Tuesday, 18 December 2012

Research: Hyaluronidase is used for getting white cells in the brain

Winkler CW, Foster SC, Matsumoto SG, Preston MA, Xing R, Bebo BF, Banine F, Berny-Lang MA, Itakura A, McCarty OJ, Sherman LS. Hyaluronan anchored to activated CD44 on central nervous system vascular endothelial cells promotes lymphocyte extravasation in experimental autoimmune encephalomyelitis. J Biol Chem. 2012 ;287:33237-51.
The extravasation of lymphocytes across central nervous system (CNS) vascular endothelium is a key step in inflammatory demyelinating diseases including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The glycosaminoglycan hyaluronan (HA) and its receptor, CD44, have been implicated in this process but their precise roles are unclear. We find that CD44(-/-) mice have a delayed onset of EAE compared with wild type animals. Using an in vitro lymphocyte rolling assay, we find that fewer slow rolling (<1 μm/s) wild type (WT) activated lymphocytes interact with CD44(-/-) brain vascular endothelial cells (ECs) than with WT ECs. We also find that CD44(-/-) ECs fail to anchor HA to their surfaces, and that slow rolling lymphocyte interactions with WT ECs are inhibited when the ECs are treated with a pegylated form of the PH20 hyaluronidase (PEG-PH20). Subcutaneous injection of PEG-PH20 delays the onset of EAE symptoms by ~1 day and transiently ameliorates symptoms for 2 days following disease onset. These improved symptoms correspond histologically to degradation of HA in the lumen of CNS blood vessels, decreased demyelination, and impaired CD4(+) T-cell extravasation. Collectively these data suggest that HA tethered to CD44 on CNS ECs is critical for the extravasation of activated T cells into the CNS providing new insight into the mechanisms promoting inflammatory demyelinating disease.
Transfer of Thy1.2 (CD90b) into Thy 1.1 recipients that had CD44 removved from their surface with CD44-specific (IM7) antibody.

Hyaluronidase has been in the media because it may be uesful in promoting remyelination PH20-hyaluronidase inhibited remyelination in previous work from this lab, but in this work PH2-hyaluronidase inhibited crossing of white blood cells into the CNS. Hyaluronic acid, which is broken down by a hyaluronidase, is bound by a molecule on white blood cells called CD44. So the hyaluronidase inhibited the development of EAE by a few days. This is a bit pants compared to what an antibody that gets rid of CD44 can do, where disease is prevented, not just inhibited by a few days .This because CD44 was an adhesion molecule involved in migration of effector memory cells into the brain and not the naive cells that traffic into lymph glands.

This highlights a problem of biology. A drug may be good for one thing, which can make another thing worse

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