From the Nature article, Aberrant production of
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Posted On: 07/10/2020 10:10:17 AM
From the Nature article,
So, CCR5 does seem to be involved with new MS lesions, and blocking it makes sense to try to keep the T-cells away from CNS so they won't attack myelin and cause lesions.
Regarding CCR5d32 homozygotes, who should have no CCR5 receptors, it's interesting they have a 20 fold increase in RANTES in vitro. It's not clear why that is (something to do with it not being recycled without CCR5 receptors?), and whether this increased RANTES is related to increased mortality in MS of CCR5d32 homozygotes (possibly by increased RANTES causing havoc elsewhere on other CCRx receptors besides CCR5, such as CCR1 and CCR3).
The only way to know is run the trial and see what happens. It does seem to make sense that blocking CCR5 could help prevent autoimmune damage in MS. Looking forward to another promising trial starting in MS this year.
Quote:
Aberrant production of chemokines has been described in humans and experimental CNS demyelinating lesions.10,11 β-Chemokine receptors were examined in postmortem MS CNS tissue by immunohistochemistry, and an elevated expression of CCR2, CCR3, and CCR5 was noted.12–14 HHV6 virus was additionally found in the human brain specimens and a possible association with MS was suggested.15–17 Chemokine receptor expression studies showed CCR5 and CXCR3 to have annualized increase in T2 lesion loads, suggesting these chemokines play an important role in the development of new lesions in MS than in the long-term outcome of those lesions
In addition, CD4+ T-cell clones from two homozygous persons for the CCR5 Δ32 mutation produced approximately 20-fold more RANTES than wild-type clones.20 Analysis of cytokine and cytokine receptor gene expression in MS samples showed predominantly increased levels of several Th-1 molecules (TGF-ss, RANTES, and MIP-1α), although some Th-2 genes (IL-3, IL-5, and IL-6/IL-6R) were found to be up regulated as well.
So, CCR5 does seem to be involved with new MS lesions, and blocking it makes sense to try to keep the T-cells away from CNS so they won't attack myelin and cause lesions.
Regarding CCR5d32 homozygotes, who should have no CCR5 receptors, it's interesting they have a 20 fold increase in RANTES in vitro. It's not clear why that is (something to do with it not being recycled without CCR5 receptors?), and whether this increased RANTES is related to increased mortality in MS of CCR5d32 homozygotes (possibly by increased RANTES causing havoc elsewhere on other CCRx receptors besides CCR5, such as CCR1 and CCR3).
The only way to know is run the trial and see what happens. It does seem to make sense that blocking CCR5 could help prevent autoimmune damage in MS. Looking forward to another promising trial starting in MS this year.
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