More MS news articles for Nov 2001

Immunology highlights from the recent literature

Selected from:

Nature Immunology 2, 775 (2001)

GM-CSF key in Multiple Sclerosis

J. Exp. Med. 194, 873–881 (2001)

Understanding how inflammatory lesions are initiated and perpetuated in the CNS has remained crucial to development of potential therapeutic agents that may block the demyelinating disease process in MS.

In the J. Exp. Med., Bernard and colleagues show the hematopoietic growth factor GM-CSF plays a crucial role in the effector phase of lymphocyte recruitment to the CNS parenchyma and maintenance of inflammatory lesions.

Mice deficient for GM-CSF developed fewer clinical symptoms of experimental autoimmune encephalomyelitis (EAE), as compared to WT mice, when immunized with myelin oligodendrocyte glycoprotein.

Yet, CD4+ immune responses in these mice, seen by antibody responses in vivo and Con A-stimulated proliferation in vitro, were not abrogated.

Importantly, blocking GM-CSF action in vivo ameliorated the disease process in WT mice, even after onset of symptoms.

Thus, GM-CSF may pose a potential target for treatment of MS.

Unfavorable cytotoxic T cells

J. Exp. Med. 194, 669–676 (2001)

Plaques of infiltrating CD4+ and CD8+ T cells of unknown function and specificity are found in multiple sclerosis (MS) patients.

Research has focused on CD4+ T cells, as EAE induction is CD4+ T cell–dependent, MS susceptibility is associated with MHC class II genes and the TCR sequence motifs found within MS plaques are similar to myelin-specific peripheral CD4+ T cells.

In the Journal of Experimental Medicine, Huseby et al. show that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice.

The disease induced by these CD8+ T cells exhibited some clinical signs and CNS pathology not seen in classic EAE mediated by myelin-specific CD4+ T cells. IFN-, but not TNF- or Fas-FasL, interactions played an important role in CD8+ T cells specific for myelin protein.

These results now implicate CD8+ myelin-specific CTLs, in addition to CD4+ T cells, as mediators of CNS autoimmunity.

Mimicry or nonspecific stimuli?

Immunity 15, 137–147 (2001)

The association between viral infections and induction or exacerbation of autoimmune disease is poorly understood.

In Immunity, Cantor and colleagues examine the relative roles of molecular mimicry and nonspecific inflammatory stimuli in the transition from infection to autoimmune disease.

They use a replication-competent murine herpes virus 1 (HSV-1 KOS) point mutant, which contains a single amino acid exchange in the putative mimicry epitope, and mice expressing a TCR transgene specific for the self-peptide mimic.

They show that viral mimicry is critical for disease induction after low-level viral infection of mice containing limited numbers of autoreactive T cells, whereas innate immune mechanisms are sufficient to provoke disease in animals containing expanded numbers of autoreactive T cells.

Thus, both viral mimicry and nonspecific innate immune mechanisms have dominant roles in the generation of autoimmunity under particular conditions.

Deviating TH1 cells

Immunity 15, 15–22 (2001)

DNA vaccines can be used to elicit immunity or tolerance.

To modulate the immune response to DNA vaccines, preparations that contain cytokine genes and genes to certain pathogens have been used in "covaccines."

In Immunity, Steinman and colleagues show covaccination of mice with a construct encoding IL-4 and residues 139–151 of the self-peptide proteolipid protein, PLP(139–151), protects against experimental autoimmune encephalomyelitis (EAE) induction by PLP(139–151).

IL-4–dependent STAT6 phosphorylation induced autoreactive T cells to shift their cytokine profile to TH2. In addition, DNA covaccination with the genes encoding myelin basic protein and IL-4 can reverse established EAE.

Thus, this method of protective immunity using DNA vaccination and local gene delivery could prove beneficial in the treatment of multiple sclerosis and other autoimmune diseases caused by TH1 autoreactive cells.

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