. Steinman L (Stanford University, Stanford, CA, USA). Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity (foresight). J Intern Med 2010: 267: 441–451.
DNA‐based ...vaccines to induce antigen‐specific inhibition of immune responses in human autoimmune diseases represent the inverse of what Jenner intended when he invented vaccination. Jenner’s vaccine induced antigen‐specific immunity to small pox. DNA vaccines for autoimmunity have been developed in preclinical settings, and now tested in human trials. The first two clinical trials, one in relapsing remitting multiple sclerosis, and the other in type 1 diabetes indicate that specific inhibition of antigen‐specific antibody and T‐cell responses is attainable in humans. Further development of this approach is ongoing. This new version of immunization termed ‘inverse vaccination’ when applied to autoimmune diseases, may allow targeted reduction of unwanted antibody and T‐cell responses to autoantigens, while leaving the remainder of the immune system intact. The method of specifically reducing a pathological adaptive autoimmune response is termed inverse vaccination.
The immune system plays a major role in certain diseases of the brain like multiple sclerosis and neuromyelitis optica, while the brain may play a major role in modulating certain immunologic ...diseases of the periphery like inflammatory bowel disease. The most significant developments in neuroimmunology will involve explorations of the roles for the immune system in neurodegenerative conditions often associated with the presence of amyloid deposits. Here I present my personal perspectives on four of the most intriguing challenges that we face in the future of neuroimmunology: (1) Why are the traditional hallmarks of innate and adaptive inflammation conspicuously absent from brains of individuals with prion disease and amyloid pathology? (2) What is the role of adaptive and innate immunity in progressive forms of multiple sclerosis? (3) Is molecular mimicry an adequate explanation for the initiation of neuroinflammatory disease and for exacerbations in conditions like multiple sclerosis, narcolepsy, and neuromyelitis optica? (4) Do neural pathways regulate inflammatory diseases outside the nervous system?
Le système immunitaire joue un rôle majeur dans certaines maladies du système nerveux central comme la sclérose en plaques et la neuromyélite optique alors que le système nerveux central joue un rôle majeur en modulant certaines maladies immunologiques périphériques telles que les maladies inflammatoires de l’intestin. Les développements les plus significatifs en neuro-immunologie concerneront l’exploration du rôle du système immunitaire dans les maladies neuro-dégénératives souvent associées à la présence de dépôts amyloïdes. Je présente ici mes perspectives personnelles pour quatre des défis les plus intrigants auxquels la neuro-immunologie devra faire face dans le futur. (1) Pourquoi les marqueurs habituels de l’inflammation innée et adaptative sont-ils si évidemment absents du cerveau d’individus atteints de maladie à prion ou d’une pathologie amyloïde ? (2) Quel est le rôle de l’immunité innée et adaptative dans les formes progressives de sclérose en plaques ? (3) Le mimétisme moléculaire est-il une explication adéquate à l’initiation de maladies neuro-inflammatoires et à la possibilité d’exacerbation dans des circonstances comme la sclérose en plaques, la narcolepsie ou la neuromyélite optique ? (4) Les voies neuronales contrôlent-elles les maladies inflammatoires en dehors du système nerveux ?
The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as ...acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and alpha-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.
Summary
Recently, there has been considerable interest in using 4‐methylumbelliferone (4‐MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other ...inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4‐MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4‐MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1‐week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4‐methylumbelliferyl glucuronide (4‐MUG), with the sulphated metabolite, 4‐methylumbelliferyl sulphate (4‐MUS) comprising most of the remainder. Chow containing 5% but not 0·65% 4‐MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4‐MU was effective at preventing EAE, daily intraperitoneal injections of 4‐MU were not. Factors potentially affecting 4‐MU uptake and plasma concentrations in mice include its taste, short half‐life and low bioavailability. These studies provide a practical resource for implementing oral 4‐MU treatment protocols in mice.
Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, alpha4beta1 integrin was identified as the key molecule involved in ...homing to inflamed regions of the brain. An antibody to alpha4beta1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds alpha4beta1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.
Inflammatory infiltrates in tissue-specific autoimmune disease comprise a collection of T cells with specificity for an antigen in the target organ. These specific cells recruit a population of ...nonspecific T cells and macrophages. The rare tissue-specific T cells in the infiltrate have the capacity to regulate both the influx and the efflux of cells from the tissue. Administration of an altered peptide ligand for the specific T cell which triggers autoimmunity can lead to the regression of the entire inflammatory ensemble in a few hours. Interleukin 4 is a critical cytokine involved in the regression of the inflammatory infiltrate.
Anterior ischemic optic neuropathy (AION) is an important cause of acute vision loss in adults, and there is no effective treatment. We studied early changes following experimental AION and tested ...the benefit of a potential treatment.
We induced experimental AION in adult mice and tested the effects of short-term (daily for 3 days) and long-term (every other day for 3 weeks) αB-crystallin (αBC) treatment using histological and serial intracranial flash visual evoked potential recordings.
One day after experimental AION, there was swelling at the optic nerve (ON) head and increased expression of αBC, a small heat shock protein important in ischemia and inflammation. This upregulation coincided with microglial and astrocytic activation. Our hypothesis was that αBC may be part of the endogenous protective mechanism against injury, thus we tested the effects of αBC on experimental AION. Daily intraveneous or intravitreal αBC injections did not improve visual evoked potential amplitude or latency at days 1-2. However, αBC treatment decreased swelling and dampened the microglial and astrocytic activation on day 3. Longer treatment with intravenous αBC led to acceleration of visual evoked potential latency over 3 weeks, without improving amplitude. This latency acceleration did not correlate with increased retinal ganglion cell survival but did correlate with complete rescue of the ON oligodendrocytes, which are important for myelination.
We identified αBC as an early marker following experimental AION. Treatment with αBC enhanced this endogenous, post-ischemic response by decreasing microglial activation and promoting ON oligodendrocyte survival.
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