Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system.

Multiple sclerosis is a demyelinating disorder of the central nervous system (CNS), in which an immune attack directed against myelin constituents causes myelin destruction and death of oligodendrocytes, the myelin-producing cells. Here, the efficacy of nerve growth factor (NGF), a growth factor for neurons and oligodendrocytes, in promoting myelin repair was evaluated using the demyelinating model of experimental allergic encephalomyelitis (EAE) in the common marmoset. Surprisingly, we found that NGF delayed the onset of clinical EAE and, pathologically, prevented the full development of EAE lesions. We demonstrate by immunocytochemistry that NGF exerts its antiinflammatory effect by downregulating the production of interferon gamma by T cells infiltrating the CNS, and upregulating the production of interleukin 10 by glial cells in both inflammatory lesions of EAE and normal-appearing CNS white matter. Thus, NGF, currently under investigation in human clinical trials as a neuronal trophic factor, may be an attractive candidate for therapy of autoimmune demyelinating disorders.

Scutoid mutation of Drosophila melanogaster specifically decreases olfactory responses to short-chain acetate esters and ketones.

A molecular-genetic approach has been taken to identify genes involved in olfactory transduction in Drosophila melanogaster. Two independent lines of research led to the finding that the dominant Scutoid (Sco) mutation causes a diminished extracellular electroantennogram response to the odorants ethyl acetate (EtAC) and acetone (AC). Sco flies showed about 4- and 2.5-fold reduced responses to EtAC and AC, respectively, compared to Canton-S wild-type and sibling control flies lacking the Sco mutation when electroantennogram recordings were made from the proximal anterior third antennal segment. The responses to five other odors from three different chemical classes were unaltered. The maximum response to either EtAC or AC was decreased with no change in apparent affinity. Responses to short-chain (but not long-chain) acetate esters and ketones were dramatically affected at all antennal locations tested. Only in the proximal quadrants were responses to ethyl acetoacetate also reduced. Most Sco revertants tested had a normal olfactory response; duplications of the region including no-ocelli partially suppress the Sco bristle as well as olfactory phenotypes. Sco adults had an impaired behavioral response to EtAC but not to banana or propionate. There was no effect of the mutation on larval chemosensory behavior or extracellularly recorded adult compound eye and ocellar visual responses. These findings suggest the involvement of Sco in an olfactory pathway in adults which is specific for short-chain acetate esters and ketones.

Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates.

Auto-reactive T cells present in healthy subjects remain in a state of unresponsiveness, but may trigger autoimmunity under various situations. Although myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen in multiple sclerosis (MS), MOG-reactive T cell responses are present in the blood of both healthy subjects and MS-affected individuals. To investigate the disease-inducing potential and regulation of these autoreactive T cells in healthy outbred populations, we have characterized MOG-reactive T cell clones obtained by limiting dilution from peripheral blood of unimmunized C. jacchus marmosets. We report an extraordinarily high prevalence of circulating MOG-reactive T cells in these naive animals (2.6 +/- 1.4 / 10(5) PBMC), and a broadly diverse repertoire of epitope recognition encompassing at least three regions within the extracellular domain of MOG. Adoptive transfer of a MOG21-40-specific T cell clone resulted in mild clinical experimental allergic encephalomyelitis, characterized pathologically by rare foci of inflammation and minimal demyelination. We conclude that MOG-reactive T cells are present in healthy primates at a highly prevalent frequency, and are potentially capable of triggering central nervous system autoimmunity. Expansion of these autoreactive T cells must be tightly controlled to maintain immune homeostasis in healthy individuals.