IRF4 as a Discriminating Target for Selective Destruction of Immune Cells

There are many issues that might be solved by destroying a sufficiently large number of immune cells. Take autoimmune disease, for example, in which the immune system attacks tissues. This is a configuration problem, and that configuration is entirely contained in immune cells. If those cells are removed, autoimmunity is cured. The age-related decline in the immune system, similarly, is in part a problem of too many unhelpful, over-specialized, or damaged, senescent, and exhausted immune cells cluttering up the body.

The only currently working approach involves high doses of harsh immune suppressant drugs to clear out near all immune cells, accompanied by some form of cell therapy to speed replenishment. It has been used to cure multiple sclerosis and type 1 diabetes in trials, but is hard on the patients. This isn't something that would be risked in anything other than a severe condition, and is probably too dangerous for older, less robust individuals. Better, safer methods of shutting down or destroying the unwanted parts of the immune system are needed.

In the research noted here, the authors have identified IRF4 as a single target protein that can disable active T cells, and thus potentially shut off many forms of autoimmunity. Quite aside from that, it has the look of a suitable target for the Oisin Biotechnologies cell-killing gene therapy that is triggered by the presence of specific proteins inside a cell, as IRF4 only occurs in immune cells. The researchers will no doubt pursue a pharmacological option for inhibition, but it is worth keeping in mind that this is only one of an expanding number of options nowadays.

Researchers have identified a critical switch that controls T-cell function and dysfunction and have discovered a pathway to target it. T-cells, which are a type of white blood cells that protect the body from infection, play a central role not only in infections, but also autoimmune diseases and transplant rejection. Understanding how T-cells work is of critical importance for treating these diseases. Researchers are doing this by systematically deleting different molecules in T-cells to check which ones are required for the T-cells to function.

What they have found is that one of the most critical molecules controlling gene expression in T-cells is the transcription factor IRF4, which is usually only found in the immune system and not expressed in other cells. IRF4 is what needs to be targeted to solve the problem of transplant rejection or to develop an autoimmunity cure. "If we delete IRF4 in T-cells they become dysfunctional. In doing so, you can solve the issue of autoimmunity and have a potential solution for organ transplant rejection. You need them functional, however, to control infection. If we can find an IRF4 inhibitor, then those issues would be solved. That's big."

The way they will be able to do this is by only targeting active T-cells that have already been exposed to antigens, leaving the so-called naïve T-cells - those that have never seen antigens and produce no or little IRF4 - alone. These naïve T-cells produce IRF4 only when needed to fight infections. It's the activated T-cells armed with IRF4 that are responsible for organ transplant rejection and autoimmunity. These are the ones that are a potential target, thereby leaving other T cells in the immune system still armed against infection.

Their initial results were promising. By inhibiting IRF4 expression for 30 days - the usual timeframe required for transplant patients to remain infection free - the T-cells became irreversibly dysfunctional. In practice, this could mean prolonging a patient's ability to tolerate a transplanted organ. "How to therapeutically inhibit IRF4 is the Nobel-prize winning question. If we can find a way to inhibit IRF4 as desired in activated T-cells, then I think most autoimmune diseases and transplant rejection will be solved."

Link: https://www.eurekalert.org/pub_releases/2017-12/hm-rfk122017.php

Comments

Yes if Oisin can adapt their technology to target IRF4 then hopefully they will make a lot of money.

Imagine the suffering that could be alleviated if this worked in even one autoimmune disease such as MS.

Posted by: Jim at December 21st, 2017 11:14 AM

Wonder if it would be effective for Hashimoto's. That could make them a LOT of money...

Posted by: James Corbally at December 21st, 2017 5:48 PM

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