Adoptive Cell Therapy As An Anti-Inflammatory

As an immunologist I am always eager to see immune cells being used in new and innovative ways. Many of the current immunotherapies that are being developed for chronic inflammatory diseases include regulatory T cells (Treg). We discussed a paper in class that used Treg in an Inflammatory Bowel Disease model. While that paper and others like it are useful in examining the useful properties of Treg, I feel that they do not address the controversy that can also come with using these cells in certain contexts.

In most papers, I feel that they fail to differentiate between induced Treg (iTreg) and natural Treg (nTreg). But a paper I found that was published in 2010 in The Journal of Immunology, seemed to acknowledge this controversy and its limitations openly. Entitled Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson’s Disease, they look closely at an interesting use of drugs, vaccination, and adoptive cell therapy to improve the mouse model of Parkinson’s Disease, MPTP. I know that we have discussed endlessly in class how this mouse model does not accurately portray human disease, but let me summarize their argument for you and how they related their findings, and your opinion might be changed, at least for this paper.

Previous work that they had done described how a particular protein 4YSyn was a protein aggregate found in the brain that causes no known neuronal damage. But when this protein is nitrated into N-4YSyn, it causes a large adaptive immune response skewed toward a Th17 T cell response, and subsequently, severe neurodegeneration. Using a drug called vasoactive intestinal peptide (VIP) that is known to induce Treg proliferation in vivo, they looked at the ability of these expanded Treg to protect against N-4YSyn Th17 mediated neurodegeneration. What they found was that cells that are adoptively transferred from VIP treated mice into diseased mice are protective. And this neuroprotection is due to the induced Tregs ability to decrease effector T cell proliferation. Tested both in vitro and in vivo the results appear interesting. Where is the controversy in these finding you ask?

The current understanding of Th17 and Treg are not concrete and are very controversial, with many labs reporting conflicting evidence. It is thought that based on the cytokine conditions Th17 cells can be induced into Treg or Th1 cells. And the question most people would be asking about this paper’s finding would be that if you are inducing Treg in a Th17 environment, are they Th17 that evolved into Treg, or are they true Treg? This makes sense when you consider that it is unknown whether the Th17/Treg can then revert back to Th17 at a later date and cytokine storm, or if the Treg differentiation is terminal. I like this paper for this reason. They freely state that they don’t know!! Imagine that. They acknowledge in the very beginning of their discussion section the limits of their model and the possibility that what they have seen is not the only finding that can be found. I like that they try to address the issue and not just ignore that it exists. Science is about openminded discourse, and these sort of papers are exciting not just for their findings, but for their ability to spark discussion.