MHC Class II Isotype- and Allele-Specific Attenuation of Experimental Autoimmune Encephalomyelitis

Graaf, Katrien L. de; Barth, Silvia; Herrmann, M.; Storch, Maria K.; Otto, Christoph; Olsson, Tomas; Melms, Arthur; Jung, Günther; Wiesmüller, Karl‐Heinz; Weissert, Robert

doi:10.4049/jimmunol.173.4.2792

Cited by 8 publications

(9 citation statements)

References 43 publications

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“…Therefore, the model described here can be considered to be highly relevant for the preclinical testing of novel strategies for the treatment of MS. Furthermore, it might contribute to a better understanding of the pathogenesis of MS. 29,[32][33][34] In agreement with earlier studies we demonstrate that BMT leads to disease attenuation and protects from further induced relapses with the disease-inducing antigen, strongly suggesting that this therapy is a promising option for the treatment of MS in humans. [17][18][19][20][21][22][23][24] For the first time we demonstrate in direct comparisons that protection can be achieved by MHC-matched allogeneic, syngeneic, and BM grafts from EAE-diseased DA rats.…”

Section: Discussionsupporting

confidence: 90%

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Herrmann

Gaertner

Stadelmann

et al. 2005

Blood

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Experimental autoimmune encephalomyelitis (EAE) in rats is a highly valuable model of multiple sclerosis (MS) because it mimics major hallmarks of the human disease. EAE induced with myelin-oligodendrocyte-glycoprotein (MOG) in DA rats is relapsing/ remitting, and lesions in the central nervous system show inflammation, demyelination, and axonal and neuronal loss. Recently, bone marrow transplantation (BMT) was introduced as a novel strategy to treat MS, but its efficiency and the underlying mechanism are debatable. In MOG-induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation. In both settings, rats receiving bone marrow (BM) transplants were protected from subsequently induced relapses. These findings could be confirmed by histopathology in which rats receiving BM transplants did not have lesions compared with controls not receiving transplants. Importantly, the protective effect was achieved by allogeneic, syngeneic, and BM grafts from diseased rats. BMT resulted in increased numbers of CD4 ؉ CD25 bright regulatory T cells, increased IntroductionMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that is characterized by demyelinating plaques and axonal loss. 1 Although MS is highly prevalent in Northern Europe and the United States, 2 no cure is presently available and the clinical management of the disease is unsatisfactory. 1 The etiology of MS is unknown. However, it is generally believed that both genetic and environmental factors contribute to the development of its pathology. 3 The onset of MS is presumably characterized by autoreactive T cells crossing the blood brain barrier (BBB) and initiating an inflammatory response that results in an opening of the BBB. This allows influx of additional immune cells such as granulocytes, macrophages, natural killer (NK) cells, and B cells as well as antibodies and complement. 4 Subsequently, this process leads to myelin destruction, induction of oligodendrocyte death, axonal degeneration and, ultimately, to the functional deficits seen in MS patients. 5 Experimental autoimmune encephalomyelitis (EAE) is a frequently used animal model for MS that can be induced in rodents and monkeys. 6 In particular, myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE in DA rats mimics major hallmarks of the human disease. These include the relapsing/remitting type of disease course, the occurrence of demyelinated plaques in the brain and spinal cord, axonal loss, and the involvement of both antibodies and complement in the pathogenesis. [7][8][9][10][11] Autologous bone marrow transplantation (BMT) and hematopoietic stem cell transplantation (HSCT) are presently discussed as novel options for the treatment of patients with MS with fast progressive disease courses that do not respond to conventional treatment. 12,13 Clinical trials were to some extent inconclusive because they arrived at divergent results. [14][15][16] Preclinical studies were performed in EAE that assessed...

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Section: Discussionsupporting

confidence: 90%

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Herrmann

Gaertner

Stadelmann

et al. 2005

Blood

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“…Susceptibility to EAE and MS is associated with the major histocompatibility complex class II (MHC II) genes (1,2), suggesting that presentation of antigens on MHC II plays an important role in CD4 ϩ T cell activation and disease initiation. After priming of encephalitogenic T cells in the periphery, they migrate into the CNS, where they trigger inflammatory responses including microglial activation.…”

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confidence: 99%

Minocycline Down-regulates MHC II Expression in Microglia and Macrophages through Inhibition of IRF-1 and Protein Kinase C (PKC)α/βII

Nikodémová

Watters

Jackson

et al. 2007

Journal of Biological Chemistry

142

105

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Experimental allergic encephalomyelitis, an autoimmune disorder mediated by T cells, results in demyelination, inflammation, and axonal loss in the central nervous system (CNS). Microglia play a critical role in major histocompatibility complex class II (MHC II)-dependent antigen presentation and in reactivation of CNS-infiltrated encephalitogenic T cells. Minocycline, a tetracycline antibiotic, has profound anti-inflammatory properties and is experimentally used for treatment of many CNS disorders; however, the mechanisms involved in minocycline effects remain unknown. We show that administration of minocycline for 2 weeks ameliorated clinical severity of experimental allergic encephalomyelitis, an effect that partially involves the down-regulation of MHC II proteins in the spinal cord. Therefore, we sought to elucidate the molecular mechanisms of minocycline inhibitory effects on MHC II expression in microglia. Although complex, the co-activator class II transactivator (CIITA) is a key regulator of MHC II expression. Here we show that minocycline inhibited interferon ␥ (IFN␥)-induced CIITA and MHC II mRNA. Interestingly, however, it was without effect on STAT1 phosphorylation or IRF-1 expression, transcription factors that are activated by IFN␥ and necessary for CIITA expression. Further experiments revealed that MHC II expression is down-regulated in the presence of the PKC ␣ inhibitor Gö6976. Minocycline inhibited IFN␥-induced PKC ␣/␤II phosphorylation and the nuclear translocation of both PKC ␣/␤II and IRF-1 that subsequently inhibits CIITA expression. Our present data delineate a molecular pathway of minocycline action that includes inhibitory effects on PKC ␣/␤II and transcription factors that regulate the expression of critical inflammatory genes such as MHC II.

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“…3). We previously showed that the T cell restriction of MOG 91–108‐specific T cells in LEW.1N (RT1 n ) was RT1.D restricted (data not shown) 9.…”

Section: Resultsmentioning

confidence: 87%

“…Anti‐RT1.B (OX‐6) nearly completely blocked the peptide specific T cell response but not anti‐RT1.D (OX‐17) or control antibody (Tib191) (each n =4). In LEW.1N rats the MOG 91–108‐specific T cell response was RT1.D restricted (data not shown, 9). Error bars represent SEM.…”

Section: Resultsmentioning

confidence: 90%

“…RT1.B and RT1.D molecules were purified from MHC congenic LEW rat [LEW (RT1 l ), LEW.1A (RT1 a ), LEW.1N (RT1 n ), LEW.1W (RT1 u )] thymic and splenic tissues by affinity chromatography using OX‐6 (specific for RT1.B molecules) and OX‐17 (specific for RT1.D molecules) antibodies as described 7, 9. Briefly, tissues were lysed in PBS containing 1% Nonidet P‐40 (NP‐40; Boehringer, Mannheim, Germany) in the presence of protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

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Characterization of the encephalitogenic immune response in a model of multiple sclerosis

et al. 2007

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Experimental autoimmune encephalomyelitis (EAE) can be actively induced with the extracellular domain of myelin oligodendrocyte glycoprotein (MOG 1-125). MOG-EAE closely mimics multiple sclerosis (MS) especially as far as demyelination, lesion formation and axonal pathology are concerned. MOG 91-108 is the encephalitogenic stretch within MOG 1-125 in two EAE-susceptible MHC congenic LEW rat strains [LEW.1AV1 (RT1 av1 ) and LEW.1N (RT1 n )] and DA (RT1 av1 ) rats. In LEW.1AV1 rats, disease could be induced with MOG 96-104 and to a lesser extent with MOG 98-106, whereas in LEW.1N rats, only MOG 98-106 was pathogenic. Both peptides bound well to their restricting MHC class II molecules, i.e., RT1.D n in the LEW.1N rat and RT1.B a in the LEW.1AV1 rat. TCR spectratyping of MOG 91-108 immunized LEW.1N, LEW.1AV1 and DA rats revealed that MHC class II determined the TCRBV preference of CNS infiltrating T cells. The data demonstrate that the most critical factor in inducing MS like pathology is presentation of autoantigenic peptides on MHC class II molecules resulting in demyelination and axonal pathology.

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MHC Class II Isotype- and Allele-Specific Attenuation of Experimental Autoimmune Encephalomyelitis

Cited by 8 publications

References 43 publications

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Tolerance induction by bone marrow transplantation in a multiple sclerosis model

Minocycline Down-regulates MHC II Expression in Microglia and Macrophages through Inhibition of IRF-1 and Protein Kinase C (PKC)α/βII

Characterization of the encephalitogenic immune response in a model of multiple sclerosis

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