@irenekwshiu @stanjupiter This is a Klinker science paper from...

@irenekwshiu @stanjupiter

This is a Klinker science paper from 2021 ---

https://www.biorxiv.org/content/10.1101/2021.02.23.432501v1

Whilst it would be hard to understand all of it in detail without some science background - it isn't hard I'd submit to see that Klinker understands and it isn't hard to see that TNF alpha and INF gamma are referred to. And if you do read some of the intro some of it will make sense to you and more can make sense as you learn more - the science in the paper is relevant.

TNF alpha is a cytokine stan it binds to a TNFR1 receptor so its a molecule that binds to a set of molecules on the surface of a cell (as opposed to a transcription factor - which is a molecule that is inside a cell and causes some part of the DNA to be transcribed into proteins - gene products - which do other things in the cell).

Many cytokines (cell signaling molecules - so they signal a cell - they are outside of it) if not all would be able to be manufactured by third parties - it might not be easy or cheap - but its in principle possible using recombinant dna technology - but its expensive. Insulin for diabetics is made that way. Some human recombinant proteins - artifically produced would be involved in cell culture - ie the expansion of MSCs from a few into a lot.

Before MSB took over Osiris there were some researchers Aggarwahl and Pittenger around 2005 doing early work around meenchymal stem cells - those researchers are still cited by MSB in patent applications and in their submissions to ODAC. They in their papers refer to the role of INF gamma.

Here is a diagram from one of their papers. It shows two ways that INF gamma is reduced by MSCs.

#1 Shows T helper cells being downregulated - resulting in them producing less INF gamma. Anything in the enviroment adding more INf gamma would be counteracting what is desired which is less INF gamma.

#6 shows MSBs inhibiting or downregulating the action of NK (natural killer) cells such that as a result INF gamma is reduced in the place in the patient where cellular signals, cytokines, the messengers cells send to each other are bouncing around as the cells decide whether they are going to be immunomodulatory (reducing an immune response - like making an immune response (GVHD would be an immune response) or increasing it.

You want more T reg action and less helper T cell action if you are trying to get GVHD down in a patient. So you want the therapeutic space where GvHD is taking place to have less INF gamma bounding around as a cell messenger - you certainly don't want you rouge batch of MSCs to be increasing INF gamma.



You don't want to be adding MSCs from any batch of MSB MSCs and seeing MORE interferon gamma in the mix after adding the MSCs because you want less INF gamma not more when the cells are put into a human patient. If the MSCs are causing INF gamma to go up in the lab dish they are also likely (the same MSCs) to misbehave and cause INF gamma to go up in a patient.

You don't want that.

Yet some of MSBs own diagrams (at least one presented to ODAC) show INF gamma increasing in some batches.

Its a confounding variable.