Contributions
Abstract: P953
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
The human CNS is confronted with age- and peripheral disease-related increases in cellular iron contents, expression of pro-oxidative mediators (e.g. NADPH oxidases) as well as neurodegeneration and pre-activation/priming of microglia. Lately, we and others could show that oxidative damage and the pro-oxidant iron contribute to MS pathology. This is in striking contrast to mice and rats, which are species commonly used for induction of EAE, the major animal model in MS research. Contrary to humans, inflammation in rodent EAE is elicited on a background of resting microglia, low iron levels and undetectable neurodegeneration. To overcome these limitations, we examined the effects of EAE in the Zitter rat. This rat model presents with a high number of pre-activated microglia, dysregulated expression of oxidative stress mediators and detoxifiers as well as a pronounced accumulation of iron within microglia, oligodendrocytes and axons.
To induce passive EAE, we cultured MBP-specific CD4+ T cells from Lewis and Zitter rats and transferred them into naïve Lewis and Zitter animals. Disease started significantly earlier and presented with a more severe disease course in Zitter compared with Lewis rats. However, EAE-related neuropathology was surprisingly dampened in Zitter rats. Although naïve Zitter animals had high numbers of activated microglia, the levels of CD68+ phagocytes (microglia and peripheral macrophages) was not increased at the peak of EAE compared to Lewis rats. Likewise, the phagocyte activation markers iNOS and p22phox as well as APP-positive neuronal spheroids and endbulbs (representing neuronal injury and damage, respectively) followed the same expression pattern. Interestingly, significantly less CD3+ T cells were recruited to the lumbar spinal cords of Zitter rats and also the number of Iba+ phagocytes, which was strongly elevated in naïve Zitter rats, was either equal or lower at the peak of EAE compared to Lewis animals. Interestingly, only the rat genotype but neither the T cell genotype (Lewis or Zitter) nor the age or the rats (4 or 8 months) did influence EAE scores or spinal cord pathology to a major part.
Our data show that the Zitter-specific background of pre-activated microglia and neurodegeneration did not exacerbate EAE-induced neurodegeneration and inflammation. Higher clinical scores might have resulted from EAE pathology adding up to Zitter symptomatology; however, EAE-induced inflammation did not potentiate Zitter pathology.
Disclosure: This study was supported by the Austrian Science Fund.
Lassmann: honoraries from Biogen, Novartis and Sanofi
All others: nothing to disclose
Abstract: P953
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
The human CNS is confronted with age- and peripheral disease-related increases in cellular iron contents, expression of pro-oxidative mediators (e.g. NADPH oxidases) as well as neurodegeneration and pre-activation/priming of microglia. Lately, we and others could show that oxidative damage and the pro-oxidant iron contribute to MS pathology. This is in striking contrast to mice and rats, which are species commonly used for induction of EAE, the major animal model in MS research. Contrary to humans, inflammation in rodent EAE is elicited on a background of resting microglia, low iron levels and undetectable neurodegeneration. To overcome these limitations, we examined the effects of EAE in the Zitter rat. This rat model presents with a high number of pre-activated microglia, dysregulated expression of oxidative stress mediators and detoxifiers as well as a pronounced accumulation of iron within microglia, oligodendrocytes and axons.
To induce passive EAE, we cultured MBP-specific CD4+ T cells from Lewis and Zitter rats and transferred them into naïve Lewis and Zitter animals. Disease started significantly earlier and presented with a more severe disease course in Zitter compared with Lewis rats. However, EAE-related neuropathology was surprisingly dampened in Zitter rats. Although naïve Zitter animals had high numbers of activated microglia, the levels of CD68+ phagocytes (microglia and peripheral macrophages) was not increased at the peak of EAE compared to Lewis rats. Likewise, the phagocyte activation markers iNOS and p22phox as well as APP-positive neuronal spheroids and endbulbs (representing neuronal injury and damage, respectively) followed the same expression pattern. Interestingly, significantly less CD3+ T cells were recruited to the lumbar spinal cords of Zitter rats and also the number of Iba+ phagocytes, which was strongly elevated in naïve Zitter rats, was either equal or lower at the peak of EAE compared to Lewis animals. Interestingly, only the rat genotype but neither the T cell genotype (Lewis or Zitter) nor the age or the rats (4 or 8 months) did influence EAE scores or spinal cord pathology to a major part.
Our data show that the Zitter-specific background of pre-activated microglia and neurodegeneration did not exacerbate EAE-induced neurodegeneration and inflammation. Higher clinical scores might have resulted from EAE pathology adding up to Zitter symptomatology; however, EAE-induced inflammation did not potentiate Zitter pathology.
Disclosure: This study was supported by the Austrian Science Fund.
Lassmann: honoraries from Biogen, Novartis and Sanofi
All others: nothing to disclose