25) of AVIP personnel compared to 15.7% (3/19) of controls were positive (P > 0.05). Further analysis revealed that ASA were associated with specific lots of vaccine. The incidence of ASA in personnel in the blinded study receiving these lots was 47% (8/17) compared to an incidence of 0% (0/8; P < 0.025) of the AVIP participants receiving other lots of vaccine. Analysis of additional personnel revealed that in all but one case (19/20; 95%), ASA were restricted to personnel immunized with lots of vaccine known to contain squalene. Except for one symptomatic individual, positive clinical findings in 17 ASA-negative personnel were restricted to 4 individuals receiving vaccine from lots containing squalene. ASA were not present prior to vaccination in preimmunization sera available from 4 AVIP personnel. Three of these individuals became ASA positive after vaccination. These results suggest that the production of ASA in GWS patients is linked to the presence of squalene in certain lots of anthrax vaccine.
Die Ergebnisse legen nahe, dass die Produktion von Anti-Squalen Antikörpern in Patienten mit Golfkriegs-Syndrom mit der Anwesenheit von Squalen in gewiessen Chargen des Antrax-Impfstoffs verbunden ist.
[Satoh2003]: M. Satoh et.al.: Induction of lupus autoantibodies by adjuvants. J Autoimmun. 2003 Aug;21(1):1-9.
Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNFalpha production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies.The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines.
Das Potiential, Autoimmunität auszulösen, könnte die Verwendung von Öl-Adjuvantien in menschlichen und tierischen Impfstoffen verkomplizieren.
[Kuroda2004]: Y. Kuroda et.al.: Autoimmunity induced by adjuvant hydrocarbon oil components of vaccine. Biomed Pharmacother. 2004 Jun;58(5):325-37.
Adjuvant oils such as Bayol F (Incomplete Freund's adjuvant: IFA) and squalene (MF59) have been used in human and veterinary vaccines despite poor understanding of their mechanisms of action. Several reports suggest an association of vaccination and various autoimmune diseases, however, few were confirmed epidemiologically and the risk of vaccination for autoimmune diseases has been considered minimal. Microbial components, not the adjuvant components, are considered to be of primary importance for adverse effects of vaccines. We have reported that a single intraperitoneal injection of the adjuvant oils pristane, IFA or squalene induces lupus-related autoantibodies to nRNP/Sm and -Su in non-autoimmune BALB/c mice. Induction of these autoantibodies appeared to be associated with the hydrocarbon's ability to induce IL-12, IL-6, and TNF-alpha, suggesting a relationship with hydrocarbon's adjuvanticity. Whether this is relevant in human vaccination is a difficult issue due to the complex effects of vaccines and the fact that immunotoxicological effects vary depending on species, route, dose, and duration of administration. Nevertheless, the potential of adjuvant hydrocarbon oils to induce autoimmunity has implications in the use of oil adjuvants in human and veterinary vaccines as well as basic research.
.. das Potential von Adjuvantien auf Kohlenwasserstoff-Öl Basis, Autoimmunität zu erzeugen, hat Auswirkungen auf die Verwendung von Öl-Adjuvantien in meschlichen und tierischen Impfstoffen ...
[Holmdahl2001]: R. Holmdahl et.al.: Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev. 2001 Dec;184:184-202.
Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of alphabetaTCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans.
Injektion von nicht nur der klassischen vollständigen Freund-Adjuvantien, sondern auch von Mineralöl ohne Mycobakterien und reinen Adjuvantien wie Pristan und Squalen, induzieren schwere Arthritis in vielen Rattenstämmen.
[Koppang2008]: E.O.Koppang et.al.: Vaccination-induced systemic autoimmunity in farmed Atlantic salmon. J Immunol. 2008 Oct 1;181(7):4807-14.
Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.
Thrombosen und granulomatöse Entzündungen der Leber, und Immunkomplex-Glomerulonephritis sind in geimpftem Fisch verbreitet. Autoimmunität ähnlich dem bei Mäusen durch Öl-induziertem Lupus ist bei geimpftem Atlantik-Farmlachs verbreitet.