IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP 2 and NK cell function (Marshall-Gradisnik et al 2021)

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The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP 2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Natalie Eaton-Fitch 1 2 3 , Hélène Cabanas 4 5 , Stanley du Preez 6 4 5 , Donald Staines 4 5 , Sonya Marshall-Gradisnik 4 5


Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.

Methods: NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.

Results: Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.


Conclusion: Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

Keywords: Chronic Fatigue Syndrome; IL-2; Myalgic Encephalomyelitis; Natural killer cells; PIP2; Transient receptor potential melastatin 3.

© 2021. The Author(s).
 

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junkcrap50

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IL-2 can be given as a therapeutic drug.

There are recombinant IL2 and a couple IL2 analogues. Usually, it is used for certain cancers at high doses, which can be toxic and cause side effects. However, there are lower dose regimens given subq at home. Lower doses are too low to cause side effects.

It is also being explored to use in other cases such as viral infections and immune modulation.

In general high doses are immune suppressive, while low doses can stimulate type 1 immunity.[29] Low-dose IL-2 has been reported to reduce hepatitis C and B infection.[30]

IL-2 has been used in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009.[31]

More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis.[32] There are also promising studies looking to use low dose IL-2 in ischaemic heart disease.[33]

https://en.wikipedia.org/wiki/Interleukin_2#Medical_use
Wonder if this would be a good therapeutic for researchers and doctors to pursue for ME/CFS patients.
 

mitoMAN

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IL-2 can be given as a therapeutic drug.

There are recombinant IL2 and a couple IL2 analogues. Usually, it is used for certain cancers at high doses, which can be toxic and cause side effects. However, there are lower dose regimens given subq at home. Lower doses are too low to cause side effects.

It is also being explored to use in other cases such as viral infections and immune modulation.



Wonder if this would be a good therapeutic for researchers and doctors to pursue for ME/CFS patients.
Do we have any dosing data on the "low dose subq"?
 

Pyrrhus

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IL-2 can be given as a therapeutic drug.

There are recombinant IL2 and a couple IL2 analogues. Usually, it is used for certain cancers at high doses, which can be toxic and cause side effects. However, there are lower dose regimens given subq at home. Lower doses are too low to cause side effects.
I tried subcutaneous IL-2 many years ago. I started at what was considered a "standard" dose, which was beyond intolerable, with signs of brain inflammation and a strong urge to throw myself out a window to make it all stop.

Then I tried 1/4 the "standard" dose and it was more tolerable, but the side effects were still really quite horrendous. Loratadine took a bit of the edge off the side effects, but they were still intolerable. I imagine the side effects are similar to the side effects of Interferon.

The only positive thing that came out of my IL-2 experiment was that my chronic sore throat that I had suffered from for years disappeared and is still gone to this day.
 

junkcrap50

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Do we have any dosing data on the "low dose subq"?
I haven't looked into it.

I tried subcutaneous IL-2 many years ago. I started at what was considered a "standard" dose, which was beyond intolerable, with signs of brain inflammation and a strong urge to throw myself out a window to make it all stop.

Then I tried 1/4 the "standard" dose and it was more tolerable, but the side effects were still really quite horrendous. Loratadine took a bit of the edge off the side effects, but they were still intolerable. I imagine the side effects are similar to the side effects of Interferon.

The only positive thing that came out of my IL-2 experiment was that my chronic sore throat that I had suffered from for years disappeared and is still gone to this day.
Wow. So they aren't kidding when they say it has horrible side effects. What was the reasoning/test results your doctor tried IL-2 with you?

There are in development several IL-2 analogues, but most have failed to be effective: NKTR-214 and ALKS 423. Two have been successful and are advancing in trials.

One IL-2 analogue is NL-210 (aka Neoleukin-2/15 or Neo-2/15) has no side effects (link 1, link 2).Unfortunately, NL210 is only now entering Phase I trials for use in advanced cancer, which began in May 2021 (Source)

Another IL-2 drug is THOR-707, which is slightly ahead in Phase I/II trials, which began in 2019 (source), This year some interim data released validating its effectiveness (Source).